Impact of delirium on weaning from mechanical ventilation in medical patients

Transcription

1 bs_bs_banner ORIGINAL ARTICLE Impact of delirium on weaning from mechanical ventilation in medical patients KYEONGMAN JEON, 1,2 *BYEONG-HO JEONG, 2 *MYEONG GYUN KO, 3 JIMYOUNG NAM, 3 HONGSEOK YOO, 2 CHI RYANG CHUNG 1 AND GEE YOUNG SUH 1,2 1 Department of Critical Care Medicine, 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine and 3 Intensive Care Unit Nursing Department, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea ABSTRACT Background and objective: Delirium is an important predictor of negative clinical outcomes in intensive care unit (ICU), including prolonged mechanical ventilation (MV). However, delirium has not yet proven to be directly linked to weaning difficulties. The objective of this cohort study was to evaluate the association between delirium, as observed on the day of the weaning trial, and subsequent weaning outcomes in medical patients. Methods: This is a retrospective analysis with prospectively collected data on weaning from mechanical ventilation (MV) and delirium, as assessed by bedside ICU nurses using the Confusion Assessment Method for the ICU (CAM-ICU) between October 2011 and September Results: During the study period, a total of 393 patients with MV support underwent a spontaneous breathing trial (SBT) according to the standardized protocol. Of these patients, 160 (40.7%) were diagnosed with delirium on the day of the first SBT. Patients without delirium were more successfully extubated than those with delirium (81.5% vs 69.4%, P = 0.005). Delirium was found to be associated with final weaning outcomes, including difficult (OR 1.962, 95% CI ) and prolonged weaning (OR 2.318, 95% CI ) when simple weaning was used as a reference category. After adjusting for potential confounding factors, delirium was still significantly associated with difficult weaning (adjusted OR 2.073, 95% CI ), but not with prolonged weaning (adjusted OR 2.001, 95% CI ). Conclusion: Delirium, as assessed by the CAM-ICU at the time of first weaning trial, was significantly associated with weaning difficulties in medical patients. Correspondence: Kyeongman Jeon, Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea. kjeon@skku.edu *KJ and BHJ contributed equally to this study. Received 14 May 2015; invited to revise 13 July 2015; revised 21 July 2015; accepted 18 August 2015 (Associate Editor: Amanda Piper). Article first published online: 4 November 2015 SUMMARY AT A GLANCE Delirium, as assessed through the CAM-ICU on the day of the first weaning trial, was independently associated with weaning difficulties and resulted in prolonged mechanical ventilation. Delirious patients had a higher risk of extubation failure and reintubation, even if they had been successfully weaned from MV and subsequently extubated. Key words: adverse effect, cognition disorder, mechanical ventilator, ventilator weaning. Abbreviations: CAM-ICU, Confusion Assessment Method for the Intensive Care Unit; CI, confidence interval; ICU, intensive care unit; IQR, interquartile range; MV, mechanical ventilation; OR, odds ratio; RCP, respiratory care practitioner; RSBI, rapid shallow breathing index; SAPS 3, Simplified Acute Physiology Score 3; SBT, spontaneous breathing trial; SOFA, Sequential Organ Failure Assessment. INTRODUCTION Delirium, an acute and fluctuating disturbance of consciousness and cognition, is a common manifestation of acute brain dysfunction in critically ill patients. 1 The prevalence of delirium in the intensive care unit (ICU) reportedly ranges from 20% to 80%, depending on the severity of the illness and diagnostic method used. 2 6 Delirium is an important independent predictor of negative clinical outcomes among ICU patients, including high mortality rates, 4,7 9 longer ICU or hospital stays, 5,6,8 10 and longterm cognitive impairment Accordingly, the Society of Critical Care Medicine guidelines recommend routine monitoring of delirium with valid and reliable monitoring tools. 1 Several tools are available for assessing delirium in ICU patients; of these, the Confusion Assessment Method for the ICU (CAM- ICU) has the highest sensitivity and specificity. 14, Asian Pacific Society of Respirology Respirology (2016) 21, doi: /resp.12673

2 314 Mechanically ventilated patients are at a high risk of developing delirium. 16 Previous studies have found that delirium develops in 20 50% of patients not receiving mechanical ventilation (MV), and in sharp contrast in 60 80% of ICU patients receiving MV. 2 6 In a survey of critical care clinicians, the majority of respondents perceived delirium as a significant factor in prolonged ventilation, the development of nosocomial pneumonia and longer hospital stays. 17 Although delirium has been found to be associated with several complications and clinical outcomes in mechanically ventilated patients 3,10 its direct link with weaning difficulties has not been proven. 18 Therefore, the objective of this cohort study was to evaluate the association between delirium, as observed on the day of the weaning trial, and subsequent weaning outcomes. We hypothesized that delirium is also associated with weaning difficulties and results in a prolonged period of MV. METHODS Study population All consecutive patients admitted to the medical ICU and requiring MV for more than 24 h were prospectively registered between October 2011 and September For this study, we selected patients who K Jeon et al. underwent a spontaneous breathing trial (SBT) for weaning from MV according to the standardized protocol, had not undergone unplanned extubation or tracheostomy before weaning, and had been screened for delirium with the CAM-ICU (Fig. 1). The study was approved by the Institutional Review Board of Samsung Medical Center to conduct the study and review and publish information from patient records. Informed consent was waived because of the study s observational nature. Standardized weaning process Since 2010, our centre has implemented a specific, protocol-based weaning programme based on recent recommendations for weaning from MV. 18 Details of our weaning programme were described in a previous report. 19 Respiratory care practitioners (RCP), who are registered nurses specializing in respiratory care, screened patients daily for weaning readiness and conducted SBT according to the protocol. When a patient passed the SBT, extubation would proceed according to the weaning programme. If a patient failed the SBT, MV was resumed and the team reviewed possible reversible aetiologies for the failure. Again, when a patient had been proven ready for weaning, the SBT was repeated the following day. Extubation failure referred to the need to reinstitute ventilatory support within 48 h of planned Overall cohort (patients with ventilator support in MICU between and ) n = 1154 Excluded non-intubation and transfer-in (n = 116) Transfer-in from other hospital after intubation >48 h (n = 52) Successful non-invasive ventilation (n = 33) Tracheostomy prior to mechanical ventilation (n = 31) Intubation n = 1038 Excluded not meeting criteria for weaning (n = 557) Died without weaning trial (n = 281) Tracheostomy before weaning trial (n = 143) Unplanned extubation before weaning trial (n = 64) Not received SBT (n = 44) Transfer to other hospital before weaning trial (n = 25) Received SBT n = 481 Negative CAM-ICU n = 233 Excluded no data of CAM-ICU and unclassifiable weaning (n = 88) Unable to assess CAM-ICU (n = 60) Not checked CAM-ICU (n = 22) Unclassifiable weaning (n = 5) Positive CAM-ICU n = 160 Figure 1 A flow chart of patients selection from the overall cohort for the analysis. CAM-ICU, Confusion Assessment Method for the Intensive Care Unit; MICU, medical intensive care unit; SBT, spontaneous breathing trial. Respirology (2016) 21, Asian Pacific Society of Respirology

3 Delirium and weaning difficulty 315 extubation. 18 Patients were classified into the simple, difficult or prolonged weaning group, according to the difficulty and duration of the weaning process, as previously described. 18,19 Assessment of delirium with the CAM-ICU Before the study, nurses were exposed to the implementation programme on delirium assessment using the CAM-ICU prior to daily, routine implementation thereof in the medical ICU. After 9 months of implementation, bedside nurses assessed all mechanically ventilated patients at least once per nursing shift, using the validated Korean version of the CAM-ICU. 20 The CAM-ICU results obtained just before the first weaning trial were used in this study. Data collection The following information pertaining to each registered patient was prospectively obtained: demographic data, primary reasons for ICU admission, the Simplified Acute Physiology Score 3 (SAPS 3) and Sequential Organ Failure Assessment (SOFA) at the time of ICU admission, the day of MV initiation and indications for MV. The duration of MV before the first weaning trial, CAM-ICU results, SOFA score, and weaning indexes (respiratory rate, maximum negative inspiratory pressure, PaO 2/FiO 2 ratios, and the rapid shallow breathing index (RSBI, the ratio of respiratory frequency to tidal volume)) on the day of the first weaning trial, as well as the weaning results, were collected prospectively. Maximum negative inspiratory pressure was defined as the lowest pressure generated during a forceful inspiratory effort against an occluded airway, which is determined by occluding the ventilator s inspiratory port at the end of expiration for 20 s and reading the maximum negative pressure registered on the ventilator s pressure manometer. The following data and events were assessed as outcomes: extubation failure, reintubation after extubation, the need for a tracheostomy during the weaning process after the first weaning trial, length of stay in the ICU and hospital, mortality in the ICU and hospital, and type of hospital discharges. Statistical analysis The data are presented as medians and interquartile ranges for continuous variables, and as numbers and percentages for categorical variables. The data were compared using the Mann Whitney U-test or Kruskal Wallis test for continuous variables and Pearson s χ 2 test or Fisher s exact test for categorical variables. The Kaplan Meier method was used to estimate the cumulative rate for successful extubation following initiation of MV by positivity of the CAM- ICU, which was then compared using the log rank test. We used the multinomial logistic regression analysis to adjust for potential confounding factors in the association between the positivity of the CAM-ICU and weaning classification, with simple weaning as the reference category. Three models were constructed: Model 1 was adjusted for demographic data such as age, sex and underlying disease; Model 2 was additionally adjusted for causes of respiratory failure and severity of illness on ICU admission; Model 3 additionally included the data pertaining to the day of the first weaning trial, such as the SOFA score, duration of MV before the first weaning trial and weaning indexes. Data are presented as adjusted odds ratios (OR) with 95% confidence intervals (CI). All the tests were two-tailed, and a P-value of <0.05 was considered significant. The data were analysed using PASW Statistics 18 (SPSS Inc, Chicago, IL, USA). RESULTS Patient characteristics Table 1 shows a comparison of baseline characteristics by the results of the CAM-ICU obtained on the day of the first weaning trial. Patients with CAM-ICU (+) were older and obtained higher SAPS 3 and SOFA scores on ICU admission. However, there were no significant differences in sex, underlying disease, reason for ICU admission or causes of respiratory failure. Clinical outcomes Data pertaining to the day of the first weaning trial are presented in Table 2. The SOFA score on the day of the first SBT was higher in patients with CAM-ICU (+). There were no significant differences in the objective weaning indices relating to weaning from MV, except for forceful inspiratory effort; this was measured by negative inspiratory pressure, which was better in patients with CAM-ICU ( ) than in those with CAM- ICU (+) ( 24 ( 19 31) cmh 2O vs 21 ( 18 27) cmh 2O, P = 0.008). Clinical outcomes according to the results of the CAM-ICU are presented in Table 3. The extubation rate at the first SBT was higher among patients with CAM-ICU ( ) than among those with CAM-ICU (+) (81.5% vs 69.4%, P = 0.005). Furthermore, extubation failure and reintubation were also greater in patients with CAM-ICU (+) than in those with CAM-ICU ( ) (39.6% vs 25.3%, P = 0.009; 35.1% vs 16.8%, P < 0.001, respectively). Therefore, the median time to successful extubation was longer in patients with CAM-ICU (+) than in those with CAM-ICU ( ) (5 (3 11) days vs 3 (2 7) days, P = 0.012) (Fig. 2). Consequently, simple weaning was more common in patients with CAM- ICU ( ) than those with CAM-ICU (+) (70.8% vs 53.8%, P = 0.001). Patients with CAM-ICU (+) were more commonly classified into difficult or prolonged weaning (28.1% vs 18.9%, P = 0.032; 18.1% vs 10.3%, P = 0.026, respectively). Tracheostomy during the weaning process was more frequently performed in patients with CAM-ICU (+) than in those with CAM- ICU ( ) (34.4% vs 15.0%, P < 0.001). Although there were no differences in ICU and hospital mortality, ICU and hospital stays were found to be longer in patients with CAM-ICU (+) than in those with CAM- ICU ( ) (10 (6 16) days vs 6 (4 12) days, P < 0.001; 33 (18 59) days vs 25 (15 49) days, P = 0.022, respectively). In addition, patients with CAM-ICU ( ) were 2015 Asian Pacific Society of Respirology Respirology (2016) 21,

4 316 K Jeon et al. Table 1 Patients baseline characteristics according to the results of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), obtained on the day of the first weaning trial Total (n = 393) CAM-ICU ( ) (n = 233) CAM-ICU (+) (n = 160) P-value Age, years 65 (54 72) 61 (47 71) 70 (61 75) <0.001 Sex, male 272 (69.2) 163 (70.0) 109 (68.1) Underlying disease Malignancy 235 (59.8) 139 (59.7) 96 (60.0) Respiratory 137 (34.9) 90 (38.6) 47 (29.4) Cardiovascular 62 (15.8) 38 (16.3) 24 (15.0) Gastrointestinal 53 (13.5) 27 (11.6) 26 (16.3) Genitourinary 53 (13.5) 25 (10.7) 28 (17.5) Neurological 44 (11.2) 26 (11.2) 18 (11.3) Reason for ICU admission Pulmonary 227 (57.8) 139 (59.7) 88 (55.0) Sepsis 89 (22.6) 45 (19.3) 44 (27.5) Cardiovascular 33 (8.4) 22 (9.4) 11 (6.9) Neurological 17 (4.3) 10 (4.3) 7 (4.4) Gastrointestinal 14 (3.6) 8 (3.4) 6 (3.8) Miscellaneous 13 (3.3) 9 (3.9) 4 (2.5) Cause of respiratory failure Pneumonia 134 (34.1) 83 (35.6) 51 (31.9) Extrapulmonary sepsis 75 (19.1) 37 (15.9) 38 (23.8) Pulmonary edema 39 (9.9) 24 (10.3) 15 (9.4) ARDS 39 (9.9) 22 (9.4) 17 (10.6) Neurological (coma) 22 (5.6) 11 (4.7) 11 (6.9) Ventilatory failure 21 (5.3) 15 (6.4) 6 (3.8) Exacerbation of ILD 14 (3.6) 10 (4.3) 4 (2.5) Post-CPR 14 (3.6) 12 (5.2) 2 (1.3) Central airway obstruction 13 (3.3) 8 (3.4) 5 (3.1) Miscellaneous 22 (5.6) 11 (4.7) 11 (6.9) SAPS 3 on ICU admission 60 (50 74) 57 (47 70) 66 (54 80) <0.001 SOFA score on ICU admission 7 (5 11) 6 (4 9) 9 (6 12) <0.001 Data are presented as number (%) or median (interquartile range). Ventilator failure includes acute exacerbations of chronic obstructive pulmonary disease, bronchial asthma and bronchiectasis. ARDS, acute respiratory distress syndrome; CPR, cardiopulmonary resuscitation; ICU, intensive care unit; ILD, interstitial lung disease; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment. Table 2 A comparison of patients characteristics on the day of the first weaning trial according to the results of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) Total (n = 393) CAM-ICU ( ) (n = 233) CAM-ICU (+) (n = 160) P-value Duration of MV before the first weaning trial, days 3 (2 6) 3 (2 5) 3.5 (2 7) SOFA score on the day of the first weaning trial 5 (3 7) 4 (2 6) 6 (4 9) <0.001 Weaning index Respiratory rate 18 (14 21) 18 (14 20) 18 (15 22) NIP, cmh 2O 23 ( 18 29) 24 ( 19 31) 21 ( 18 27) PaO 2/FiO ( ) 262 ( ) 257 ( ) RSBI 49 (32 67) 47 (34 67) 50 (30 67) Data are presented as number (%) or median (interquartile range). MV, mechanical ventilation; NIP, negative inspiratory pressure; SOFA, Sequential Organ Failure Assessment; RSBI, rapid shallow breathing index. Respirology (2016) 21, Asian Pacific Society of Respirology

5 Delirium and weaning difficulty 317 Table 3 A comparison of clinical outcomes according to the results of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) on the day of the first weaning trial Total (n = 393) CAM-ICU ( ) (n = 233) CAM-ICU (+) (n = 160) P-value Extubation 301 (76.6) 190 (81.5) 111 (69.4) Extubation failure within 48 h 92/301 (30.6) 48/190 (25.3) 44/111 (39.6) Reintubation 71/301 (23.6) 32/190 (16.8) 39/111 (35.1) <0.001 Classification of weaning Simple weaning 251 (63.9) 165 (70.8) 86 (53.8) Difficult weaning 89 (22.6) 44 (18.9) 45 (28.1) Prolonged weaning 53 (13.5) 24 (10.3) 29 (18.1) Tracheostomy after the first weaning trial 90 (22.6) 35 (15.0) 55 (34.4) <0.001 ICU mortality 44 (11.2) 26 (11.2) 18 (11.3) Length of stay in ICU, days 8 (4 14) 6 (4 12) 10 (6 16) <0.001 Hospital mortality 117 (29.9) 62 (26.6) 55 (34.8) Length of stay in hospital, days 29 (16 52) 25 (15 49) 33 (18 59) Type of hospital discharge Home 197 (50.4) 136 (58.4) 61 (38.6) <0.001 Other hospital 63 (16.1) 30 (12.9) 33 (20.9) Other ICU 1 (0.3) 1 (0.4) 0 (0) Hospice 13 (3.3) 4 (1.7) 9 (5.6) Death 117 (29.9) 62 (26.6) 55 (34.8) Data are presented as number (%) or median (interquartile range). ICU, intensive care unit. Figure 2 Kaplan Meier curves of the probability of successful extubation after initiation of invasive mechanical ventilation on the basis of the results of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) on the day of the first weaning trial (the solid line represents the CAM-ICU ( ) group; the dotted line represents the CAM-ICU (+) group). more commonly discharged home than those with CAM-ICU (+) (58.4% vs 38.6%, P < 0.001). Association between delirium and weaning difficulties Comparisons of the clinical characteristics and outcomes of patients according to weaning classification are presented in Table 4. Significant associations were found between weaning classifications and underlying disease, causes of respiratory failure, severity of illness on ICU admission, longer duration of MV before the first weaning trial, higher SOFA scores on the day of the first weaning trial, CAM-ICU positivity, and a poor weaning index. Finally, patients experiencing difficult or prolonged weaning had worse clinical outcomes, such as higher instances of tracheostomy, longer ICU and hospital stays, and higher ICU and hospital mortality. Table 5 shows the crude and adjusted OR of CAM- ICU (+) for difficult and prolonged weaning in various statistical models, with simple weaning specified as the reference category. CAM-ICU (+) had an OR of (95% CI , P = 0.007) for difficult weaning and (95% CI , P = 0.006) for prolonged weaning in the crude state. In Model 1, which was adjusted for demographic data, CAM-ICU (+) had an adjusted OR of (95% CI , P = 0.019) for difficult weaning and (95% CI , P = 0.019) for prolonged weaning. In Model 2, which was additionally adjusted for causes of respiratory failure and severity of illness on admission to ICU, CAM-ICU (+) maintained a similar trend as in Model 1 (adjusted OR 2.091, 95% CI , P = for difficult weaning; adjusted OR 2.496, 95% CI , P = for prolonged weaning, respectively). Finally, in Model 3, which also included data obtained on the day of the first weaning trial, CAM-ICU (+) was independently associated with difficult weaning (adjusted OR 2.073, 95% CI , P = 0.020), but not with prolonged weaning (adjusted OR 2.001, 95% CI , P = 0.100). DISCUSSION To our knowledge, this is the first study to evaluate the association between delirium, as assessed through 2015 Asian Pacific Society of Respirology Respirology (2016) 21,

6 318 K Jeon et al. Table 4 A comparison of clinical characteristics and outcomes upon weaning classification Simple weaning (n = 251) Difficult weaning (n = 89) Prolonged weaning (n = 53) P-value Age, years 64 (53 72) 69 (54 75) 68 (54 74) Sex, male 179 (71.3) 62 (69.7) 31 (58.5) Underlying disease Malignancy 145 (57.8) 51 (57.3) 39 (73.6) Respiratory 87 (34.7) 29 (32.6) 21 (39.6) Cardiovascular 44 (17.5) 13 (14.6) 5 (9.4) Gastrointestinal 39 (15.5) 13 (14.6) 1 (1.9) Genitourinary 34 (13.5) 12 (13.5) 7 (13.2) Neurological 20 (8.0) 15 (16.9) 9 (17.0) Cause of respiratory failure Pneumonia 78 (31.1) 29 (32.6) 27 (50.9) Extrapulmonary sepsis 54 (21.5) 16 (18.0) 5 (9.4) Pulmonary edema 30 (12.0) 8 (9.0) 1 (1.9) ARDS 20 (8.0) 12 (13.5) 7 (13.2) Neurological (coma) 12 (4.8) 6 (6.7) 4 (7.5) Ventilatory failure 17 (8.8) 3 (3.4) 1 (1.9) Exacerbation of ILD 11 (4.4) 2 (2.2) 1 (1.9) Post-CPR 7 (2.8) 6 (6.7) 1 (1.9) Central airway obstruction 8 (3.2) 2 (2.2) 3 (5.7) Miscellaneous 14 (5.6) 5 (5.6) 3 (5.7) SAPS 3 on ICU admission 58 (48 71) 60 (64 76) 66 (53 76) SOFA score on ICU admission 7 (4 11) 8 (5 11) 7 (5 11) Duration of MV before the first weaning trial, days 3 (2 5) 3 (2 7) 4 (2 8) SOFA score on the day of the first weaning trial 4 (3 7) 6 (3 8) 6 (4 9) <0.001 CAM-ICU (+) on the day of the first weaning trial 86 (34.3) 45 (50.6) 29 (54.7) Weaning index Respiratory rate 17 (14 20) 18 (15 22) 20 (18 24) <0.001 NIP, cmh 2O 24 ( 18 29) 22 ( 18 27) 22 ( 19 28) PaO 2/FiO ( ) 218 ( ) 241 ( ) <0.001 RSBI 47 (30 61) 50 (31 69) 59 (42 77) Outcomes Tracheostomy after the first weaning trial 23 (9.2) 28 (31.5) 39 (73.6) <0.001 ICU mortality 14 (5.6) 8 (9.0) 22 (41.5) <0.001 Length of stay in ICU, days 6 (3 9) 10 (7 15) 23 (16 30) <0.001 Hospital mortality 57 (22.7) 26 (29.2) 34 (66.7) <0.001 Length of stay in hospital, days 25 (14 44) 34 (19 58) 42 (30 73) <0.001 Type of hospital discharge Home 149 (59.4) 43 (48.3) 5 (9.8) <0.001 Other hospital 39 (15.5) 17 (19.1) 7 (13.7) <0.001 Other ICU (2.0) Hospice 6 (2.4) 3 (3.4) 4 (7.8) Death 57 (22.7) 26 (29.2) 34 (66.7) <0.001 Data are presented as number (%) or median (interquartile range). Ventilator failure includes acute exacerbations of chronic obstructive pulmonary disease, bronchial asthma and bronchiectasis. ARDS, acute respiratory distress syndrome; CAM-ICU, Confusion Assessment Method for the Intensive Care Unit; CPR, cardiopulmonary resuscitation; ICU, intensive care unit; ILD, interstitial lung disease; NIP, negative inspiratory pressure; RSBI, rapid shallow breathing index; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment. the CAM-ICU on the day of the first weaning trial, and the outcomes of weaning from MV in medical ICU patients. The results of our cohort study indicated that delirium was independently associated with weaning difficulties and resulted in prolonged MV. We also found that delirious patients had a higher risk of extubation failure and reintubation, even if they had been successfully weaned from MV and subsequently extubated. Respirology (2016) 21, Weaning from MV is a major issue in the ICU, 21 since prolonged MV is associated with significant morbidity and mortality. 22 A recent meta-analysis revealed that, in most trials, protocol-based weaning tended to reduce the duration of MV and the weaning process. 23 In addition, many studies have tried to identify simple measurements that can help clinicians predict which patients are ready for the weaning trials and who, among those who undergo the trials, 2015 Asian Pacific Society of Respirology

7 Delirium and weaning difficulty 319 Table 5 Associations between delirium, as assessed by the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), on the day of the first weaning trial and weaning classification after adjustment for potential confounding factors Difficult weaning Prolonged weaning CAM-ICU (+) χ 2 P OR 95% CI OR 95% CI Crude state Adjusted state Model Model Model Simple weaning is the reference category. Model 1 was adjusted for demographic data, such as age, sex and underlying disease. Model 2 was additionally adjusted for the severity of illness on ICU admission (Sequential Organ Failure Assessment, Simplified Acute Physiology Score 3) and causes of respiratory failure. Model 3 additionally adjusted for data obtained on the day of the first weaning trial, such as Sequential Organ Failure Assessment score, duration of mechanical ventilation before the first weaning trial and the weaning indexes. are most likely to be successful. 18 In this study, all patients had been screened daily for weaning readiness by RCP, based on the protocol-based weaning programme. In addition, calculation of the RSBI was used as a final assessment of patients readiness for the SBT. Therefore, pretest probability of successful weaning at the first SBT might be high. Nevertheless, the risk of weaning failure at the first SBT in patients with delirium on the day of the first weaning trial was twice as high compared with patients without delirium (OR 1.899, 95% CI , P = 0.007). In addition, in case of a successful SBT, extubation failure was also significantly associated with the presence of delirium on the day of the first weaning trial. Therefore, our data suggest that assessment of delirium could be helpful in predicting that a subsequent weaning trial would be successful in patients meeting the weaning readiness criteria, which are based on physiological measurements. Delirium has been found to be associated with negative clinical outcomes in critically ill patients, including increased length of stays and mortality. 3,7,10 In a prospective multicentre observational study involving surgical and trauma patients requiring MV, Lat et al. found that delirium is associated with an increased duration of MV and lengthy stays, independent of a patient s illness or injury severity. 24 A recent meta-analysis of the impact of delirium on clinical outcomes in critically ill patients also demonstrated that delirious patients were exposed to MV 7 days longer than non-delirious patients were. 25 However, previous results showed that a longer duration of MV in patients with delirium could not be directly linked with a longer weaning process due to delirium. Time spent in the weaning process after an underlying cause of respiratory failure has been addressed accounts for 40 50% of the total duration of MV. 22,23,26,27 Therefore, the duration of MV could increase along with the duration of the weaning process, in part because of weaning difficulties in patients with delirium. In this study, although the median duration of MV before the first weaning trial was similar (around 3 days) between delirious and non-delirious patients, the duration of the weaning process after the first weaning trial was longer in delirious patients as a result of failure of subsequent SBT and extubation. Therefore, our data indicated that prolonged MV in patients with delirium may be related to a prolonged weaning process that is associated with delirium, although a causal relationship between these factors could not be determined. Our study has several limitations. First, given its observational nature, there is always the possibility that selection bias might have influenced the significance of our findings. However, the data were collected prospectively from all consecutive patients who had been admitted to the medical ICU, were on MV support for more than 24 h, and were screened daily for weaning readiness through the standardized weaning protocol. Second, we did not evaluate the influence of critical illness polyneuropathy and myopathy associated with prolonged MV and weaning failure, 28 although muscle strength was assessed through the measurement of forceful inspiratory effort with negative inspiratory pressure. Finally, delirium was assessed by bedside nurses, rather than trained research nurses. This may have led to the under-diagnosis of delirium in daily practice, as compared with a research setting. 29 In addition, although adequate mentation was achieved by interruption of sedation or continuous titration of sedation to a level that allowed the patient to be adequately responsive, we could not take the degree of sedation into account in assessment of delirium. 30,31 Therefore, the association between delirium and weaning in our cohort may have been overestimated. However, our results represent actual practices at a tertiary referral hospital. In conclusion, delirium, as assessed through the CAM-ICU on the day of the first weaning trial, was found to be independently associated with weaning difficulties and resulted in prolonged MV in patients who had been mechanically ventilated for more than 24 h in the medical ICU. Acknowledgements The authors thank Sookyoung Woo (Samsung Biomedical Research Institute, Seoul, Republic of Korea) for advice regarding 2015 Asian Pacific Society of Respirology Respirology (2016) 21,

8 320 statistical analysis. This work was supported by a Samsung Medical Center grant (CRO ). REFERENCES 1 Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit. Care Med. 2013; 41: Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM- ICU). JAMA 2001; 286: Dubois MJ, Bergeron N, Dumont M, Dial S, Skrobik Y. Delirium in an intensive care unit: a study of risk factors. Intensive Care Med. 2001; 27: Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291: Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, Truman B, Dittus R, Bernard R, Inouye SK. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001; 27: Thomason JW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit. Care 2005; 9: R Lin SM, Liu CY, Wang CH, Lin HC, Huang CD, Huang PY, Fang YF, Shieh MH, Kuo HP. The impact of delirium on the survival of mechanically ventilated patients. Crit. Care Med. 2004; 32: Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007; 33: Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit. Care Med. 2010; 38: Lin SM, Huang CD, Liu CY, Lin HC, Wang CH, Huang PY, Fang YF, Shieh MH, Kuo HP. Risk factors for the development of earlyonset delirium and the subsequent clinical outcome in mechanically ventilated patients. J. Crit. Care 2008; 23: Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK, Gordon SM, Canonico AE, Dittus RS, Bernard GR et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit. Care Med. 2010; 38: van den Boogaard M, Schoonhoven L, Evers AW, van der Hoeven JG, van Achterberg T, Pickkers P. Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning. Crit. Care Med. 2012; 40: Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK et al. Long-term cognitive impairment after critical illness. N. Engl. J. Med. 2013; 369: Neto AS, Nassar AP Jr, Cardoso SO, Manetta JA, Pereira VG, Esposito DC, Damasceno MC, Slooter AJ. Delirium screening in critically ill patients: a systematic review and meta-analysis. Crit. Care Med. 2012; 40: Gusmao-Flores D, Salluh JI, Chalhub RA, Quarantini LC. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC) for the diagnosis of delirium: a systematic review and meta-analysis of clinical studies. Crit. Care 2012; 16: R115. K Jeon et al. 16 Jones SF, Pisani MA. ICU delirium: an update. Curr. Opin. Crit. Care 2012; 18: Patel RP, Gambrell M, Speroff T, Scott TA, Pun BT, Okahashi J, Strength C, Pandharipande P, Girard TD, Burgess H et al. Delirium and sedation in the intensive care unit: survey of behaviors and attitudes of 1384 healthcare professionals. Crit. Care Med. 2009; 37: Boles JM, Bion J, Connors A, Herridge M, Marsh B, Melot C, Pearl R, Silverman H, Stanchina M, Vieillard-Baron A et al. Weaning from mechanical ventilation. Eur. Respir. J. 2007; 29: Jeong BH, Ko MG, Nam J, Yoo H, Chung CR, Suh GY, Jeon K. Differences in clinical outcomes according to weaning classifications in medical intensive care units. PLoS ONE 2015; 10: e Heo EY, Lee BJ, Hahm BJ, Song EH, Lee HA, Yoo CG, Kim YW, Han SK, Shim YS, Lee SM. Translation and validation of the Korean Confusion Assessment Method for the Intensive Care Unit. BMC Psychiatry 2011; 11: McConville JF, Kress JP. Weaning patients from the ventilator. N. Engl. J. Med. 2012; 367: Esteban A, Anzueto A, Frutos F, Alia I, Brochard L, Stewart TE, Benito S, Epstein SK, Apezteguia C, Nightingale P et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA 2002; 287: Kollef MH, Shapiro SD, Silver P, St John RE, Prentice D, Sauer S, Ahrens TS, Shannon W, Baker-Clinkscale D. A randomized, controlled trial of protocol-directed versus physician-directed weaning from mechanical ventilation. Crit. Care Med. 1997; 25: Lat I, McMillian W, Taylor S, Janzen JM, Papadopoulos S, Korth L, Ehtisham A, Nold J, Agarwal S, Azocar R et al. The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients. Crit. Care Med. 2009; 37: Zhang Z, Pan L, Ni H. Impact of delirium on clinical outcome in critically ill patients: a meta-analysis. Gen. Hosp. Psychiatry 2013; 35: Ely EW, Baker AM, Dunagan DP, Burke HL, Smith AC, Kelly PT, Johnson MM, 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: Esteban A, Ferguson ND, Meade MO, Frutos-Vivar F, Apezteguia C, Brochard L, Raymondos K, Nin N, Hurtado J, Tomicic V et al. Evolution of mechanical ventilation in response to clinical research. Am. J. Respir. Crit. Care Med. 2008; 177: Garnacho-Montero J, Amaya-Villar R, Garcia-Garmendia JL, Madrazo-Osuna J, Ortiz-Leyba C. Effect of critical illness polyneuropathy on the withdrawal from mechanical ventilation and the length of stay in septic patients. Crit. Care Med. 2005; 33: van Eijk MM, van den Boogaard M, van Marum RJ, Benner P, Eikelenboom P, Honing ML, van der Hoven B, Horn J, Izaks GJ, Kalf A et al. Routine use of the confusion assessment method for the intensive care unit: a multicenter study. Am. J. Respir. Crit. Care Med. 2011; 184: Haenggi M, Blum S, Brechbuehl R, Brunello A, Jakob SM, Takala J. Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC. Intensive Care Med. 2013; 39: Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit. Am. J. Respir. Crit. Care Med. 2014; 189: Respirology (2016) 21, Asian Pacific Society of Respirology