ORIGINAL ARTICLE
The Clinical Respiratory Journal
High-frequency chest wall oscillation in prolonged mechanical ventilation patients: a randomized controlled trial Wei-Chang Huang1,2, Pi-Chu Wu3, Chao-Jung Chen3, Ya-Hua Cheng4, Sou-Jen Shih3, Hui-Chen Chen1 and Chieh-Liang Wu4,5,6 1 Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 2 Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan 3 Nursing Department, Taichung Veterans General Hospital, Taichung, Taiwan 4 Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 5 Department of Internal Medicine, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan 6 Department of Respiratory Therapy, College of Health Care, China Medical University, Taichung, Taiwan
Abstract Background and Aims: Patients with prolonged mechanical ventilation (PMV) often retain airway secretions, which may be cleared with the assistance of highfrequency chest wall oscillation (HFCWO). This study aimed to determine the effectiveness, safety and tolerance/comfort of HFCWO after extubation in PMV patients. Methods: This parallel-designed, randomized controlled trial enrolled subjects with both intra-tracheal intubation and mechanical ventilator support continuously for at least 21 days between January 2011 and December 2012. Upon extubation, the participants were randomly assigned to either receive HFCWO for 5 days or not. The effectiveness [based on weaning success rates, daily clearance volume of sputum, serial changes in sputum coloration and chest X-ray (CXR) improvement rates], safety (by physiologic parameters) and tolerance/comfort [using the Modified Borg Scale (MBS) and Hamilton Anxiety Scale (HAS)] of HFCWO were investigated. Results: There were 43 PMV subjects, including 23 in the HFCWO group and 20 in the non-HFCWO group. The weaning success rates were 82.6% (19/23) and 85% (17/20) in the HFCWO and non-HFCWO groups, respectively (P = 1.000). The HFCWO group had persistently greater numbers of daily sputum suctions and higher CXR improvement rates compared with the non-HFCWO group. There was significant sputum coloration lightening in the HFCWO group only. There was no significant difference in the MBS and HAS between the two groups and between pre- and post-HFCWO physiologic parameters. Conclusion: In PMV patients, HFCWO was safe, comfortable and effective in facilitating airway hygiene after removal of endotracheal tubes, but had no positive impact on weaning success. Please cite this paper as: Huang W-C, Wu P-C, Chen C-J, Cheng Y-H, Shih S-J, Please H-Cand and High-frequency wall oscillation in prolonged Chen H-C WuWu C-L.C-L. High-frequency chest chest wall oscillation in prolonged mechanmechanical ventilation a randomized controlled Clin Respir10: J 2014; ical ventilation patients:patients: a randomized controlled trial. Clintrial. Respir J 2016; 272– ••: ••–••. DOI:10.1111/crj.12212. 281. DOI:10.1111/crj.12212.
Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
The 272Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Registration: Clinical Trials.gov (identifier NCT02077738).
Key words effectiveness – elderly – high-frequency chest wall oscillation – mechanical ventilation – pneumonia – randomized controlled trial Correspondence Chieh-Liang Wu, PhD, Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, 40705 Taichung, Taiwan. Tel: +886 4 23592525 ext. 3201 Fax: +886 4 23500034 email: [email protected] Received: 09 April 2014 Revision requested: 10 July 2014 Accepted: 27 August 2014 DOI:10.1111/crj.12212 Authorship and contributorship Designed the study: Chieh-Liang Wu, Wei-Chang Huang, Pi-Chu Wu, Chao-Jung Chen, Ya-Hua Cheng and Sou-Jen Shih. Performed the study: Wei-Chang Huang, Pi-Chu Wu, Chao-Jung Chen and Ya-Hua Cheng. Collected the data: Wei-Chang Huang, Pi-Chu Wu, Chao-Jung Chen, Ya-Hua Cheng and Hui-Chen Chen. Analyzed the data: Wei-Chang Huang, Chieh-Liang Wu, Sou-Jen Shih and Hui-Chen Chen. Wrote the paper: Wei-Chang Huang and Chieh-Liang Wu. Ethics The Institutional Review Board and Ethics Committee of Taichung Veterans General Hospital approved this study (Approval number: C10216).
1 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
Huang etin al.PMV patients HFCWO
Introduction The number of patients with prolonged mechanical ventilation (PMV), defined as continuous use of mechanical ventilatory support for at least 21 days, is rapidly increasing worldwide because of an aging population and improved intensive care (1–3). Intratracheal intubation and mechanical ventilation can impair muco-ciliary clearance and cause the retention of secretions, deterioration of lung conditions and subsequently reintubation if they pass the spontaneous breathing trial (4). High-frequency chest wall oscillation (HFCWO) applies rapid external compressions to the thorax that can generate changes in volume of 15–57 mL and in flow of up to 1.6 L/s followed by minimal coughing to mobilize broncho-pulmonary secretions (5). For over 20 years, studies have attempted to examine the effectiveness, safety and tolerance/comfort of HFCWO in the management of surgical and non-surgical patients who had impaired bronchial secretion clearance, including those with neuromuscular disorders, chronic obstructive pulmonary disease, cystic fibrosis and blunt thoracic trauma, or those hospitalized for critical cardiac/abdominal/ thoracic surgery (6–14). However, these outcomes of HFCWO on PMV patients remain unknown. This study aimed to test the hypothesis that HFCWO can produce greater clearance volume of sputum, greater improvement rates in serial changes in the chest X-ray (CXR) and greater weaning success rates after extubation in PMV patients with intra-tracheal intubation. Moreover, the safety and tolerance/comfort of HFCWO in PMV patients after removal of endotracheal tubes were also evaluated.
Materials and methods This single-center, parallel-designed, randomized controlled trial was conducted at the Respiratory Care Center of Taichung Veterans General Hospital from January 2011 to December 2012. The inclusion criteria included the following: continuous intra-tracheal intubation and mechanical ventilator support for at least 21 days; age ≥20 years old; having an acute or chronic pulmonary condition concomitant with the presence of persistent sputum production and requiring secretion mobilization as judged by the physician; alert consciousness; completion of the Modified Borg Scale (MBS) (15) and Hamilton Anxiety Scale (HAS) (16); scheduled extubation within 24 h after enrollment; and without any contraindication for HFCWO (i.e. recent spinal injuries that have not yet been
The Clinical Respiratory Journal (2016) • ISSN 1752-6981 2
C 2014 John Wiley & Sons Ltd V
HFCWO in PMV patients Huang et al.
stabilized and active hemorrhage with hemodynamic instability). Those who had undergone tracheostomy were excluded from this study. The Institutional Review Board and Ethics Committee of Taichung Veterans General Hospital approved this study (Approval number: C10216), and informed consent was provided by the patients’ relatives or guardians. The study was registered at Clinical Trials.gov (identifier NCT02077738). All of the participants were screened and enrolled by the investigators, who were blinded to the intervention, and received multidisciplinary rehabilitation treatments that included conventional chest percussion and nutritionist and physiotherapist consultations for individualized nutrition formulas and exercise programs by hospital staff members who were blinded to the intervention. After enrollment, study subjects were assigned to receive HFCWO (HFCWO group) or not (nonHFCWO group) with an allocation ratio of 1:1 based on tables of random numbers by the interviewer who was blinded to the intervention. Subjects in the HFCWO group received HFCWO treatment for 15 min twice daily for 5 days from the day of extubation and were fitted with appropriate-sized vests. These vests were attached to an air-pulse delivery system (Hill-Rom Vest Airway Clearance System, HillRom, Inc., St. Paul, MN, USA) via two flexible plastic tubes. The Vest system was set to a frequency of 10–12 Hz and pressure of 1–2 (arbitrary unit) according to the manufacturer’s instructions. Subjects in the HFCWO group were seated upright during the entire session, and the HFCWO treatments were performed by nurses who were not blinded to the intervention. Successful weaning was defined as continuous liberation from mechanical ventilator support longer than 5 days. The daily clearance volume of sputum, as determined by the numbers of sputum suction per day, and sputum color, based on the Color Card for Body Fluid (CCBF) (Fig. 1), were recorded from the day of extubation to the fifth day after extubation in both groups (HFCWO vs non-HFCWO). The timing for sputum suction, which was defined by nurses who were not blinded to the intervention, was as follows: presence of voluntary coughs by study subjects; presence of rhonchi; and a drop of oxyhemoglobin saturation ≧4% by pulse oximetry with no obvious clue. The CCBF was designed to have 27 different categories to describe the color of the body fluid. Each category was assigned an Arabic numeral, where the larger the numeral, the darker the color of the body fluid. The 273 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Huang al.PMV patients HFCWOetin
HFCWO in PMV patients Huang et al.
Figure 1. Color Card for Body Fluid. A total of 27 categories are used to describe the color.
scoring of sputum coloration was based on the perception of the interviewer who was blinded to the intervention. Baseline and follow-up CXRs were taken on the day of extubation and on the fifth day after extubation, respectively, in both groups. Serial changes in CXR were graded as ‘improved’, ‘no change’ or ‘progressed’, as determined by the severity of lung infiltrates, which were defined by two independent chest specialists blinded to the study groupings. If there was no consistency between the two specialists, the grading was judged by a third chest specialist. Physiologic parameters, including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory rate (RR) and oxyhemoglobin saturation by pulse oximetry (SpO2), were recorded before and after each HFCWO treatment by nurses who were not blinded to the study groupings. Considering that post-extubation dyspnea and anxiety, rather than pain, were associated with the weaning success in PMV patients who were alert and could communicate with hospital staff members, MBS (15) as a representative of dyspnea severity and HAS (16) as a representative of anxiety severity were adopted as proxies of subject tolerance/comfort and measured before and after treatment in the HFCWO group and at the same time in the non-HFCWO group by the interviewer who was blinded to the intervention from the day of extubation to the fifth post-extubation day. Briefly, to study dyspnea severity by MBS, the subjects were free to score dyspnea severity in a 0–10 scale, with higher scores denoting more severe dyspnea. To study anxiety severity, the HAS, which included 14 items, was administered by an interviewer. For the 14 items of HAS, the values on the scale ranged from zero to four. The total anxiety score ranged from 0 to 56, with the larger scores indicating more severe anxiety. The 274Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Statistical analysis Clinical data were expressed as mean and standard deviation. Comparisons between the HFCWO and non-HFCWO groups were conducted using the chisquared test, Yates’ correction chi-squared test, Fisher’s exact test and Student’s t-test, as appropriate. Statistical significance was set at P < 0.05.
Results General data Between January 2011 and December 2012, a total of 322 subjects were screened for eligibility. Forty-five subjects were considered to be eligible for inclusion in the study and were randomly assigned between those who would or would not receive HFCWO (n = 25 and n = 20, respectively). A total of 23 of the 25 subjects assigned to receive HFCWO, and all 20 subjects assigned to not receive HFCWO were included in the per-protocol analysis (Fig. 2). The baseline characteristics were similar between the HFCWO and nonHFCWO groups (Table 1). Most of the enrolled subjects were elderly. Pneumonia was the cause of acute respiratory failure in nearly half of the enrolled subjects (n = 11 in the HFCWO group; n = 10 in the non-HFCWO group). The weaning success rates were 82.6% (19/23) in the HFCWO group and 85% (17/20) in the non-HFCWO group, without any statistically significant difference (P = 1.000) (Table 1).
HFCWO and airway hygiene The HFCWO group had significantly greater numbers of daily sputum suction on the third, fourth and fifth days after extubation compared with the non-HFCWO group (Fig. 3). Subjects receiving HFCWO needed 3 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
Huang etin al.PMV patients HFCWO
HFCWO in PMV patients Huang et al.
Figure 2. The flow diagram of study enrollment, randomization and assessment.
persistently similar numbers of daily sputum suction throughout the 5-day period whereas the nonHFCWO group had significantly decreased need day by day (Fig. 4). Serial changes in CXR revealed more resolution of lung infiltrates and less progression in the HFCWO group than in the non-HFCWO group (Table 1). The CCBF scores were significantly reduced in the third and fifth days after extubation in the HFCWO group but not in the non-HFCWO group (Fig. 5). These findings indicate that HFCWO could produce persistently greater daily clearance volume of sputum, higher CXR improvement rate and lighter sputum coloration after extubation in PMV patients with intra-tracheal intubation.
HFCWO: patient safety and tolerance The pre- and post-HFCWO physiologic parameters in the HFCWO group in the 5-day post-extubation period were presented in Table 2. Except for a few measurements, the SBP, DBP, R, and RR were similar before and after the HFCWO treatment. However, these differences had no significant clinical impact on
The Clinical Respiratory Journal (2016) • ISSN 1752-6981 4
C 2014 John Wiley & Sons Ltd V
the study subjects. The daily maximal MBS and HAS in the 5-day period were not significantly different between the two groups (Fig. 6). These findings suggested that PMV patients tolerated HFCWO treatment well and did not feel uncomfortable.
Discussion The effectiveness, safety and patient tolerance/comfort of HFCWO in PMV patients after removal of endotracheal tubes remain unreported. Its use in such a condition is novel and indicates that HFCWO facilitated airway hygiene and was safe and well-tolerated for PMV patients after extubation. To date, with the exception of two studies, there has been no trial of HFCWO in the elderly whose functional reserve and the ability to compensate for various physiologic stresses are reduced (17–19). One study demonstrated that the use of HFCWO, compared with chest physiotherapy (CPT), produced significant improvements in parameters of blood inflammation (C-reactive protein), lung functionality, dyspnea and quality of life scales in elderly patients with non-cystic fibrosis 275 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Huang al.PMV patients HFCWOetin
HFCWO in PMV patients Huang et al.
Table 1. Baseline characteristics of the study participants (n = 43) Non-HFCWO group (n = 20)
Characteristic Sex‡ Male Female Age¶ Causes of acute respiratory failure† Pneumonia Urologic tract infection ICH Intra-abdominal infection CHF CAD Cerebral infarction COPD Neurologic disorder Miscellaneous Co-morbidities Malignancy§ DM‡ OAD‡ Old CVA‡ HTN‡ CAD§ Neurologic disease‡ Liver disease§ Chronic kidney disease§ Autoimmune disorder§ Modified GCS score¶** Baseline WBC (x1000/cumm)¶ Post-HFCWO WBC (x1000/cumm)¶ HGB (g/dL)¶ ALB (g/dL)¶ PaO2 (mmHg)¶ FiO2 (%)¶ Length of ICU stay (days)¶ Weaning outcomes§ Failure Success CXR† Improved No change Progressed
HFCWO group (n = 23)
P value 0.994
14 (70.0%) 6 (30.0%) 77.1 ± 1.3
15 (65.2%) 8 (34.8%) 78.7 ± 8.7
10 (50.0%) 0 (0.0%) 5 (25.0%) 2 (10.0%) 1 (5.0%) 0 (0.0%) 1 (5.0%) 1 (5.0%) 0 (0.0%) 0 (0.0%)
11 (47.8%) 1 (4.3%) 6 (26.1%) 0 (0.0%) 0 (0.0%) 1 (4.3%) 2 (8.7%) 0 (0.0%) 1 (4.3%) 1 (4.3%)
6 (30.0%) 7 (35.0%) 8 (40.0%) 4 (20.0%) 11 (55.0%) 5 (25.0%) 4 (20.0%) 3 (15.0%) 4 (20.0%) 0 (0.0%) 10.3 ± 0.9 10.72 ± 3.661 11.45 ± 4.246 10.21 ± 1.3 3.1 ± 0.5 129.0 ± 77.2 0.4 ± 0.0 19.4 ± 11.6
2 (8.7%) 8 (34.8%) 14 (60.9%) 8 (34.8%) 7 (30.4%) 4 (17.4%) 8 (34.8%) 0 (0.0%) 4 (17.4%) 1 (4.3%) 10.5 ± 0.7 10.06 ± 2.968 12.81 ± 5.218 10.19 ± 1.2 3.0 ± 0.4 140.4 ± 71.9 0.4 ± 0.0 22.5 ± 10.5
3 (15.0%) 17 (85.0%)
4 (17.4%) 19 (82.6%)
3 (15.0%) 12 (60.0%) 5 (25.0%)
8 (34.8%) 15 (65.2%) 0 (0.0%)
0.594 0.423
0.118 1.000 0.289 0.461 0.187 0.711 0.461 0.092 1.000 1.000 0.349 0.518 0.463 0.961 0.714 0.646 0.240 0.414 1.000
0.024* 11 27 5
Data are presented as mean ± standard deviation (SD) or number (%). *P < 0.05. †By chi-squared test. ‡By Yates’ correction chi-squared test. §By Fisher’s exact test. ¶By independent t-test. **Modified GCS score, verbal score as one. HFCWO, high-frequency chest wall oscillation; ICH, intracranial hemorrhage; CHF, congestive heart failure; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; OAD, obstructive airway disease; CVA, cerebrovascular accident; HTN, hypertension; GCS, Glasgow Coma Scale; WBC, white blood count; HGB, hemoglobin; ALB, albumin; PaO2, partial pressure of oxygen in the blood; FiO2, Fraction of inspired oxygen; ICU, intensive care unit; CXR, chest X-ray.
The 276Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
5 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
Huang etin al.PMV patients HFCWO
HFCWO in PMV patients Huang et al.
Figure 3. The number of daily sputum suction in the 5-day period after extubation in the high-frequency chest wall oscillation (HFCWO) and nonHFCWO groups. By independent t-test; P < 0.05.
Figure 4. The difference in the numbers of daily sputum suction compared with that in the first day post-extubation within the 5-day period after extubation between the high-frequency chest wall oscillation (HFCWO) and non-HFCWO groups. By paired t-test; P < 0.05.
Figure 5. The mean changes of daily maximal score of the Color Card for Body Fluid compared with that in the first day post-extubation within the 5-day period after extubation between the high-frequency chest wall oscillation (HFCWO) and non-HFCWO groups. By paired t-test; P < 0.05.
The Clinical Respiratory Journal (2016) • ISSN 1752-6981 6
C 2014 John Wiley & Sons Ltd V
277 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Huang al.PMV patients HFCWOetin
HFCWO in PMV patients Huang et al.
Table 2. Pre- and post-HFCWO physiologic parameters in the HFCWO group 5 days after extubation HFCWO therapy
SBP (mmHg)
Day
Time
Before Mean ± SD
After Mean ± SD
1
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
127.9 ± 25.4 132.6 ± 21.6 137.4 ± 15.8 130.2 ± 21.2 134.0 ± 17.5 132.3 ± 20.8 135.2 ± 22.2 128.7 ± 19.1 128.0 ± 19.3 132.1 ± 17.6
133.7 ± 22.5 132.4 ± 22.5 133.2 ± 15.6 130.8 ± 17.4 131.3 ± 19.4 127.2 ± 18.6 126.6 ± 21.3 128.8 ± 19.3 126.4 ± 24.7 128.4 ± 18.6
−4.3 ± 18.2 0.3 ± 14.1 4.2 ± 11.5 −0.6 ± 11.0 2.8 ± 14.3 5.1 ± 18.4 8.6 ± 15.1 −0.2 ± 16.7 1.6 ± 16.8 3.6 ± 16.3
0.283 0.929 0.110 0.814 0.385 0.215 0.016* 0.968 0.687 0.343
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
66.7 ± 9.5 66.7 ± 9.5 66.2 ± 14.2 66.2 ± 14.2 67.5 ± 13.9 67.5 ± 13.9 67.4 ± 11.8 67.4 ± 11.8 65.1 ± 11.6 65.1 ± 11.6
67.2 ± 13.6 67.2 ± 13.6 68.7 ± 14.6 68.7 ± 14.6 65.0 ± 13.0 65.0 ± 13.0 64.2 ± 13.1 64.2 ± 13.1 63.5 ± 11.8 63.5 ± 11.8
−0.7 ± 10.2 −0.7 ± 10.2 −2.5 ± 8.5 −2.5 ± 8.5 2.6 ± 10.9 2.6 ± 10.9 3.1 ± 10.3 3.1 ± 10.3 1.6 ± 8.0 1.6 ± 8.0
0.740 0.740 0.189 0.189 0.293 0.293 0.189 0.189 0.403 0.403
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
87.4 ±15.2 94.1 ± 17.4 94.0 ± 13.0 90.6 ± 12.8 96.3 ± 8.9 97.5 ± 13.0 93.4 ± 25.0 96.7 ± 11.7 95.1 ± 11.4 96.8 ± 11.2
90.5 ± 15.8 97.4 ± 17.0 90.0 ± 11.3 94.0 ± 11.1 95.9 ± 12.0 95.3 ± 12.0 101.2 ± 11.4 95.5 ± 13.9 97.3 ± 11.5 96.5 ± 11.2
−2.3 ± 10.1 −2.1 ± 6.1 4.0 ± 11.5 −3.4 ± 9.2 0.5 ± 6.6 2.2 ± 6.4 −7.8 ± 24.6 1.3 ± 5.6 −2.2 ± 6.1 0.3 ± 6.6
0.293 0.114 0.124 0.109 0.744 0.124 0.162 0.331 0.132 0.838
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
20.9 ± 6.7 25.3 ± 5.3 25.6 ± 5.0 24.0 ± 4.4 23.5 ± 3.0 24.0 ± 4.1 30.4 ± 21.3 25.0 ± 6.2 22.2 ± 3.8 23.6 ± 3.6
23.5 ± 6.0 25.1 ± 3.8 23.7 ± 5.1 24.2 ± 4.5 24.4 ± 3.8 23.8 ± 4.3 25.6 ± 4.5 24.6 ± 6.3 22.9 ± 4.1 22.7 ± 3.7
−3.2 ± 5.6 0.0 ± 4.9 1.9 ± 4.1 −0.2 ± 3.5 −0.9 ± 3.2 0.3 ± 4.6 4.8 ± 20.5 0.4 ± 4.1 −0.7 ± 3.6 0.9 ± 2.8
0.014* 1.000 0.049* 0.806 0.215 0.778 0.295 0.632 0.386 0.187
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
0.998 ± 0.005 0.995 ± 0.008 0.989 ± 0.016 0.987 ± 0.021 0.987 ± 0.019 0.983 ± 0.016 0.984 ± 0.019 0.982 ± 0.018 0.984 ± 0.018 0.979 ± 0.020
0.996 ± 0.009 0.995 ± 0.011 0.985 ± 0.025 0.988 ± 0.017 0.986 ± 0.018 0.989 ± 0.017 0.980 ± 0.022 0.976 ± 0.021 0.979 ± 0.024 0.982 ± 0.017
0.002 ± 0.006 0.000 ± 0.010 0.004 ± 0.028 −0.001 ± 0.025 0.000 ± 0.019 −0.006 ± 0.011 0.003 ± 0.020 0.006 ± 0.024 0.005 ± 0.020 −0.003 ± 0.025
0.162 0.833 0.543 0.792 0.911 0.024* 0.456 0.276 0.275 0.585
2 3 4 5 DBP (mmHg)
1 2 3 4 5
HR (bpm)
1 2 3 4 5
RR (bpm)
1 2 3 4 5
SPO2 (%)
1 2 3 4 5
Difference Mean ± SD
P value
By paired t-test. *P < 0.05. HFCWO, high-frequency chest wall oscillation; SD, standard deviation; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rates; RR, respiratory rates; SpO2, oxyhemoglobin saturation by pulse oximetry.
The 278Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
7 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
Huang etin al.PMV patients HFCWO
HFCWO in PMV patients Huang et al.
A
B
Figure 6. (A) Daily maximal Modified Borg Scale and (B) daily maximal Hamilton Anxiety Scale in the 5-day period after extubation in the high-frequency chest wall oscillation (HFCWO) and nonHFCWO groups.
bronchiectasis (18). The other study demonstrated that HFCWO treatment was well-tolerated, led to improvement in quality of life and reduced symptoms in patients with COPD (19). Similarly, most of the enrolled subjects in the present study were elderly. Thus, the outcomes in these three studies might be applied to the age group in the above-mentioned scenarios.
The Clinical Respiratory Journal (2016) • ISSN 1752-6981 8
C 2014 John Wiley & Sons Ltd V
In the elderly, a particular respiratory concern is the increased risk of aspiration and pneumonia (20, 21). In this study, pneumonia is the cause of acute respiratory failure in nearly half of the enrolled subjects. Although CPT is not recommended for the routine treatment of uncomplicated pneumonia (22), the effectiveness of HFCWO on patients with severe pneumonia has not 279 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Huang al.PMV patients HFCWOetin
yet been investigated. The findings may be applied to such scenario. The daily clearance volume of sputum decreases gradually after extubation in patients in the nonHFCWO group but not in those of the HFCWO group. As the baseline and post-HFCWO white blood counts (Table 1) are similar between the two groups, control of pulmonary infection within the study period in the non-HFCWO group, rather than in the HFCWO group, is less likely to be related to the results. Instead, this indicates that impaired muco-ciliary clearance by intra-tracheal intubation and mechanical ventilation does exist after extubation in PMV patients. Furthermore, the tidal volume may decrease after weaning from mechanical ventilators, thus impairing sputum movement from the peripheral to the central airways. HFCWO treatment can break this vicious cycle and facilitate airway hygiene. As previously noted, there was a significant increase in wet sputum production after HFCWO treatment compared with CPT in patients with hospitalized cystic fibrosis or in chronically ventilated patients (10, 23). The data here also show that HFCWO can facilitate pulmonary secretion clearance. This may be because CPT is highly operator dependent and thus subject to variable efficacy. In contrast, HFCWO is more consistently effective because it is entirely machine based (24). Contrary to the preliminary data of a previous study showing that more chronically ventilated patients who received HFCWO for 40 days were weaned from ventilators compared with those who received CPT (P = 0.063) (23), we found that HFCWO treatment did not increase the weaning success rate in PMV patients after removal of the endotracheal tubes. However, the study designs were different in these two studies. The present study focused on the impact of HFCWO on airway hygiene after removal of the endotracheal tubes rather than before weaning from mechanical ventilators. It also aimed at preventing reintubation because of retention of airway secretions. Moreover, all of the study subjects passed the spontaneous breathing trial before enrollment. The difference in study designs may obscure the impact of HFCWO on weaning success rate in the present study. Using CCBF (Fig. 1) to describe serial changes of sputum coloration and to determine the patient’s airway hygiene has been extensively adopted in the study institute and is convenient for multidisciplinary communication among team members. The present study is the first report to clarify that HFCWO can lighten sputum coloration. Thus, it may reduce the risk of pneumonia following extubation in PMV patients The 280Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
HFCWO in PMV patients Huang et al.
with intra-tracheal intubation. Although future studies are needed to validate the application, the CCBF, as an important tool, can be used to determine the effectiveness of HFCWO. Because both dyspnea and anxiety, rather than pain, may be involved in weaning success in PMV patients who were alert and communicable, MBS and HAS were chosen, rather than average scores of pain, as proxies of patient tolerance/comfort to HFCWO. Although HFCWO, compared with CPT, has been associated with statistically lower pain scores in intubated and non-intubated adults (25), we found that patients receiving HFCWO had similar average scores of MBS and HAS as patients who did not receive HFCWO in the 5-day period after extubation. This distinction may be because either diverse proxies were chosen in the two studies or most of the study subjects were elderly in our study in contrast to the middleaged ones in the previous study (25). Consistent with previous safety reports (14, 23), the present study reveals that physiologic parameters, including SBP, DBP, HR, RR and SpO2, have no clinically significant difference before and after HFCWO treatment, suggesting that HFCWO treatment is safe in PMV patients for a short period after extubation. Our study has several limitations. First, the small sample sizes of both groups may influence outcomes, which warrant studies with larger sample sizes to validate. Second, a low ratio of respiratory care center/ intensive care unit beds (12 beds to 143 beds) makes it possible for patients with clinically higher weaning success potential to be the priority for admission. This may be an effect of the weaning success rates between patients who received HFCWO and those who did not. Third, vests without oscillation were not applied in the non-HFCWO group, leading to a possible placebo effect. Fourth, using the numbers of sputum suction and serial changes of sputum coloration, as determined by CCBF, as the proxies of the clearance volume of sputum and the risk of pneumonia, respectively, there is a need to validate the findings further in future studies. In summary, for PMV patients, HFCWO is a safe and comfortable treatment that can significantly increase both the daily clearance volume of sputum and CXR improvement rates together with lightening sputum coloration within a short period after removal of endotracheal tubes. However, HFCWO has no positive impact on the success rate of weaning.
Acknowledgement The authors thank Mrs. Hui-Chen Nien for assistance in statistical analysis. 9 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
HFCWO Huang etin al.PMV patients
Huang et al. HFCWO in PMV patients
References 13. 1. Macintyre NR, Epstein SK, Carson S, Scheinhorn D, Christopher K, Muldoon S, National Association for Medical Direction of Respiratory Care. Management of patients requiring prolonged mechanical ventilation: report of a NAMDRC consensus conference. Chest. 2005;128: 3937–54. 2. Needham DM, Bronskill SE, Sibbald WJ, Pronovost PJ, Laupacis A. Mechanical ventilation in Ontario, 1992–2000: incidence, survival, and hospital bed utilization of non-cardiac surgery adult patients. Crit Care Med. 2004;32: 1504–9. 3. Hung MC, Lu HM, Chen L, et al. Life expectancies and incidence rates of patients under prolonged mechanical ventilation: a population-based study during 1998 to 2007 in Taiwan. Crit Care. 2011;15: R107. 4. Konrad F, Schreiber T, Brecht-Kraus D, Georgieff M. Mucociliary transport in ICU patients. Chest. 1994;105: 237–41. 5. King M, Phillips DM, Gross D, Vartian V, Chang HK, Zidulka A. Enhanced tracheal mucus clearance with high frequency chest wall compression. Am Rev Respir Dis. 1983;128: 511–5. 6. Giarraffa P, Berger KI, Chaiken AA, Axelrod FB, Davey C, Becker B. Assessing efficacy of high-frequency chest wall oscillation in patients with familial dysautonomia. Chest. 2005;128: 3377–81. 7. Lange DJ, Lechtzin N, Davey C, David W, Heiman-Patterson T, Gelinas D, Becker B, Mitsumoto H, HFCWO Study Group. High-frequency chest wall oscillation in ALS: an exploratory randomized, controlled trial. Neurology. 2006;67: 991–7. 8. Chaisson KM, Walsh S, Simmons Z, Vender RL. A clinical pilot study: high frequency chest wall oscillation airway clearance in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2006;7: 107–11. 9. Perry RJ, Man GC, Jones RL. Effects of positive endexpiratory pressure on oscillated flow rate during highfrequency chest compression. Chest. 1998;113: 1028–33. 10. Arens R, Gozal D, Omlin KJ, Vega J, Boyd KP, Keens TG, Woo MS. Comparison of high frequency chest compression and conventional chest physiotherapy in hospitalized patients with cystic fibrosis. Am J Respir Crit Care Med. 1994;150: 1154–7. 11. Oermann CM, Sockrider MM, Giles D, Sontag MK, Accurso FJ, Castile RG. Comparison of high-frequency chest wall oscillation and oscillating positive expiratory pressure in the home management of cystic fibrosis: a pilot study. Pediatr Pulmonol. 2001;32: 372–7. 12. Tecklin JS, Clayton RG, Scanlin TF. High frequency chest wall oscillation vs. traditional chest physical therapy in
10 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
14.
15.
16. 17. 18.
19.
20. 21. 22.
23.
24.
25.
CF-a large, one-year, controlled study. Pediatr Pulmonol. 2000;20(Suppl.): S459. Varekojis SM, Douce FH, Flucke RL, Filbrun DA, Tice JS, McCoy KS, Castile RG. A comparison of the therapeutic effectiveness of and preference for postural drainage and percussion, intrapulmonary percussive ventilation, and high-frequency chest wall compression in hospitalized cystic fibrosis patients. Respir Care. 2003;48: 24–8. Anderson CA, Palmer CA, Ney AL, Becker B, Schaffel SD, Quickel RR. Evaluation of the safety of high-frequency chest wall oscillation (HFCWO) therapy in blunt thoracic trauma patients. J Trauma Manag Outcomes. 2008;2: 8. Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Campbell EJ. The perception of breathlessness in asthma. Am Rev Respir Dis. 1982;126: 825–8. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32: 50–5. Zeleznik J. Normative aging of the respiratory system. Clin Geriatr Med. 2003;19: 1–18. Nicolini A, Cardini F, Landucci N, Lanata S, Ferrari-Bravo M, Barlascini C. Effectiveness of treatment with high-frequency chest wall oscillation in patients with bronchiectasis. BMC Pulm Med. 2013;13: 21. Chakravorty I, Chahal K, Austin G. A pilot study of the impact of high-frequency chest wall oscillation in chronic obstructive pulmonary disease patients with mucus hypersecretion. Int J Chron Obstruct Pulmon Dis. 2011;6: 693–9. Chan ED, Welsh CH. Geriatric respiratory medicine. Chest. 1998;114: 1704–33. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344: 665–71. Strickland SL, Rubin BK, Drescher GS, Haas CF, O’Malley CA, Volsko TA, Branson RD, Hess DR. AARC clinical practice guideline: effectiveness of nonpharmacologic airway clearance therapies in hospitalized patients. Respir Care. 2013;58: 2187–93. Ndukwu IM, Shapiro S, Nam AJ, Schumm PL. Comparison of high-frequency chest wall oscillation (HFCWO) and manual chest therapy (MCPT) in long-term acute care hospital (LTAC) ventilator dependent patients. Chest. 1999;116(4 Suppl. 2): S311. Warwick WJ, Wielinski CL, Hansen LG. Comparison of expectorated sputum after manual chest physical therapy and high-frequency chest compression. Biomed Instrum Technol. 2004;38: 470–5. Clinkscale D, Spihlman K, Watts P, Rosenbluth D, Kollef MH. A randomized trial of conventional chest physical therapy versus high frequency chest wall compressions in intubated and non-intubated adults. Respir Care. 2012;57: 221–8.
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 281 © 2014 John Wiley & Sons Ltd
The Clinical Respiratory Journal
High-frequency chest wall oscillation in prolonged mechanical ventilation patients: a randomized controlled trial Wei-Chang Huang1,2, Pi-Chu Wu3, Chao-Jung Chen3, Ya-Hua Cheng4, Sou-Jen Shih3, Hui-Chen Chen1 and Chieh-Liang Wu4,5,6 1 Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 2 Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan 3 Nursing Department, Taichung Veterans General Hospital, Taichung, Taiwan 4 Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 5 Department of Internal Medicine, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan 6 Department of Respiratory Therapy, College of Health Care, China Medical University, Taichung, Taiwan
Abstract Background and Aims: Patients with prolonged mechanical ventilation (PMV) often retain airway secretions, which may be cleared with the assistance of highfrequency chest wall oscillation (HFCWO). This study aimed to determine the effectiveness, safety and tolerance/comfort of HFCWO after extubation in PMV patients. Methods: This parallel-designed, randomized controlled trial enrolled subjects with both intra-tracheal intubation and mechanical ventilator support continuously for at least 21 days between January 2011 and December 2012. Upon extubation, the participants were randomly assigned to either receive HFCWO for 5 days or not. The effectiveness [based on weaning success rates, daily clearance volume of sputum, serial changes in sputum coloration and chest X-ray (CXR) improvement rates], safety (by physiologic parameters) and tolerance/comfort [using the Modified Borg Scale (MBS) and Hamilton Anxiety Scale (HAS)] of HFCWO were investigated. Results: There were 43 PMV subjects, including 23 in the HFCWO group and 20 in the non-HFCWO group. The weaning success rates were 82.6% (19/23) and 85% (17/20) in the HFCWO and non-HFCWO groups, respectively (P = 1.000). The HFCWO group had persistently greater numbers of daily sputum suctions and higher CXR improvement rates compared with the non-HFCWO group. There was significant sputum coloration lightening in the HFCWO group only. There was no significant difference in the MBS and HAS between the two groups and between pre- and post-HFCWO physiologic parameters. Conclusion: In PMV patients, HFCWO was safe, comfortable and effective in facilitating airway hygiene after removal of endotracheal tubes, but had no positive impact on weaning success. Please cite this paper as: Huang W-C, Wu P-C, Chen C-J, Cheng Y-H, Shih S-J, Please H-Cand and High-frequency wall oscillation in prolonged Chen H-C WuWu C-L.C-L. High-frequency chest chest wall oscillation in prolonged mechanmechanical ventilation a randomized controlled Clin Respir10: J 2014; ical ventilation patients:patients: a randomized controlled trial. Clintrial. Respir J 2016; 272– ••: ••–••. DOI:10.1111/crj.12212. 281. DOI:10.1111/crj.12212.
Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
The 272Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Registration: Clinical Trials.gov (identifier NCT02077738).
Key words effectiveness – elderly – high-frequency chest wall oscillation – mechanical ventilation – pneumonia – randomized controlled trial Correspondence Chieh-Liang Wu, PhD, Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, 40705 Taichung, Taiwan. Tel: +886 4 23592525 ext. 3201 Fax: +886 4 23500034 email: [email protected] Received: 09 April 2014 Revision requested: 10 July 2014 Accepted: 27 August 2014 DOI:10.1111/crj.12212 Authorship and contributorship Designed the study: Chieh-Liang Wu, Wei-Chang Huang, Pi-Chu Wu, Chao-Jung Chen, Ya-Hua Cheng and Sou-Jen Shih. Performed the study: Wei-Chang Huang, Pi-Chu Wu, Chao-Jung Chen and Ya-Hua Cheng. Collected the data: Wei-Chang Huang, Pi-Chu Wu, Chao-Jung Chen, Ya-Hua Cheng and Hui-Chen Chen. Analyzed the data: Wei-Chang Huang, Chieh-Liang Wu, Sou-Jen Shih and Hui-Chen Chen. Wrote the paper: Wei-Chang Huang and Chieh-Liang Wu. Ethics The Institutional Review Board and Ethics Committee of Taichung Veterans General Hospital approved this study (Approval number: C10216).
1 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
Huang etin al.PMV patients HFCWO
Introduction The number of patients with prolonged mechanical ventilation (PMV), defined as continuous use of mechanical ventilatory support for at least 21 days, is rapidly increasing worldwide because of an aging population and improved intensive care (1–3). Intratracheal intubation and mechanical ventilation can impair muco-ciliary clearance and cause the retention of secretions, deterioration of lung conditions and subsequently reintubation if they pass the spontaneous breathing trial (4). High-frequency chest wall oscillation (HFCWO) applies rapid external compressions to the thorax that can generate changes in volume of 15–57 mL and in flow of up to 1.6 L/s followed by minimal coughing to mobilize broncho-pulmonary secretions (5). For over 20 years, studies have attempted to examine the effectiveness, safety and tolerance/comfort of HFCWO in the management of surgical and non-surgical patients who had impaired bronchial secretion clearance, including those with neuromuscular disorders, chronic obstructive pulmonary disease, cystic fibrosis and blunt thoracic trauma, or those hospitalized for critical cardiac/abdominal/ thoracic surgery (6–14). However, these outcomes of HFCWO on PMV patients remain unknown. This study aimed to test the hypothesis that HFCWO can produce greater clearance volume of sputum, greater improvement rates in serial changes in the chest X-ray (CXR) and greater weaning success rates after extubation in PMV patients with intra-tracheal intubation. Moreover, the safety and tolerance/comfort of HFCWO in PMV patients after removal of endotracheal tubes were also evaluated.
Materials and methods This single-center, parallel-designed, randomized controlled trial was conducted at the Respiratory Care Center of Taichung Veterans General Hospital from January 2011 to December 2012. The inclusion criteria included the following: continuous intra-tracheal intubation and mechanical ventilator support for at least 21 days; age ≥20 years old; having an acute or chronic pulmonary condition concomitant with the presence of persistent sputum production and requiring secretion mobilization as judged by the physician; alert consciousness; completion of the Modified Borg Scale (MBS) (15) and Hamilton Anxiety Scale (HAS) (16); scheduled extubation within 24 h after enrollment; and without any contraindication for HFCWO (i.e. recent spinal injuries that have not yet been
The Clinical Respiratory Journal (2016) • ISSN 1752-6981 2
C 2014 John Wiley & Sons Ltd V
HFCWO in PMV patients Huang et al.
stabilized and active hemorrhage with hemodynamic instability). Those who had undergone tracheostomy were excluded from this study. The Institutional Review Board and Ethics Committee of Taichung Veterans General Hospital approved this study (Approval number: C10216), and informed consent was provided by the patients’ relatives or guardians. The study was registered at Clinical Trials.gov (identifier NCT02077738). All of the participants were screened and enrolled by the investigators, who were blinded to the intervention, and received multidisciplinary rehabilitation treatments that included conventional chest percussion and nutritionist and physiotherapist consultations for individualized nutrition formulas and exercise programs by hospital staff members who were blinded to the intervention. After enrollment, study subjects were assigned to receive HFCWO (HFCWO group) or not (nonHFCWO group) with an allocation ratio of 1:1 based on tables of random numbers by the interviewer who was blinded to the intervention. Subjects in the HFCWO group received HFCWO treatment for 15 min twice daily for 5 days from the day of extubation and were fitted with appropriate-sized vests. These vests were attached to an air-pulse delivery system (Hill-Rom Vest Airway Clearance System, HillRom, Inc., St. Paul, MN, USA) via two flexible plastic tubes. The Vest system was set to a frequency of 10–12 Hz and pressure of 1–2 (arbitrary unit) according to the manufacturer’s instructions. Subjects in the HFCWO group were seated upright during the entire session, and the HFCWO treatments were performed by nurses who were not blinded to the intervention. Successful weaning was defined as continuous liberation from mechanical ventilator support longer than 5 days. The daily clearance volume of sputum, as determined by the numbers of sputum suction per day, and sputum color, based on the Color Card for Body Fluid (CCBF) (Fig. 1), were recorded from the day of extubation to the fifth day after extubation in both groups (HFCWO vs non-HFCWO). The timing for sputum suction, which was defined by nurses who were not blinded to the intervention, was as follows: presence of voluntary coughs by study subjects; presence of rhonchi; and a drop of oxyhemoglobin saturation ≧4% by pulse oximetry with no obvious clue. The CCBF was designed to have 27 different categories to describe the color of the body fluid. Each category was assigned an Arabic numeral, where the larger the numeral, the darker the color of the body fluid. The 273 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Huang al.PMV patients HFCWOetin
HFCWO in PMV patients Huang et al.
Figure 1. Color Card for Body Fluid. A total of 27 categories are used to describe the color.
scoring of sputum coloration was based on the perception of the interviewer who was blinded to the intervention. Baseline and follow-up CXRs were taken on the day of extubation and on the fifth day after extubation, respectively, in both groups. Serial changes in CXR were graded as ‘improved’, ‘no change’ or ‘progressed’, as determined by the severity of lung infiltrates, which were defined by two independent chest specialists blinded to the study groupings. If there was no consistency between the two specialists, the grading was judged by a third chest specialist. Physiologic parameters, including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory rate (RR) and oxyhemoglobin saturation by pulse oximetry (SpO2), were recorded before and after each HFCWO treatment by nurses who were not blinded to the study groupings. Considering that post-extubation dyspnea and anxiety, rather than pain, were associated with the weaning success in PMV patients who were alert and could communicate with hospital staff members, MBS (15) as a representative of dyspnea severity and HAS (16) as a representative of anxiety severity were adopted as proxies of subject tolerance/comfort and measured before and after treatment in the HFCWO group and at the same time in the non-HFCWO group by the interviewer who was blinded to the intervention from the day of extubation to the fifth post-extubation day. Briefly, to study dyspnea severity by MBS, the subjects were free to score dyspnea severity in a 0–10 scale, with higher scores denoting more severe dyspnea. To study anxiety severity, the HAS, which included 14 items, was administered by an interviewer. For the 14 items of HAS, the values on the scale ranged from zero to four. The total anxiety score ranged from 0 to 56, with the larger scores indicating more severe anxiety. The 274Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Statistical analysis Clinical data were expressed as mean and standard deviation. Comparisons between the HFCWO and non-HFCWO groups were conducted using the chisquared test, Yates’ correction chi-squared test, Fisher’s exact test and Student’s t-test, as appropriate. Statistical significance was set at P < 0.05.
Results General data Between January 2011 and December 2012, a total of 322 subjects were screened for eligibility. Forty-five subjects were considered to be eligible for inclusion in the study and were randomly assigned between those who would or would not receive HFCWO (n = 25 and n = 20, respectively). A total of 23 of the 25 subjects assigned to receive HFCWO, and all 20 subjects assigned to not receive HFCWO were included in the per-protocol analysis (Fig. 2). The baseline characteristics were similar between the HFCWO and nonHFCWO groups (Table 1). Most of the enrolled subjects were elderly. Pneumonia was the cause of acute respiratory failure in nearly half of the enrolled subjects (n = 11 in the HFCWO group; n = 10 in the non-HFCWO group). The weaning success rates were 82.6% (19/23) in the HFCWO group and 85% (17/20) in the non-HFCWO group, without any statistically significant difference (P = 1.000) (Table 1).
HFCWO and airway hygiene The HFCWO group had significantly greater numbers of daily sputum suction on the third, fourth and fifth days after extubation compared with the non-HFCWO group (Fig. 3). Subjects receiving HFCWO needed 3 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
Huang etin al.PMV patients HFCWO
HFCWO in PMV patients Huang et al.
Figure 2. The flow diagram of study enrollment, randomization and assessment.
persistently similar numbers of daily sputum suction throughout the 5-day period whereas the nonHFCWO group had significantly decreased need day by day (Fig. 4). Serial changes in CXR revealed more resolution of lung infiltrates and less progression in the HFCWO group than in the non-HFCWO group (Table 1). The CCBF scores were significantly reduced in the third and fifth days after extubation in the HFCWO group but not in the non-HFCWO group (Fig. 5). These findings indicate that HFCWO could produce persistently greater daily clearance volume of sputum, higher CXR improvement rate and lighter sputum coloration after extubation in PMV patients with intra-tracheal intubation.
HFCWO: patient safety and tolerance The pre- and post-HFCWO physiologic parameters in the HFCWO group in the 5-day post-extubation period were presented in Table 2. Except for a few measurements, the SBP, DBP, R, and RR were similar before and after the HFCWO treatment. However, these differences had no significant clinical impact on
The Clinical Respiratory Journal (2016) • ISSN 1752-6981 4
C 2014 John Wiley & Sons Ltd V
the study subjects. The daily maximal MBS and HAS in the 5-day period were not significantly different between the two groups (Fig. 6). These findings suggested that PMV patients tolerated HFCWO treatment well and did not feel uncomfortable.
Discussion The effectiveness, safety and patient tolerance/comfort of HFCWO in PMV patients after removal of endotracheal tubes remain unreported. Its use in such a condition is novel and indicates that HFCWO facilitated airway hygiene and was safe and well-tolerated for PMV patients after extubation. To date, with the exception of two studies, there has been no trial of HFCWO in the elderly whose functional reserve and the ability to compensate for various physiologic stresses are reduced (17–19). One study demonstrated that the use of HFCWO, compared with chest physiotherapy (CPT), produced significant improvements in parameters of blood inflammation (C-reactive protein), lung functionality, dyspnea and quality of life scales in elderly patients with non-cystic fibrosis 275 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Huang al.PMV patients HFCWOetin
HFCWO in PMV patients Huang et al.
Table 1. Baseline characteristics of the study participants (n = 43) Non-HFCWO group (n = 20)
Characteristic Sex‡ Male Female Age¶ Causes of acute respiratory failure† Pneumonia Urologic tract infection ICH Intra-abdominal infection CHF CAD Cerebral infarction COPD Neurologic disorder Miscellaneous Co-morbidities Malignancy§ DM‡ OAD‡ Old CVA‡ HTN‡ CAD§ Neurologic disease‡ Liver disease§ Chronic kidney disease§ Autoimmune disorder§ Modified GCS score¶** Baseline WBC (x1000/cumm)¶ Post-HFCWO WBC (x1000/cumm)¶ HGB (g/dL)¶ ALB (g/dL)¶ PaO2 (mmHg)¶ FiO2 (%)¶ Length of ICU stay (days)¶ Weaning outcomes§ Failure Success CXR† Improved No change Progressed
HFCWO group (n = 23)
P value 0.994
14 (70.0%) 6 (30.0%) 77.1 ± 1.3
15 (65.2%) 8 (34.8%) 78.7 ± 8.7
10 (50.0%) 0 (0.0%) 5 (25.0%) 2 (10.0%) 1 (5.0%) 0 (0.0%) 1 (5.0%) 1 (5.0%) 0 (0.0%) 0 (0.0%)
11 (47.8%) 1 (4.3%) 6 (26.1%) 0 (0.0%) 0 (0.0%) 1 (4.3%) 2 (8.7%) 0 (0.0%) 1 (4.3%) 1 (4.3%)
6 (30.0%) 7 (35.0%) 8 (40.0%) 4 (20.0%) 11 (55.0%) 5 (25.0%) 4 (20.0%) 3 (15.0%) 4 (20.0%) 0 (0.0%) 10.3 ± 0.9 10.72 ± 3.661 11.45 ± 4.246 10.21 ± 1.3 3.1 ± 0.5 129.0 ± 77.2 0.4 ± 0.0 19.4 ± 11.6
2 (8.7%) 8 (34.8%) 14 (60.9%) 8 (34.8%) 7 (30.4%) 4 (17.4%) 8 (34.8%) 0 (0.0%) 4 (17.4%) 1 (4.3%) 10.5 ± 0.7 10.06 ± 2.968 12.81 ± 5.218 10.19 ± 1.2 3.0 ± 0.4 140.4 ± 71.9 0.4 ± 0.0 22.5 ± 10.5
3 (15.0%) 17 (85.0%)
4 (17.4%) 19 (82.6%)
3 (15.0%) 12 (60.0%) 5 (25.0%)
8 (34.8%) 15 (65.2%) 0 (0.0%)
0.594 0.423
0.118 1.000 0.289 0.461 0.187 0.711 0.461 0.092 1.000 1.000 0.349 0.518 0.463 0.961 0.714 0.646 0.240 0.414 1.000
0.024* 11 27 5
Data are presented as mean ± standard deviation (SD) or number (%). *P < 0.05. †By chi-squared test. ‡By Yates’ correction chi-squared test. §By Fisher’s exact test. ¶By independent t-test. **Modified GCS score, verbal score as one. HFCWO, high-frequency chest wall oscillation; ICH, intracranial hemorrhage; CHF, congestive heart failure; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; OAD, obstructive airway disease; CVA, cerebrovascular accident; HTN, hypertension; GCS, Glasgow Coma Scale; WBC, white blood count; HGB, hemoglobin; ALB, albumin; PaO2, partial pressure of oxygen in the blood; FiO2, Fraction of inspired oxygen; ICU, intensive care unit; CXR, chest X-ray.
The 276Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
5 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
Huang etin al.PMV patients HFCWO
HFCWO in PMV patients Huang et al.
Figure 3. The number of daily sputum suction in the 5-day period after extubation in the high-frequency chest wall oscillation (HFCWO) and nonHFCWO groups. By independent t-test; P < 0.05.
Figure 4. The difference in the numbers of daily sputum suction compared with that in the first day post-extubation within the 5-day period after extubation between the high-frequency chest wall oscillation (HFCWO) and non-HFCWO groups. By paired t-test; P < 0.05.
Figure 5. The mean changes of daily maximal score of the Color Card for Body Fluid compared with that in the first day post-extubation within the 5-day period after extubation between the high-frequency chest wall oscillation (HFCWO) and non-HFCWO groups. By paired t-test; P < 0.05.
The Clinical Respiratory Journal (2016) • ISSN 1752-6981 6
C 2014 John Wiley & Sons Ltd V
277 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Huang al.PMV patients HFCWOetin
HFCWO in PMV patients Huang et al.
Table 2. Pre- and post-HFCWO physiologic parameters in the HFCWO group 5 days after extubation HFCWO therapy
SBP (mmHg)
Day
Time
Before Mean ± SD
After Mean ± SD
1
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
127.9 ± 25.4 132.6 ± 21.6 137.4 ± 15.8 130.2 ± 21.2 134.0 ± 17.5 132.3 ± 20.8 135.2 ± 22.2 128.7 ± 19.1 128.0 ± 19.3 132.1 ± 17.6
133.7 ± 22.5 132.4 ± 22.5 133.2 ± 15.6 130.8 ± 17.4 131.3 ± 19.4 127.2 ± 18.6 126.6 ± 21.3 128.8 ± 19.3 126.4 ± 24.7 128.4 ± 18.6
−4.3 ± 18.2 0.3 ± 14.1 4.2 ± 11.5 −0.6 ± 11.0 2.8 ± 14.3 5.1 ± 18.4 8.6 ± 15.1 −0.2 ± 16.7 1.6 ± 16.8 3.6 ± 16.3
0.283 0.929 0.110 0.814 0.385 0.215 0.016* 0.968 0.687 0.343
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
66.7 ± 9.5 66.7 ± 9.5 66.2 ± 14.2 66.2 ± 14.2 67.5 ± 13.9 67.5 ± 13.9 67.4 ± 11.8 67.4 ± 11.8 65.1 ± 11.6 65.1 ± 11.6
67.2 ± 13.6 67.2 ± 13.6 68.7 ± 14.6 68.7 ± 14.6 65.0 ± 13.0 65.0 ± 13.0 64.2 ± 13.1 64.2 ± 13.1 63.5 ± 11.8 63.5 ± 11.8
−0.7 ± 10.2 −0.7 ± 10.2 −2.5 ± 8.5 −2.5 ± 8.5 2.6 ± 10.9 2.6 ± 10.9 3.1 ± 10.3 3.1 ± 10.3 1.6 ± 8.0 1.6 ± 8.0
0.740 0.740 0.189 0.189 0.293 0.293 0.189 0.189 0.403 0.403
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
87.4 ±15.2 94.1 ± 17.4 94.0 ± 13.0 90.6 ± 12.8 96.3 ± 8.9 97.5 ± 13.0 93.4 ± 25.0 96.7 ± 11.7 95.1 ± 11.4 96.8 ± 11.2
90.5 ± 15.8 97.4 ± 17.0 90.0 ± 11.3 94.0 ± 11.1 95.9 ± 12.0 95.3 ± 12.0 101.2 ± 11.4 95.5 ± 13.9 97.3 ± 11.5 96.5 ± 11.2
−2.3 ± 10.1 −2.1 ± 6.1 4.0 ± 11.5 −3.4 ± 9.2 0.5 ± 6.6 2.2 ± 6.4 −7.8 ± 24.6 1.3 ± 5.6 −2.2 ± 6.1 0.3 ± 6.6
0.293 0.114 0.124 0.109 0.744 0.124 0.162 0.331 0.132 0.838
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
20.9 ± 6.7 25.3 ± 5.3 25.6 ± 5.0 24.0 ± 4.4 23.5 ± 3.0 24.0 ± 4.1 30.4 ± 21.3 25.0 ± 6.2 22.2 ± 3.8 23.6 ± 3.6
23.5 ± 6.0 25.1 ± 3.8 23.7 ± 5.1 24.2 ± 4.5 24.4 ± 3.8 23.8 ± 4.3 25.6 ± 4.5 24.6 ± 6.3 22.9 ± 4.1 22.7 ± 3.7
−3.2 ± 5.6 0.0 ± 4.9 1.9 ± 4.1 −0.2 ± 3.5 −0.9 ± 3.2 0.3 ± 4.6 4.8 ± 20.5 0.4 ± 4.1 −0.7 ± 3.6 0.9 ± 2.8
0.014* 1.000 0.049* 0.806 0.215 0.778 0.295 0.632 0.386 0.187
Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon Morning Afternoon
0.998 ± 0.005 0.995 ± 0.008 0.989 ± 0.016 0.987 ± 0.021 0.987 ± 0.019 0.983 ± 0.016 0.984 ± 0.019 0.982 ± 0.018 0.984 ± 0.018 0.979 ± 0.020
0.996 ± 0.009 0.995 ± 0.011 0.985 ± 0.025 0.988 ± 0.017 0.986 ± 0.018 0.989 ± 0.017 0.980 ± 0.022 0.976 ± 0.021 0.979 ± 0.024 0.982 ± 0.017
0.002 ± 0.006 0.000 ± 0.010 0.004 ± 0.028 −0.001 ± 0.025 0.000 ± 0.019 −0.006 ± 0.011 0.003 ± 0.020 0.006 ± 0.024 0.005 ± 0.020 −0.003 ± 0.025
0.162 0.833 0.543 0.792 0.911 0.024* 0.456 0.276 0.275 0.585
2 3 4 5 DBP (mmHg)
1 2 3 4 5
HR (bpm)
1 2 3 4 5
RR (bpm)
1 2 3 4 5
SPO2 (%)
1 2 3 4 5
Difference Mean ± SD
P value
By paired t-test. *P < 0.05. HFCWO, high-frequency chest wall oscillation; SD, standard deviation; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rates; RR, respiratory rates; SpO2, oxyhemoglobin saturation by pulse oximetry.
The 278Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
7 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
Huang etin al.PMV patients HFCWO
HFCWO in PMV patients Huang et al.
A
B
Figure 6. (A) Daily maximal Modified Borg Scale and (B) daily maximal Hamilton Anxiety Scale in the 5-day period after extubation in the high-frequency chest wall oscillation (HFCWO) and nonHFCWO groups.
bronchiectasis (18). The other study demonstrated that HFCWO treatment was well-tolerated, led to improvement in quality of life and reduced symptoms in patients with COPD (19). Similarly, most of the enrolled subjects in the present study were elderly. Thus, the outcomes in these three studies might be applied to the age group in the above-mentioned scenarios.
The Clinical Respiratory Journal (2016) • ISSN 1752-6981 8
C 2014 John Wiley & Sons Ltd V
In the elderly, a particular respiratory concern is the increased risk of aspiration and pneumonia (20, 21). In this study, pneumonia is the cause of acute respiratory failure in nearly half of the enrolled subjects. Although CPT is not recommended for the routine treatment of uncomplicated pneumonia (22), the effectiveness of HFCWO on patients with severe pneumonia has not 279 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Huang al.PMV patients HFCWOetin
yet been investigated. The findings may be applied to such scenario. The daily clearance volume of sputum decreases gradually after extubation in patients in the nonHFCWO group but not in those of the HFCWO group. As the baseline and post-HFCWO white blood counts (Table 1) are similar between the two groups, control of pulmonary infection within the study period in the non-HFCWO group, rather than in the HFCWO group, is less likely to be related to the results. Instead, this indicates that impaired muco-ciliary clearance by intra-tracheal intubation and mechanical ventilation does exist after extubation in PMV patients. Furthermore, the tidal volume may decrease after weaning from mechanical ventilators, thus impairing sputum movement from the peripheral to the central airways. HFCWO treatment can break this vicious cycle and facilitate airway hygiene. As previously noted, there was a significant increase in wet sputum production after HFCWO treatment compared with CPT in patients with hospitalized cystic fibrosis or in chronically ventilated patients (10, 23). The data here also show that HFCWO can facilitate pulmonary secretion clearance. This may be because CPT is highly operator dependent and thus subject to variable efficacy. In contrast, HFCWO is more consistently effective because it is entirely machine based (24). Contrary to the preliminary data of a previous study showing that more chronically ventilated patients who received HFCWO for 40 days were weaned from ventilators compared with those who received CPT (P = 0.063) (23), we found that HFCWO treatment did not increase the weaning success rate in PMV patients after removal of the endotracheal tubes. However, the study designs were different in these two studies. The present study focused on the impact of HFCWO on airway hygiene after removal of the endotracheal tubes rather than before weaning from mechanical ventilators. It also aimed at preventing reintubation because of retention of airway secretions. Moreover, all of the study subjects passed the spontaneous breathing trial before enrollment. The difference in study designs may obscure the impact of HFCWO on weaning success rate in the present study. Using CCBF (Fig. 1) to describe serial changes of sputum coloration and to determine the patient’s airway hygiene has been extensively adopted in the study institute and is convenient for multidisciplinary communication among team members. The present study is the first report to clarify that HFCWO can lighten sputum coloration. Thus, it may reduce the risk of pneumonia following extubation in PMV patients The 280Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
HFCWO in PMV patients Huang et al.
with intra-tracheal intubation. Although future studies are needed to validate the application, the CCBF, as an important tool, can be used to determine the effectiveness of HFCWO. Because both dyspnea and anxiety, rather than pain, may be involved in weaning success in PMV patients who were alert and communicable, MBS and HAS were chosen, rather than average scores of pain, as proxies of patient tolerance/comfort to HFCWO. Although HFCWO, compared with CPT, has been associated with statistically lower pain scores in intubated and non-intubated adults (25), we found that patients receiving HFCWO had similar average scores of MBS and HAS as patients who did not receive HFCWO in the 5-day period after extubation. This distinction may be because either diverse proxies were chosen in the two studies or most of the study subjects were elderly in our study in contrast to the middleaged ones in the previous study (25). Consistent with previous safety reports (14, 23), the present study reveals that physiologic parameters, including SBP, DBP, HR, RR and SpO2, have no clinically significant difference before and after HFCWO treatment, suggesting that HFCWO treatment is safe in PMV patients for a short period after extubation. Our study has several limitations. First, the small sample sizes of both groups may influence outcomes, which warrant studies with larger sample sizes to validate. Second, a low ratio of respiratory care center/ intensive care unit beds (12 beds to 143 beds) makes it possible for patients with clinically higher weaning success potential to be the priority for admission. This may be an effect of the weaning success rates between patients who received HFCWO and those who did not. Third, vests without oscillation were not applied in the non-HFCWO group, leading to a possible placebo effect. Fourth, using the numbers of sputum suction and serial changes of sputum coloration, as determined by CCBF, as the proxies of the clearance volume of sputum and the risk of pneumonia, respectively, there is a need to validate the findings further in future studies. In summary, for PMV patients, HFCWO is a safe and comfortable treatment that can significantly increase both the daily clearance volume of sputum and CXR improvement rates together with lightening sputum coloration within a short period after removal of endotracheal tubes. However, HFCWO has no positive impact on the success rate of weaning.
Acknowledgement The authors thank Mrs. Hui-Chen Nien for assistance in statistical analysis. 9 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
HFCWO Huang etin al.PMV patients
Huang et al. HFCWO in PMV patients
References 13. 1. Macintyre NR, Epstein SK, Carson S, Scheinhorn D, Christopher K, Muldoon S, National Association for Medical Direction of Respiratory Care. Management of patients requiring prolonged mechanical ventilation: report of a NAMDRC consensus conference. Chest. 2005;128: 3937–54. 2. Needham DM, Bronskill SE, Sibbald WJ, Pronovost PJ, Laupacis A. Mechanical ventilation in Ontario, 1992–2000: incidence, survival, and hospital bed utilization of non-cardiac surgery adult patients. Crit Care Med. 2004;32: 1504–9. 3. Hung MC, Lu HM, Chen L, et al. Life expectancies and incidence rates of patients under prolonged mechanical ventilation: a population-based study during 1998 to 2007 in Taiwan. Crit Care. 2011;15: R107. 4. Konrad F, Schreiber T, Brecht-Kraus D, Georgieff M. Mucociliary transport in ICU patients. Chest. 1994;105: 237–41. 5. King M, Phillips DM, Gross D, Vartian V, Chang HK, Zidulka A. Enhanced tracheal mucus clearance with high frequency chest wall compression. Am Rev Respir Dis. 1983;128: 511–5. 6. Giarraffa P, Berger KI, Chaiken AA, Axelrod FB, Davey C, Becker B. Assessing efficacy of high-frequency chest wall oscillation in patients with familial dysautonomia. Chest. 2005;128: 3377–81. 7. Lange DJ, Lechtzin N, Davey C, David W, Heiman-Patterson T, Gelinas D, Becker B, Mitsumoto H, HFCWO Study Group. High-frequency chest wall oscillation in ALS: an exploratory randomized, controlled trial. Neurology. 2006;67: 991–7. 8. Chaisson KM, Walsh S, Simmons Z, Vender RL. A clinical pilot study: high frequency chest wall oscillation airway clearance in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2006;7: 107–11. 9. Perry RJ, Man GC, Jones RL. Effects of positive endexpiratory pressure on oscillated flow rate during highfrequency chest compression. Chest. 1998;113: 1028–33. 10. Arens R, Gozal D, Omlin KJ, Vega J, Boyd KP, Keens TG, Woo MS. Comparison of high frequency chest compression and conventional chest physiotherapy in hospitalized patients with cystic fibrosis. Am J Respir Crit Care Med. 1994;150: 1154–7. 11. Oermann CM, Sockrider MM, Giles D, Sontag MK, Accurso FJ, Castile RG. Comparison of high-frequency chest wall oscillation and oscillating positive expiratory pressure in the home management of cystic fibrosis: a pilot study. Pediatr Pulmonol. 2001;32: 372–7. 12. Tecklin JS, Clayton RG, Scanlin TF. High frequency chest wall oscillation vs. traditional chest physical therapy in
10 The Clinical Respiratory Journal (2016) • ISSN 1752-6981 C 2014 John Wiley & Sons Ltd V
14.
15.
16. 17. 18.
19.
20. 21. 22.
23.
24.
25.
CF-a large, one-year, controlled study. Pediatr Pulmonol. 2000;20(Suppl.): S459. Varekojis SM, Douce FH, Flucke RL, Filbrun DA, Tice JS, McCoy KS, Castile RG. A comparison of the therapeutic effectiveness of and preference for postural drainage and percussion, intrapulmonary percussive ventilation, and high-frequency chest wall compression in hospitalized cystic fibrosis patients. Respir Care. 2003;48: 24–8. Anderson CA, Palmer CA, Ney AL, Becker B, Schaffel SD, Quickel RR. Evaluation of the safety of high-frequency chest wall oscillation (HFCWO) therapy in blunt thoracic trauma patients. J Trauma Manag Outcomes. 2008;2: 8. Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Campbell EJ. The perception of breathlessness in asthma. Am Rev Respir Dis. 1982;126: 825–8. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32: 50–5. Zeleznik J. Normative aging of the respiratory system. Clin Geriatr Med. 2003;19: 1–18. Nicolini A, Cardini F, Landucci N, Lanata S, Ferrari-Bravo M, Barlascini C. Effectiveness of treatment with high-frequency chest wall oscillation in patients with bronchiectasis. BMC Pulm Med. 2013;13: 21. Chakravorty I, Chahal K, Austin G. A pilot study of the impact of high-frequency chest wall oscillation in chronic obstructive pulmonary disease patients with mucus hypersecretion. Int J Chron Obstruct Pulmon Dis. 2011;6: 693–9. Chan ED, Welsh CH. Geriatric respiratory medicine. Chest. 1998;114: 1704–33. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344: 665–71. Strickland SL, Rubin BK, Drescher GS, Haas CF, O’Malley CA, Volsko TA, Branson RD, Hess DR. AARC clinical practice guideline: effectiveness of nonpharmacologic airway clearance therapies in hospitalized patients. Respir Care. 2013;58: 2187–93. Ndukwu IM, Shapiro S, Nam AJ, Schumm PL. Comparison of high-frequency chest wall oscillation (HFCWO) and manual chest therapy (MCPT) in long-term acute care hospital (LTAC) ventilator dependent patients. Chest. 1999;116(4 Suppl. 2): S311. Warwick WJ, Wielinski CL, Hansen LG. Comparison of expectorated sputum after manual chest physical therapy and high-frequency chest compression. Biomed Instrum Technol. 2004;38: 470–5. Clinkscale D, Spihlman K, Watts P, Rosenbluth D, Kollef MH. A randomized trial of conventional chest physical therapy versus high frequency chest wall compressions in intubated and non-intubated adults. Respir Care. 2012;57: 221–8.
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 281 © 2014 John Wiley & Sons Ltd
