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Supplementary Online Content 1 van Meenen DMP, van der Hoeven SM, Binnekade JM, et al. Effect of on–demand vs routine nebulization of acetylcysteine with salbutamol on ventilator-free days in intensive care unit patients receiving invasive ventilation: a randomized clinical trial. JAMA. doi:10.1001/jama.2018.0949 Study Protocol
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PROTOCOL TITLE ‘Effectiveness of routine nebulisation of mucolitycs and bronchodilators in mechanically ventilated intensive care patients’
Protocol ID Nebulae NL47807 018 14
Short title Effectiveness of routine nebulisation of mucolitycs and bronchodilators in intubated and mechanically ventilated patients
EudraCT number N.A.
Version 6.0
Coordinating investigator Sophia van der Hoeven Department of Intensive Care Academic Medical Center, University of
Amsterdam Meibergdreef 9, G3-228 1105 AZ Amsterdam, The Netherlands Telephone: +31-20-5666345 E–mail: [email protected] David van Meenen Department of Intensive Care Academic Medical Center, University of
Amsterdam Meibergdreef 9, C3-311 1105 AZ Amsterdam, The Netherlands Telephone: +31-20-5666339 E–mail: [email protected]
Principal investigator
Multicenter research: per site
Marcus J. Schultz, MD PhD C3–415 Department of Intensive Care Academisch Medisch Centrum Amsterdam Meibergdreef 9, C3–415 1105 AZ Amsterdam The Netherlands Telephone: +31-20-5662509; pager 58268 E–mail: [email protected]
H. S. Moeniralam, MD PhD
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Sint Antonius ziekenhuis Nieuwegein Department of Intensive Care Koekoekslaan 1 3430 EM Nieuwegein Telephone 088 3204729 [email protected]
B.J. van der Meer, MD PhD Amphia Ziekenhuis Breda: Department of Intensive care Molengracht 21 4818 Ck Breda Telephone 076 5955000 [email protected] H. Endeman, MD PhD Onze Lieve Vrouwe Gasthuis Amsterdam: Department of Intensive Care Oosterparkstraat 9 1090 HM Amsterdam Telephone 020 5993007 / 5994704 [email protected]
F.H. Bosch, MD PhD Rijnstate Ziekenhuis Arnhem Department of Intensive Care Wagnerlaan 55 6815 AD Arnhem Telephone 088 - 005 8888 [email protected] M. Slabbekorn, MD PhD Medisch Centrum Haaglanden: Department of Intensive Care Lijnbaan 32 2512 VA Den Haag Telephone 070 357 44 27 [email protected]
Sponsor (in Dutch: verrichter/opdrachtgever)
Academic Medical Center Amsterdam
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Subsidising party ZonMW Laan van Nieuw Oost-Indië 334, 2593 CE Den Haag, The Netherlands Telephone: +31 70 3495111 E-mail: [email protected] ZonMW
Independent expert (s)
Dr. D.A. Dongelmans Department of Intensive Care Room G3–221 Academic Medical Center Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Telephone: +31 20 5666336 E-mail: [email protected]
Laboratory sites NA
Pharmacy NA
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PROTOCOL SIGNATURE SHEET 29
30
Name Signature Date
Head of Department: Prof. dr. M.B. Vroom
Professor of Intensive Care Medicine
Principal Investigator: Prof. dr. Marcus J. Schultz Professor of Experimental Intensive
Care Medicine
31
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TABLE OF CONTENTS 33
1. INTRODUCTION AND HYPOTHESIS ............................................................................. 13 34
1.2 Uncertainty over the effectiveness and side effects: ........................................................ 13 35
1.3 Rational for this study: ...................................................................................................... 13 36
2. OBJECTIVES ................................................................................................................... 15 37
2.1 Primary Objective: ............................................................................................................ 15 38
2.2 Secondary Objectives ....................................................................................................... 15 39
3. STUDY DESIGN ............................................................................................................... 16 40
4. STUDY POPULATION ..................................................................................................... 17 41
4.1 Population ......................................................................................................................... 17 42
4.2 Inclusion criteria ................................................................................................................ 17 43
4.3 Exclusion criteria .............................................................................................................. 17 44
4.4 Sample size calculation .................................................................................................... 18 45
5. TREATMENT OF SUBJECTS .......................................................................................... 19 46
5.1 Investigational product/treatment ..................................................................................... 19 47
5.2 Concomitant medication: .................................................................................................. 20 48
5.3 Standard procedures ........................................................................................................ 20 49
5.3.1 Mechanical ventilation .............................................................................................. 20 50
5.3.2 Tracheostomy: ......................................................................................................... 21 51
5.3.3 Airway Care: ............................................................................................................ 21 52
5.3.4 Sedation and comfort protocol: ................................................................................ 22 53
5.3.5 Fluid management: .................................................................................................. 22 54
5.3.6 Nutrition .................................................................................................................... 22 55
6. INVESTIGATIONAL PRODUCT ....................................................................................... 23 56
6.1 Name and description of investigational products: ........................................................... 23 57
6.2 Summary of findings from non-clinical studies ................................................................. 23 58
6.3 Summary of findings from clinical studies ........................................................................ 23 59
6.4 Summary of known and potential risks and benefits ........................................................ 24 60
6.5 Description and justification of route of administration and dosage ................................. 25 61
6.6 Dosages, dosage modifications and method of administration ........................................ 25 62
6.7 Drug accountability ........................................................................................................... 25 63
7. NON-INVESTIGATIONAL PRODUCT ............................................................................. 26 64
7.1 Name and description of non-investigational product(s) .................................................. 25 65
7.2 Summary of findings from non-clinical studies ................................................................. 25 66
7.3 Summary of findings from clinical studies ........................................................................ 25 67
7.4 Summary of known and potential risks and benefits ........................................................ 25 68
7.5 Description and justification of route of administration and dosage ................................. 25 69
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7.6 Dosages, dosage modifications and method of administration ........................................ 25 70
7.7 Preparation and labelling of non investigational medicinal product ................................. 25 71
7.8 Drug accountability ........................................................................................................... 25 72
8. METHODS ........................................................................................................................ 27 73
8.1 Study parameters/endpoints ............................................................................................. 27 74
8.1.1 Main study parameter/endpoint ..................................................................................... 27 75
8.1.2Secondary study parameters/endpoints ......................................................................... 27 76
8.2 Randomisation, blinding and treatment allocation ............................................................ 27 77
8.3 Study procedures ............................................................................................................. 28 78
8.4 Data to be collected .......................................................................................................... 28 79
8.4.1 On admission and on the ICU: ................................................................................. 28 80
8.4.2 Baseline parameters 1 hour after intubation: ........................................................... 29 81
8.4.3 Data collected daily from day 1 till extubation* ........................................................ 29 82
8.4.4 Data collected daily from extubation* till discharge from the hospital ..................... 30 83
8.4.5 Data collected at day 90 of follow up ...................................................................... 30 84
8.4.5 Data to be collected for the economic evaluation .................................................... 31 85
8.5 Withdrawal of individual subjects ...................................................................................... 32 86
8.5.1 Specific criteria for withdrawal ................................................................................. 32 87
8.6 Replacement of individual subjects after withdrawal ........................................................ 32 88
8.7 Follow-up of subjects withdrawn from treatment .............................................................. 32 89
8.8 Premature termination of the study .................................................................................. 33 90
9. SAFETY REPORTING ..................................................................................................... 34 91
9.1 Section 10 WMO event ..................................................................................................... 34 92
9.2 AEs, and SAEs ................................................................................................................. 34 93
9.2.1 Adverse events (AEs) .............................................................................................. 34 94
9.2.2 Serious adverse events (SAEs) ............................................................................... 34 95
9.3 Follow-up of adverse events ............................................................................................. 36 96
9.4 Data Safety Monitoring Board (DSMB) ............................................................................. 36 97
10. STATISTICAL ANALYSIS ................................................................................................ 37 98
10.1 General considerations ................................................................................................ 37 99
10.2 Primary study parameter(s) ......................................................................................... 37 100
10.3 Secondary study parameters ....................................................................................... 38 101
10.4 Interim analysis ............................................................................................................ 38 102
10.5 Economic Evaluation ................................................................................................... 38 103
11. ETHICAL CONSIDERATIONS ......................................................................................... 41 104
11.1 Regulation statement ................................................................................................... 41 105
11.2 Recruitment and consent ............................................................................................. 41 106
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11.3 Benefits and risks assessment, group relatedness ..................................................... 41 107
11.4 Compensation for injury ............................................................................................... 42 108
11.5 Incentives .................................................................................................................... 42 109
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................... 43 110
12.1 Handling and storage of data and documents ............................................................. 43 111
12.2 Monitoring and Quality Assurance ............................................................................... 43 112
12.3 Amendments ............................................................................................................... 43 113
12.4 Annual progress report ................................................................................................ 44 114
12.5 End of study report ...................................................................................................... 44 115
12.6 Public disclosure and publication policy ...................................................................... 44 116
13. STRUCTURED RISK ANALYSIS ..................................................................................... 45 117
13.1 Synthesis ..................................................................................................................... 45 118
14. REFERENCES ................................................................................................................. 46 119
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ABR ABR form, General Assessment and Registration form, is the
application form that is required for submission to the accredited Ethics Committee (In Dutch, ABR = Algemene Beoordeling en Registratie)
AE Adverse Event ARDS Acute Respiratory Distress Syndrome CA Competent Authority CCMO Central Committee on Research Involving Human Subjects; in
Dutch: Centrale Commissie Mensgebonden Onderzoek CV Curriculum Vitae CVVH Continuous Veno-Venous Hemofiltration DSMB Data Safety Monitoring Board GCP Good Clinical Practice
IC Informed Consent ICU Intensive Care Unit METC Medical research ethics committee (MREC); in Dutch: medisch
ethische toetsing commissie (METC) NAC N-Acetylcysteine PEEP Positive End Expiratory Pressure (S)AE (Serious) Adverse Event SDD selective digestive tract decontamination SPC Summary of Product Characteristics (in Dutch: officiële
productinfomatie IB1-tekst) Sponsor The sponsor is the party that commissions the organisation or
performance of the research, for example a pharmaceutical company, academic hospital, scientific organisation or investigator. A party that provides funding for a study but does not commission it is not regarded as the sponsor, but referred to as a subsidising party.
VAP Ventilator Associated Pneumonia
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VFDs Ventilator Free Day’s Wbp Personal Data Protection Act (in Dutch: Wet Bescherming
Persoonsgevens) WMO Medical Research Involving Human Subjects Act (in Dutch: Wet
Medisch-wetenschappelijk Onderzoek met Mensen 122
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SUMMARY 123
Rationale: Routine nebulisation of mucolytics and bronchodilators is a frequently 124
used preventive strategy in intubated and mechanically ventilated intensive care unit 125
(ICU) patients. The aim of routine nebulisation of mucolytics and bronchodilators is to 126
prevent sputum plugging and as such atelectasis. It is highly uncertain whether this 127
expensive strategy is effective, and whether we should restrict nebulisation of 128
mucolytics and bronchodilators to those patients in whom sputum plugging is a 129
problem. 130
Hypothesis: We hypothesize that a strategy restricting nebulisation to patients with 131
sputum plugging is as effective as, but cheaper and safer than, a strategy using 132
routine nebulisation in all intubated and mechanically ventilated ICU patients. 133
Objective: The primary objective of this study is to determine the effectiveness of a 134
strategy using routine nebulisation of mucolytics and bronchodilators as compared to 135
a strategy that uses nebulisation only on clinical indication in intubated and ventilated 136
ICU patients. In addition we aim to compare safety, and related health care costs of 137
both strategies. 138
Study design: This study is an investigator initiated multicenter randomized 139
controlled non-inferiority trial in intubated and ventilated ICU patients. 140
Study population: Consecutive intubated and ventilated adult ICU patients with an 141
anticipated duration of ventilation > 24 hours. 142
Intervention: Routine nebulisation of mucolytics and bronchodilators administered 143
every 6 hours (i.e., in all patients for the complete duration of intubation and 144
mechanical ventilation) is compared to nebulisation of mucolytics and bronchodilators 145
on strict clinical indication (i.e., only if a patient shows to have problems with sputum 146
clearance or bronchospasm). 147
Main study parameters/endpoints: The primary endpoint is the number of 148
ventilator-free days (VFDs), defined as the number of days from day 1 to day 28 after 149
ICU admission and start of mechanical ventilation. Secondary endpoints include ICU 150
and hospital length of stay and mortality, incidence of secondary ARDS, ventilator-151
associated pneumonia, atelectasis and side effects of nebulisation of mucolytics and 152
bronchodilators. Also, related health care costs will be estimated with a cost benefit – 153
and budget impact analysis. 154
Nature and extent of the burden and risks associated with participation, benefit 155
and group relatedness: Benefits and risks of routine nebulisation of mucolytics and 156
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bronchodilators in mechanical ventilated patients are unknown. This procedure is 157
suggested to prevent endotracheal tube occlusion and sputum plugging, by diluting 158
sputum, although no solid research is conducted. Nebulisation of acetylcysteine 159
could induce bronchospasm while nebulisation of salbutamol may be associated with 160
tachycardia, tachyarrhythmia, tremor and agitation. 161
162
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1. INTRODUCTION AND HYPOTHESIS 163
164
1.1 Routine nebulisation in mechanical ventilated patients: 165 Routine nebulisation of mucolytics and bronchodilators is a frequently used 166
preventive strategy in intubated and mechanically ventilated intensive care unit (ICU) 167
patients1–3 This strategy is suggested to dilute pulmonary secretions and as such to 168
prevent sputum plugging in sedated and paralyzed patients who are less able to 169
clear their airways through coughing1–4. 170
171
1.2 Uncertainty over the effectiveness and side effects: 172
Whether this preventive strategy truly benefits ICU patients is highly unknown. There 173
is no evidence that the routine nebulisation of mucolytica and bronchodilators 174
reduces the risk of tube obstruction, duration of ventilation or the risk of ventilator 175
induced pneumonia. Randomized controlled trials have addressed neither the clinical 176
efficacy nor the economic consequences of routine nebulisation of mucolytics and 177
bronchodilators in intubated and ventilated ICU patients. Notably, as with every 178
pharmacological intervention, nebulisation of mucolytics and bronchodilators carries 179
risks of side effects. First, there is the risk for pulmonary related adverse effects, 180
including increased airway resistance due to bronchoconstriction 1 and increased risk 181
for development of ventilator–associated pneumonia5. Second, nebulisation 182
interferes with the patient-ventilator interaction, which may lead to hypoventilation, 183
decreased oxygenation and anxiety6. Additionally, nebulizing mucolytics and 184
bronchodilators is associated with systemic effects and may contribute to the 185
generation of tachycardia, tachyarrhythmia -especially in patients with underlying 186
cardiac disorders, although results are inconclusive-, tremor, and agitation1,7–10. 187
188
1.3 Rational for this study: 189
The care for ventilated ICU patients has changed fundamentally. Indeed, while deep 190
hypnosedation and neuromuscular blocking agents were used in almost all intubated 191
and ventilated ICU patients in the early years of ICU medicine, nowadays these 192
patients preferably receive analogo-sedation and almost never neuromuscular 193
blocking agents. While deep hypno-sedation and paralysis could promote stasis of 194
airway secretions, analgo–sedation increasingly allows patients to cough and as 195
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such clear the airways from sputum themselves. Also, ICU patients are mobilized 196
more early in the course of disease11, which could prevent atelectasis. 197
We hypothesize that a strategy restricting nebulisation to patients with sputum 198
plugging is as effective as, but cheaper and safer than a strategy using routine 199
nebulisation in all intubated and mechanically ventilated ICU patients. 200
201
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2. OBJECTIVES 202
203
2.1 Primary Objective: 204
The primary objective of this study is to determine whether a strategy using 205
nebulisation of mucolytics and bronchodilators on strict clinical indication has equal 206
effectiveness compared to routine nebulisation in intubated and ventilated ICU 207
patients, in terms of number of ventilator-free days. 208
209
2.2 Secondary Objectives 210
Secondary objectives are to compare the effects of both nebulisation strategies on 211
ICU- and hospital length of stay, mortality, incidence of secondary ARDS, ventilator-212
associated pneumonia, atelectasis, and side effects of nebulisation of mucolytics and 213
bronchodilators. Also, related health care costs will be estimated. 214
215
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3. STUDY DESIGN 216
This will be an investigator–initiated, multi–center, randomized, controlled, parallel 217
two group, non-inferiority trial in intubated and ventilated adult ICU patients. A total of 218
950 patients in 6 participating centers will be included. 219
220
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4. STUDY POPULATION 221
222
4.1 Population 223
Consecutive intubated and ventilated adult intensive care patients with an anticipated 224
ventilation duration of minimal 24 hours will be recruited at onset of ventilation. 225
Patients are recruited in the ICUs of 6 centers in The Netherlands. We will randomize 226
a total of 950 patients. It is expected that each participating center will randomize 227
approximately 160 patients. 228
229
230
4.2 Inclusion criteria 231
In order to be eligible to participate in this study, a patient must meet all of the 232
following criteria: 233
• Age 18 year or older; 234
• Expected duration of intubation and ventilation > 24 hours, as judged by the ICU 235
staff at time of admission; 236
• Written informed consent. 237
238
4.3 Exclusion criteria 239
A patient who meets any of the following criteria will be excluded from participation in 240
this study: 241
• Age less than 18 years; 242
• Ventilation before present ICU admission (though short-term ventilation in the 243
emergency room or in the operation room for general anesthesia during surgery is 244
allowed); 245
• Suspected or confirmed pregnancy; 246
• Diagnosed with lung diseases for which inhalation therapy and/or oral steroids are 247
used; 248
• Diagnoses of: Guillain-Barré syndrome, complete spinal cord lesion or 249
amyotrophic lateral sclerosis, Multiple Sclerosis, Myasthenia Gravis 250
• Known allergy for acetylcysteine or salbutamol 251
252
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4.4 Sample size calculation 253
254
Group size calculation is focused on demonstrating non-inferiority. When the sample 255
size in each group is 445 (890 patients in total), an one-sided non-inferiority test 256
(targeted at 0.05) for log-transformed normalized data has 80% power to reject the 257
null hypothesis that the number of ventilator-free days (VFDs) in the intervention 258
group (nebulisation on strict clinical indication) is inferior to the number of VFDs in the 259
control group (routine nebulisation) by a margin of 10% and a coefficient of variation 260
of 0.70, in favor of the alternative hypothesis that the number of VFDs in the 261
intervention group is non-inferior. The choice for a margin of 10% is motivated by 262
what we consider acceptable from a clinical point of view as the maximal acceptable 263
reduction of the ventilator-free period for non-inferiority. Clinically this margin means 264
that an increase of > 10% in the duration of mechanical ventilation will reduce the 265
ventilator free days with > 12 hours (calculated over the mean duration of mechanical 266
ventilation of 5 days) which will be considered inferior, assuming that the data will be 267
analyzed in the log scale using t-test for differences in means at the 5% level. To 268
allow for an anticipated drop out of approximately 5%, a number of 475 (950 in total) 269
patients will be included in each group. 270
271
R Core Team (2013). R: A language and environment for statistical computing. R 272
Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/. 273
Sample size is calculated in R (package PowerTost) 274
275
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5. TREATMENT OF SUBJECTS 277
278
5.1 Investigational product/treatment 279
Patients will be randomized in a 1:1 ratio to receive either: 280
- ‘routine nebulisation’, i.e. nebulisation of mucolytics and bronchodilators, 281
administered every 6 hours (i.e., 4 times per day) for the complete duration of 282
ventilation, or 283
- ‘nebulisation on strict clinical indications only’, i.e.nebulisation of mucolytics in case 284
of occurrence of persistent thick and tenacious sputum (Suzakawa criteria class 285
313), and only after active humidification is set. Nebulisation of bronchodilators in 286
case of occurrence of brochospasm and only when signs and symptoms of 287
bronchospasm (wheezing, increased airway pressures, increasing airway 288
resistance, up sloping curve of de end tidal CO2 monitoring) are confirmed. The 289
decision to start nebulisation on strict clinical indications will be made by the 290
attending ICU–physician and should be evaluated daily. In case the clinical 291
indication no longer exists, the therapy should be stopped (appendix 3). 292
293
Each routine nebulisation contains of a 3 mL-solution of acetylcysteine (fluimucil 294
100mg/ml, a mucolytic) and a 2.5 mL solution containing salbutamol (ventolin 2.5 295
Nebules 2.5mg/2.5 ml, a bronchodilator). 296
297
Each nebulisation on strict indication contains of a 3 mL-solution of acetylcysteine 298
(fluimucil 100mg/ml, a mucolytic) and/or a 2.5 mL solution containing salbutamol 299
(ventolin 2.5 Nebules 2.5mg/2.5 ml, a bronchodilator). 300
301
The solutions are nebulized using a jet nebulizer or a vibrating mesh nebuliser 302
depending on local standard in the participating center,which is attached to the 303
ventilator circuit with a T-piece adaptor. Jetebulizers will be operated synchronized 304
with the ventilator in case of an internal nebulizer or with pressured gas or oxygen 305
from an external source in case of a ventilator without an internal nebuliser, with a 306
flow of 3-5 L/min. If oxygen saturation is insufficient during nebulisation, pressured 307
gas is replaced by oxygen. The nebulizer will be placed in front of the Y-piece or 308
betweenthe Y-piece and the circuit prior to the heated humidifier or HME filter. Each 309
nebulisation session lasts about 20 minutes. If a patient becomes able to breathe 310
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without assistance for at least 24 hours but subsequently requires additional 311
mechanical ventilation within a period of 28 days, the same nebulisation strategy is 312
resumed. 313
314
5.2 Concomitant medication: 315
If indicated, nebulisation of other aerosol agents (antibiotics, antimycotics, ilomedine 316
or iloprost), is allowed in both treatment groups. These agents should be 317
administered preferably prior to the nebulisation of acetylcysteine and salbutamol, or 318
otherwise afterwards. 319
320
5.3 Standard procedures 321
322
5.3.1 Mechanical ventilation 323
Attending physicians are advised to use lung–protective ventilation strategies, 324
including the use of lower tidal volumes (≤ 6 mL/kg predicted body weight) and/or 325
lower airway pressures (≤ 30 cmH2O). Levels of positive end–expiratory pressure 326
(PEEP) and inspired oxygen (FiO2) are titrated on PaO2, preferably using a PEEP/ 327
FiO2–table, and according to local guidelines. If spontaneous ventilation is well 328
tolerated it is used from then till the end of ventilation. Thereafter, weaning from 329
ventilation is performed by stepwise lowering of pressure–support level. Daily 330
assessment of the patient’s readiness to wean will be performed. As soon as patients 331
are ready to be weaned from the ventilator, the pressure–support level is lowered 332
stepwise to 5 cmH2O. A patient is assumed to be ready for extubation when the 333
following criteria are met: 334
• Responsive and cooperative; 335
• Adequate cough reflex; 336
• PaO2/FiO2 of > 200 mmHg with FiO2 ≤ 40%; 337
• Respiratory rate of 8 to 30/minute; 338
• No signs of respiratory distress (i.e., marked accessory muscle use, abdominal 339
paradox, diaphoresis, marked dyspnea); 340
• Pressure support level < 7 cm H2O; 341
• Hemodynamically stable (systolic blood pressure 80 to 160 mmHg and heart rate 342
40 to 130/min) and no uncontrolled arrhythmia; 343
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• Rectal temperature > 36.0oC and < 38.0oC. 344
345
5.3.2 Tracheostomy: 346
Early tracheostomy has no advantage over late tracheostomy14. Tracheostomy is 347
only to be performed on strict indications and preferably not earlier than 10 days after 348
intubation. 349
Indications for tracheostomy are assumed: 350
• Failure to intubate; 351
• Expected duration of ventilation > 14 days; 352
• Glasgow Coma Score < 7 and/or inadequate swallow or cough reflex with 353
retention of sputum; 354
• Severe ICU–acquired weakness; 355
• Prolonged or unsuccessful weaning; 356
• Repeated respiratory failure after extubation. 357
Readiness for weaning with a tracheostomy follows the same criteria as those in 358
patients with an endotracheal tube. Although this is applied by a weaning schedule 359
for unassisted ventilation with a tracheostomy according to the local standard of the 360
participating centers. 361
362
5.3.3 Airway Care: 363
Endotracheal suction will be provided according to the local guidelines. Concomitant 364
normal saline installation will not be applied. 365
The choice of method of the inhaled air humidification is left to the discretion of the 366
participating center. Active humidification of the air inhaled will be supplied by the use 367
of an electrically powered humidifier. Passive humidification of the air inhaled will be 368
supplied by the use of a heat and moisture exchange (HME) filter. In case of a 369
(relative) contra-indication for passive humidification, such as lung edema, lung 370
bleeding or thick and tenacious secretions (Suzukawa classification13),active 371
humidification will be applied. Oral care consist of combining tooth brushing and 372
rinsing of the oral cavity every 6 hours. Head-of-bed elevation is pursued according 373
to the IHI ventilator bundle15, to prevent ventilator associated pneumonia. 374
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5.3.4 Sedation and comfort protocol: 376
Primary goals of sedation are patient comfort, i.e. to reduce agitation, discomfort and 377
pain, and to reduce oxygen consumption and physical resistance against daily care 378
and examination. Insufficient sedation is associated with discomfort, pain, agitation, 379
delirium and autodetubation16,17. In this matter, an analgo-sedative approach is 380
favored over hypno-sedation, and use of bolus is favored over continuous infusion of 381
sedating agents. Level of sedation will be determined using the Richmond Agitation 382
Sedation Scale (RASS) 18. Pain levels are monitored using the Numeric Rating Scale 383
(NRS), Visual Analogue Scale (VAS), Critical Care Pain Observation Tool (CCPOT) 384
or Behavorial Pain Scale (BPS) 19–21. 385
Delirium is assessed daily using a standardized tool i.e Confusion Assessment 386
Method for the ICU (CAM-ICU) or the Intensive Care Delirium Checklist Screening 387
(ICDCS) 22. 388
389
5.3.5 Fluid management: 390
Fluid management will be according to local guidelines. In general, patients are 391
resuscitated using saline solutions, targeting a urine output of 0.5 – 1.0 ml/kg/hr. After 392
the first 24 hours, fluid administration is dictated by clinical needs. Blood transfusions 393
and blood products will be provided if necessary following local guidelines of the 394
participating centers. 395
396
5.3.6 Nutrition 397
Nutrition management will be following local guidelines. Feeding will be started 398
immediately after admission to achieve an optimal nutritional balance, based on 399
nutritional status and BMI, with respect to sufficient protein and calorie intake. Enteral 400
feeding will be performed using a gastric feeding tube. If retention occurs persistently, 401
a postpyloric feeding tube will be provided. Enteral feeding is preferable to parenteral 402
feeding. 403
404
405
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406
6. INVESTIGATIONAL PRODUCT 407
408
6.1 Name and description of investigational products: 409
Acetylcysteine (a mucolytic): a registered inhalation solution for disorders of the 410
respiratory tract in which a reduction of the viscosity of the bronchial secretion is 411
required in order to facilitate expectoration and removal of the secretion, such as 412
bronchitis, emphysema, cystic fibrosis, and bronchiectasis 23 . 413
Salbutamol (a bronchodilator): a registered inhalation solution for treatment of 414
bronchospasms, exacerbations and routine maintenance therapy in asthma and 415
COPD24. 416
417
6.2 Summary of findings from non-clinical studies 418
Little research is published about the effectiveness and safety of nebulized 419
acetylcysteine. Despite in vitro mucolytic activity, there are no data demonstrating 420
that nebulized acetylcysteine is an effective therapy for any lung disease 25. 421
Significantly increased airway resistance, excessive airway secretions and 422
spontaneous cough where found after aerosol delivery of acetylcysteine (400mg 423
cumulative dose) through an endotracheal tube in six mechanical ventilated cats with 424
experimental induced asthma26. In addition in a rat model, administration of 425
acetylcysteine was found to attenuate the inflammatory responses, apoptosis and 426
ventilator induced lung injury27. Described observations of preclinical studies 427
suggested reductions of pulmonary edema and alveolar clearance in ADRS with 428
treatment of nebulized beta 2-agonists in rat models and ex vivo human lung tissue28. 429
430
6.3 Summary of findings from clinical studies 431
There are no data demonstrating that nebulized acetylcysteine is an effective therapy 432
for any lung disease25. Bronchodilator therapy is frequently administered in 433
mechanically ventilated ICU patients with the aim to resolve bronchoconstriction, 434
decrease work of breathing and relieve dyspnea. Beta-agonists enhance mucociliary 435
clearance in normal subjects, although this advantage seems to be diminished during 436
mechanical ventilation10. No significant differences were found in the number of 437
ventilator free days between patients with ARDS/ALI who received aerosolized 438
albuterol (salbutamol) versus placebo29. The assumption is that nebulisation of 439
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bronchodilators is often performed in spite of the absence of an obvious clinical 440
response in patients without asthma or COPD10,30–32 441
Nebulizing mucolytics and bronchodilators in mechanical ventilated patients carry the 442
risk of side-effects. First, mucolytic drugs have been reported to provoke 443
bronchoconstriction1. This risk can be reduced by pre-treatment with a 444
bronchodilator1. Nausea or vomiting may be provoked by the bad odor of 445
Acetylcysteine which is due to the release of hydrogen sulfide33,34. Other side effects 446
include urticarial, pruritis, stomatitis, rhinorroe, irritation of the airways and 447
hypersensitivity reactions, although frequencies of occurrence are not available22. 448
Second, nebulizing bronchodilators is associated with adverse effects on the 449
myocardium in COPD patients suffering from preexisting arrhythmias and 450
hypoxemia9. In a study in patients with ALI/ARDS who received albuterol, modest 451
elevated heart rates were found accompanied with a tendency towards more fluid 452
resuscitation. Evidence of serious adverse effects including arrhythmias have not 453
been demonstrated28. Other side effects of bronchodilators include, tremor, muscle 454
cramps, headache, tachycardia and palpitations7,23. In addition, nebulisation 455
interferes with the patient-ventilator interaction, which may lead to hypoventilation, 456
decreased oxygenation and anxiety6. 457
458
6.4 Summary of known and potential risks and benefits 459
Acetylcysteine reduces viscosity of mucus. A more liquid state of mucus may 460
facilitate aspiration of secretions with suction catheters, which may be useful in 461
intubated patients. Bronchodilators resolve bronchoconstriction, decrease work of 462
breathing and relieve dyspnea. However, there is actually no evidence that the use of 463
nebulized mucolytica and bronchodilators is useful in reducing the risk of tube 464
obstruction, the duration of mechanical ventilation, or the risk of ventilator associated 465
pneumonia. Nebulisation of acetylcysteine is associated with increased airway 466
resistance due to bronchoconstriction 1. Nebulisation of bronchodilators is associated 467
with systemic effects and could contribute to the generation of tachycardia, 468
tachyarrhythmias, tremor and agitation7,23. Additionally, nebulisation of aerosols in 469
general interferes with the patient-ventilator interaction, which may lead to 470
hypoventilation, decreased oxygenation and anxiety6. 471
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6.5 Description and justification of route of administration and dosage 472
Acetylcysteine and salbutamol will be nebulized using a jet nebulizer or a vibrating 473
mesh nebuliser, depending on local standard in the participating center. The 474
nebuliser is attached to the ventilator circuit with a T-piece adaptor. Jet nebilisers will 475
be operated with pressured gas or oxygen at a flow of 3-5 L/min or with an inline flow 476
synchronized with ventilator. The nebulizer will be placed in front of the Y-piece or 477
between the Y-piece and the circuit prior to the heated humidifier or HME filter. Each 478
nebulisation session lasts about 20 minutes. These two types of nebulisers were 479
chose since we want to study current nebulisation practice but avoid additional risks 480
by introducing a new procedure with potential serious outcomes. As a consequence 481
we decided that, although jet nebulizers are most commonly used for nebulizing 482
mucolytics and bronchodilators during mechanical ventilation, nebulising with a 483
vibrating mesh nebuliser is allowed in the participating centers were this is standard 484
practice. 485
486
6.6 Dosages, dosage modifications and method of administration 487
Nebulisation of mucolytics (acetylcysteine) and bronchodilators (salbutamol): a 3 mL-488
solution of acetylcysteine (fluimucil 100mg/ml)23 and a 2.5 mL solution of salbutamol 489
(Ventolin 2.5 Nebules 2.5mg/2.5 ml)24 will be nebulised using a jet nebuliser or 490
vibrating mesh nebuliser, which is attached to the ventilator circuit with a T-piece 491
adaptor. These dosages are currently used in Intensive Care practice. The jet 492
nebuliser will be operated with pressured gas at a flow of 3-5 L/min. The nebulizer 493
will be placed in front of the Y-piece or between the Y-piece and the circuit prior to 494
the heated humidifier or HME filter. Each nebulisation session lasts about 20 495
minutes. 496
497
6.7 Drug accountability 498
Flasks of acetylcysteine and salbutamol are provided by the pharmacy of the 499
participating center. Both agents are widely used and, therefore, are available in 500
each participating center. Since no placebo will be used, labeling of drugs is not 501
necessary. 502
503
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7. NON-INVESTIGATIONAL PRODUCT 504
7.1 Name and description of non-investigational product(s) 505
Not applicable. 506
507
7.2 Summary of findings from non-clinical studies 508
Not applicable. 509
510
7.3 Summary of findings from clinical studies 511
Not applicable. 512
513
7.4 Summary of known and potential risks and benefits 514
Not applicable. 515
516
7.5 Description and justification of route of administration and dosage 517
Not applicable. 518
519
7.6 Dosages, dosage modifications and method of administration 520
Not applicable. 521
522
7.7 Preparation and labelling of Non Investigational Medicinal Product 523
Not applicable. 524
525
7.8 Drug accountability 526
Not applicable. 527
528
529
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8. METHODS 530
531
8.1 Study parameters/endpoints 532
533
8.1.1 Main study parameter/endpoint 534
The primary endpoint is the number of ventilator-free days (VFDs), defined as the 535
number of days from day 1 to day 28 after ICU admission and start of mechanical 536
ventilation on which a patient breathes without assistance of the ventilator if the 537
period of unassisted breathing lasted at least 24 consecutive hours. Patients who die 538
or are mechanically ventilated longer than this period are assigned zero ventilator-539
free days. 540
541
8.1.2 Secondary study parameters/endpoints 542
The study will focus on the following secondary outcomes: 543
• Side effects of nebulisation of mucolytics and/or bronchodilators (due to 544
nebulisation itself, or as a result of exposure to the nebulized agents); 545
• ICU and hospital stay till day 90; 546
• ICU and hospital mortality; 547
• Incidence of secondary ARDS using consensus criteria35; 548
• Clinical defined ventilator-associated pneumonia according to the VAP criteria of 549
the CDC 2014 (see Appendix 1); 550
• Atelectasis (lung opacification on chest radiograph with shift of the mediastinum, 551
hilum, or hemidiaphragm towards the affected area, and compensatory over 552
inflation in the adjacent non-atelectatic lung); 553
• Health care related costs, including costs of ventilation, stay in ICU and/or 554
hospital, cumulative use of sedative drugs and neuromuscular blocking agents, 555
use of tracheostomies, and costs of ventilator-associated pneumonia. 556
557
8.2 Randomisation, blinding and treatment allocation 558
Patients will be randomly assigned in a 1:1 ratio to one of both nebulisation strategies 559
within 24 hours after intubation, after informed consent is signed by the patient or the 560
patient’s legal representative. Randomization will be performed using a dedicated, 561
password protected, SSL-encrypted website. Randomization sequence is generated 562
by a dedicated computer randomization software program using random block sizes 563
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and is stratified per center. Due to the nature of the intervention blinding of the 564
caregivers is not possible. Data analysis will be performed blinded for the type of 565
intervention. 566
567
8.3 Study procedures 568
Patients will be randomly assigned, after written informed consent is obtained, in a 569
1:1 ratio to one of the following two nebulisation strategies: 570
571
1. Routine nebulisation: Nebulisation of mucolytics and bronchodilators, administered 572
every 6 hours (i.e., 4 times per day) within 24 hours after initiation of ventilation 573
continuing until tracheal extubation. 574
575 2. Nebulisation on clinical indication only: Nebulisation is performed incidentally in 576
case of a clinical indication according to the same procedure applied in the routine 577
nebulisation group. Clinical indications are defined as: 578
• Occurrence of persistent thick and tenacious secretions following the Suzakawa 579
criteria13 (for which nebulisation of mucolytics can be started) and only after active 580
humidification of the ventilator circuit is set. 581
• Occurrence of bronchospasm (for which nebulisation of bronchodilators can be 582
started) and only when signs and symptoms of bronchospasm (wheezing, 583
increased airway pressures, increasing airway resistance, up sloping curve of de 584
end tidal CO2 monitoring) are confirmed. 585
The decision to nebulize mucolytics and/or bronchodilators is to be made on a daily 586
basis by the attending ICU–physician. As soon as the clinical indication no longer 587
exists, the therapy should be stopped (appendix 3). 588
589 8.4 Data to be collected 590
An overview of the type and timing of data to be collected is given in Appendix 2. 591
592
8.4.1 On admission and on the ICU: 593
• gender and age 594
• height and weight 595
• reason for ICU admission 596
• reason for ventilation 597
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• cause of respiratory failure 598
• APACHE II score and SAPS II 599
• Comorbidity (heartfailure, arrhythmia, pulmonic comorbidity, immune status) 600
• Substance abuse 601
• Non-invasive ventilation at home 602
• Treatment limitation at admission to ICU 603
604
8.4.2 Baseline parameters 1 hour after intubation: 605
• Mechanical ventilation parameters: 606
- tube size; 607
- tidal volume; 608
- respiratory rate (breath/minute); 609
- level of positive end– expiratory pressure; 610
- peak and plateau pressures, or level of pressure support (level above PEEP, 611
and maximal airway pressure, cmH2O); 612
- inspiration to expiration ratio; 613
- inspired oxygen fraction; 614
- minute volume (liters/minute); 615
- pulmonary compliance; 616
- Lung Injury Score 36 and Oxygenation Index37 617
• Respiratory parameters: 618
- peripheral oxygen saturation (%); 619
- end–tidal fractions of CO2; PaO2; PaCO2; arterial bicarbonate; 620
- arterial pH: arterial base excess. 621
• Chest ray (if available) 622
• Non respiratory parameters 623
- Heart rate, mean arterial pressure, central venous pressure 624
- Laboratory (if available): Hemoglobin, leukocytes, Potassium 625
626
8.4.3 Daily from day 1 till detubation* 627
• Mechanical ventilation parameters: 628
- tube size; 629
- tidal volume; 630
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- respiratory rate (breath/minute); 631
- level of positive end– expiratory pressure; 632
- peak and plateau pressures, or level of pressure support (level above PEEP, 633
and maximal airway pressure, cmH2O); 634
- inspiration to expiration ratio; 635
- inspired oxygen fraction; 636
- minute volume (liters/minute); 637
- pulmonary compliance; 638
- Lung Injury Score 36 and Oxygenation Index37 639
• Respiratory parameters: 640
- peripheral oxygen saturation (%); 641
- end–tidal fractions of CO2; PaO2; PaCO2; arterial bicarbonate; 642
- arterial pH: arterial base excess. 643
• Chest ray (if available) 644
• Respiratory status 645
- intubation status 646
- tracheostomy status 647
- invasiveness of ventilation (invasive, non–invasive, intermittent via 648
tracheostomy) 649
- Type of airway humidification (passive, active) 650
• Endo tracheal suctioning 651
• Cumulative endotracheal suction procedures 652
• Consistency of tracheal aspirate13 653
• Sputum culture (if available) 654
• Non respiratory parameters 655
• Heart rate, mean arterial pressure, central venous pressure 656
• Laboratory (if available): Hemoglobin, leukocytes, Potassium 657
• Location of patient (in ICU, hospital, other facility, or home) 658
• Life status (alive or deceased and cause of dead) 659
• Non-respiratory parameters: 660
- cumulative fluid balance (ml); 661
- cumulative urine output (ml); 662
- Sequential Organ Failure Assessment score (SOFA) score38; 663
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- blood transfusions (type and ml); 664
- infusion of (artificial) colloids (type and ml); 665
- extra pulmonic infection, sepsis, re-operation, cardiac arrest 666
• Pulmonary complications: 667
- presence of ARDS (yes or no; derived from other data), 668
- pneumonia (yes or no; derived from other data), 669
- atelectases (yes or no; derived from other data) 670
• Cumulative use of nebulized 671
- acetylcysteine 672
- salbutamol 673
- other medication 674
• Mode of nebulisation (with pressured gas from an external source or 675
synchronized with inspiratory airflow from the ventilator) 676
• Cumulative use and duration of 677
- Sedatives 678
- analgetics 679
- neuromuscular blocking agents 680
• Side-effects associated with: 681
- nebulisation 682
- the administration of acetylcysteine 683
- the administration of salbutamol 684
• Tube obstruction: 685
- A CT scan of the endotracheal tube will be performed to assess tube 686
obstruction. 687
688
8.4.4 Data collected daily from extubation* till discharge from the hospital: 689
• Location of patient (ICU, hospital ward) 690
• Life status (alive or deceased and cause of dead) 691
692
*in patients with a tracheostomy, detubation is defined as the moment when a 693
patient has been free from the ventilator for at least 24 hours. 694
695
8.4.5 Data collected at day 90 of follow up: 696
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• Location of patient (in ICU, hospital, other facility, or home) 697
• Life status (alive or deceased and cause of dead) 698
699
8.4.6 Data to be collected for the economic evaluation 700
The economic evaluation incorporates health care costs that will be estimated from a 701
health system perspective over the time horizon of this study. Costs will be 702
determined for both intervention groups during a 28-days follow-up period after initial 703
ICU admission. The costs of medical care will be calculated, divided into direct 704
medical and direct non-medical and indirect costs, if applicable. The direct costs 705
include the costs of (a) ventilation and (b) stay in ICU and/or hospital; (c) costs of 706
cumulative use of sedatives, and (e) neuromuscular blocking agents, (f) the use of 707
tracheostomies, and (g) ventilator-associated pneumonia. 708
709
8.5 Withdrawal of individual subjects 710
Subjects can leave the study at any time for any reason if they wish to do so without 711
any consequences. The investigator can decide to withdraw a subject from the study 712
for urgent medical reasons. 713
714
8.5.1 Specific criteria for withdrawal 715
A specific reason for withdrawal of a participating patient is translocation of the 716
patient to another hospital that does not participate in this study before discharge 717
from the ICU. If the patient is transferred to another hospital after discharge from the 718
ICU there is no reason for withdrawal. 719
720
8.6 Replacement of individual subjects after withdrawal 721
Subjects who are withdrawn from the study will not be replaced. In the sample size 722
calculation a dropout rate of 5% has been taken into account. Analysis will be 723
according to the intention-to-treat principle. 724
725
8.7 Follow-up of subjects withdrawn from treatment 726
Reason for withdrawal from nebulisation will be recorded and follow up of subjects 727
will be continued. 728
729
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8.8 Premature termination of the study 730
A concern regarding safety could be the occurrence of occlusion of the endotracheal 731
tube due to less administration of mucolytica. To date, data on side effects of 732
nebulisation of mucolytica and bronchodilators are limited. For mucolytica, 733
bronchospasms are a well-known side effect. Arrhythmia may be of major concern in 734
the administration of bronchodilators. An independent Data Safety Monitoring Board 735
(DSMB) will monitor the study on safety aspects and if necessary recommend 736
termination of the study. 737
738
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739
9. SAFETY REPORTING 740
741
9.1 Section 10 WMO event 742
In accordance to section 10, subsection 1, of the WMO, the investigator will inform 743
the subjects and the reviewing accredited METC if anything occurs, on the basis of 744
which it appears that the disadvantages of participation may be significantly greater 745
than was foreseen in the research proposal. The study will be suspended pending 746
further review by the accredited METC, except insofar as suspension would 747
jeopardize the subjects’ health. The investigator will take care that all subjects are 748
kept informed. 749
750
9.2 AEs, and SAEs 751
752
9.2.1 Adverse events (AEs) 753
Adverse events are defined as any undesirable experience occurring to a subject 754
during the study, whether or not considered related to the investigational intervention 755
judged by the attending ICU physician. All adverse events reported spontaneously by 756
the subject or observed by the investigator or his staff will be recorded. 757
758
The investigator will appreciate the severity of an event and give his opinion on 759
whether the event is related or not to the study procedures. The investigator will use 760
clinical judgement to determine the relationship. Alternative causes, such as natural 761
history of the underlying diseases, medical history, concurrent conditions, 762
concomitant therapy, other risk factors, and the temporal relationship of the event to 763
the study procedures will be considered and investigated. 764
765
Adverse events that are considered related to the study procedures include, but are 766
not limited to, development of bronchospasm, dyspnea, development of hypoxemia, 767
hypercapnia and the development of tachycardia, tachyarrhythmia. 768
769
9.2.2 Serious adverse events (SAEs) 770
A serious adverse event is any untoward medical occurrence or effect that: 771 • results in death; 772
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• is life threatening (at the time of the event); 773
• requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 774
• results in persistent or significant disability or incapacity; 775
• Any other important medical event that may not result in death, be life-776
threatening, or require hospitalization, may be considered a serious adverse 777
experience when, based upon appropriate medical judgement, the event may 778
jeopardize the subject or may require an intervention to prevent one of the 779
outcomes listed above. 780
781
SAEs, that are considered related to study procedures, include, but are not limited to, 782
development of ventilator-associated pneumonia, development of ARDS, new onset 783
ventricular tachyarrhythmia with hemodynamic instability wherefore an intervention is 784
indicated and the development of endotracheal tube occlusion. SAEs considered 785
(possibly) to be related to a study procedure will be reported by the Coordinating PI 786
to the CCMO and central METC using the CCMO module “ToetsingOnline”. The 787
reporting will occur within 15 days after the investigator has first received information 788
on the SAE. For fatal of life-threatening cases a preliminary report will be offered 789
within 7 days followed by a complete report within 8 days. 790
The local site investigator is responsible to report a SAE within 24 hours of the first 791
knowledge of the event to the Coordinating PI. 792
793
SAEs that are considered unrelated to a study procedure by the PI, will be recorded 794
and reported in an overview list (line-listing) that will be submitted once every half 795
year to the METC. 796
797
Documentation 798 799 All adverse events have to be documented in the participant’s chart and in the CRF. 800
Cases of misuse, or deviations in the administration of the study intervention have to 801
be documented even when there is no adverse event. In case the AE results in a 802
persistent disease, the AE has to be classified as a SAE and to be documented at 803
the end of the trial. 804
805
806
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807
808
9.3 Follow-up of adverse events 809
All AEs will be followed until they have abated, or until a stable situation has been 810
reached. Depending on the event, follow up may require additional tests or medical 811
procedures as indicated, and/or referral to the general physician or a medical 812
specialist. SAEs need to be reported till end of study within the Netherlands, as 813
defined in the protocol. 814
815
9.4 Data Safety Monitoring Board (DSMB) 816
An DSMB will be installed to monitor safety parameters and the overall conduct of 817
the study. The DSMB consists of 3 experts of critical care and mechanical ventilated 818
patients, one of them will be the chairman. They will be supported by an independent 819
statistician experienced in the statistical methods for clinical research. 820
The composition, tasks, responsibilities, and working procedures of the DSMB are 821
elaborated in the DSMB Charter (K5. DSMB charter Nebulae versie 2, d.d. 28-07-822
2014), which is attached. 823
Following each DSMB meeting, the DSMB will send a confidential report to the 824
Principal Investigator of each meeting. The report does not include unblinded data 825
and contains sufficient information to explain the rationale behind any specific 826
recommendation by the DSMB. Should the Coordinating PI decide not to fully 827
implement the advice of the DSMB, the Coordinating PI will send the advice to the 828
reviewing METC, including a note to substantiate why (part of) the advice of the 829
DSMB will not be follow. 830
831
832
833
834
835
836
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837 10. STATISTICAL ANALYSIS 838
839
10.1 General considerations 840
All analyses will be performed according to the intention-to-treat principle. In addition, 841
per protocol analyses will be done to check for robustness of results, considering the 842
trial being a non-inferiority trial. The intention-to-treat analysis considers all patients 843
as randomized regardless of whether they received the randomized treatment, The 844
“per protocol” group considers only those patients who complete the treatment 845
according to the originally allocated protocol. In this non-inferiority trial we include a 846
hierarchical, superiority, primary efficacy analysis. If the non-inferiority criterion is 847
satisfied, a secondary analysis for superiority for the primary endpoint will be 848
conducted. When appropriate, statistical uncertainty will be expressed by the 95% 849
confidence levels. All statistical analyses will be performed with the R language and 850
environment for statistical computing39. 851
10.2 Primary study parameter(s) 852
853
The main analysis will compare the number of ventilator free days between the two 854
treatment groups to evaluate the non-inferiority hypothesis. The null hypothesis 855
entails that the nebulisation on indication group is inferior by a margin of 10%to the 856
routine nebulisation group. If the 95% CI upper bound for inferiority of the nebulized-857
on-indication group is < 10%, the null hypothesis of inferiority is rejected. If the non-858
inferiority criterion is satisfied, then superiority for the primary endpoint, the number 859
of ventilator free days will be tested. 860
861
In addition to the parametric analysis (t-test) of the normalized log data of the mean 862
duration from the ventilator free days between the two groups, we will use a 863
nonparametric analysis method to test the confidence interval of the difference 864
between the two medians of the ventilator free days from both groups. 865
866
Additionally, time to freedom from mechanical ventilation is expressed with 867
Kaplan-Meier curves. Differences between groups will be tested by the log-rank test. 868
As this is a RCT, we expect that randomization in this study population will 869
sufficiently balance patients’ baseline characteristics. However if imbalances occur 870
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between groups, a Cox proportional hazard model will be used and adjusted 871
accordingly. The effect of nebulisation on the primary outcome will be investigated in 872
pre-specified subgroups based on humidification method (active or passive), type of 873
nebuliser (jet nebuliser or vibrating mesh) and type of flow used for nebulisation 874
(continues with external source or breath synchronised with an inline flow from the 875
ventilator). 876
877
10.3 Secondary study parameters 878
Continuous normally distributed variables will be expressed by their mean and 879
standard deviation or when not normally distributed as medians and their 880
interquartile ranges. Categorical variables will be expressed as counts (n) and 881
percentages (%). To analyze differences in continuous variables between groups the 882
two test groups Students's t test will be used, or in case continuous data is not 883
normally distributed, the Mann-Withney U test will be used. Categorical variables will 884
be compared with the Chi-square test or Fisher's exact tests. The ICU mortality, 885
hospital mortality, the length of ICU stay, and the length of hospital stay will be 886
expressed with Kaplan-Meier curves. 887
888
10.4 Interim analysis 889
An interim analysis for safety will be performed after the first one third (317) and two 890
thirds (634) of the study population, respectively are included and have completed 891
follow up for the primary outcome. The main concern is the occurrence of tube 892
related incidents in the non-nebulized group, development of ventilator associated 893
pneumonia in the nebulisation group. Serious adverse events (SAEs) such as death, 894
ventilator associated pneumonia, ARDS, new onset ventricular tachyarrhythmia with 895
hemodynamic instability wherefore an intervention is indicated or tube occlusion that 896
are possibly related to study intervention will be compared. 897
898
10.5 Economic Evaluation 899
Alongside the proposed RCT a prospective economic study will be performed. The 900
main question in the economic evaluation is whether the costs of preventive 901
nebulisation are justified by their beneficial effects compared to nebulisation only on 902
strict indication. Based on a non-inferior assumption we expect no differences in 903
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outcomes. Therefore this prospective cost study is set-up as a cost-benefit analysis 904
(CBA). 905
906
Cost Benefit Analysis 907
The cost benefit analysis (CBA) incorporates health care costs that will be estimated 908
from a health system perspective over the time horizon of this study. In this economic 909
evaluation costs will be determined for both intervention groups during a 28-days 910
follow-up period after initial ICU admission and start of mechanical ventilation. The 911
costs of medical care will be calculated, divided into direct medical and direct non-912
medical and indirect costs if applicable. Costs are defined as the volumes of used 913
resources multiplied by calculated unit prices. No discounting of costs and effects will 914
be applied. Although if any difference of interest in primary and/or secondary 915
outcomes is observed, registered resource use and related costs will be compared 916
between both intervention groups. In addition a cost-effectiveness analysis, to 917
calculate incremental cost ratio’s (ICER) will be performed. 918
919
Cost analysis 920
In this economic evaluation costs associated with 28-days follow-up will be 921
prospectively determined for 950 intubated and ventilated ICU patients included in 922
both study groups. Cost-calculations will be set up to reflect a hospital perspective 923
and will be based on actual resource use in routine care. The direct costs of follow-up 924
of the study population include the costs of (a) ventilation and (b) stay in ICU and/or 925
hospital; (c) costs of cumulative use of sedatives, and (e) neuromuscular blocking 926
agents, (f) the use of tracheostomies, and and (g) ventilator-associated pneumonia. 927
Initially costs will be estimated for the short term (1 year). Additional costs as a result 928
of co-morbid conditions will be excluded. 929
Costs are defined as the volumes of used resources multiplied by calculated unit 930
prices. Unit costs, if available, of used resources will be determined based on 931
standard current Dutch costing guidelines40 and market prices. Data on resources 932
used are collected from the hospital information system (with continuous registration), 933
the case record form (CRF) and financial reports. Protocol driven costs will be 934
excluded from the calculations. 935
936
Budget Impact Analysis (BIA): 937
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Next to the economic evaluation a budget impact analysis (BIA) will be performed 938
according to the ISPOR Task Force principles40,41. The purpose of this BIA is to 939
estimate the financial impact of the adoption of nebulisation on strict clinical indication 940
at the national level in the future. The analysis will be based on the decrease in ICU 941
costs of not applying nebulisation in ventilated assisted patients as estimated during 942
the study, and the expected number of patients eligible for this treatment in the 943
Netherlands. Overall costs of the treatment, side effects and other consequences of 944
both interventions (e.g. follow-up treatment) will be included in the BIA. These 945
registered data reflect the eligible ICU population. The BIA will be conducted from the 946
perspective of the different health care payers (i.e. health care providers: the 947
hospital). The following scenarios will be compared: (a) the intervention change is not 948
yet implemented, (b) the intervention change is implemented in 100% of the target 949
group, (c) the intervention change is gradually introduced over a period of two years. 950
Sensitivity analyses will be performed on the price of the intervention and the 951
diffusion rate from the hospital perspective. Factors that determine the budget impact 952
will be determined (clinical outcomes and costs). 953
954
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955 11. ETHICAL CONSIDERATIONS 956
11.1 Regulation statement 957
The study will be conducted according to the principles of the Declaration of Helsinki 958
(Forteleza, 2013) and in accordance with the Medical Research Involving Human 959
Subjects Act (WMO), Good Clinical Practice Guidelines (ICH-GCP) and with local 960
guidelines. 961
962
11.2 Recruitment and consent 963
Consecutive intubated and ventilated ICU patients with an anticipated duration of 964
ventilation > 24 hours will be screened whether they meet the inclusion criteria. 965
Patients will be recruited by the executive investigator or the attending ICU-966
physician. If the patient is awake and able to judge about his or her situation 967
properly, information is provided and written informed consent is asked and signed 968
by the patient within 24 hours after intubation. If a patient is not able to judge about 969
his or her situation properly, information is provided to the legal representative and 970
written informed consent is asked and signed by the legal representative within 24 971
hours after intubation. A second informed consent is asked from the patient in 972
retrospect, at the moment the patient is awake and able to judge about his or her 973
situation properly. Information on the study is then provided and written informed 974
consent is asked and signed by both the executive investigator and the patient. If a 975
patient declines consent, all collected study data on this patient will be destroyed. 976
977
11.3 Benefits and risks assessment, group relatedness 978
Both nebulisation strategies of mucolytics and bronchodilators are frequently used 979
therapies in Intensive Care Units nationwide. Benefits and risks of both strategies are 980
uncertain. Since the nebulisation procedures are the same as those in current 981
standard practice and no additional investigations or intervention will be 982
administered, the study does not pose an extra burden on patients. The risks of the 983
patients in the routine nebulisation group include possible occurrence of adverse 984
reactions due to nebulisation of mucolytics and bronchodilators. These risks are the 985
same as in current standard clinical practice. Patients randomized to the 986
‘nebulisation on indication only’ group will be less exposed to the possible adverse 987
reactions of nebulisation itself or the drugs nebulized. The risks of the patients in the 988
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only on indication nebulisation group include possible occurrence of tube occlusion. 989
However, the nebulisation treatment will not be withheld if a clinical indication is 990
present. 991
Patients needing mechanical ventilation are often considered incapacitated due 992
to their severe illness. Since the strategies to compare in this study are only used in 993
severely ill mechanical ventilated patients, we consider it inevitable to include these 994
patients. 995
996
11.4 Compensation for injury 997
In this study two standard treatment strategies will be compared. As a consequence 998
there are no additional risks of participation in this study. Therefore, exemption of 999
insurance for additional harm was granted by the Medical Ethical Research 1000
Committee of the Academic Medical Center for participants in this study. A liability 1001
insurance will be present in every participating center. 1002
1003
11.5 Incentives 1004
Enrolled patients will not receive any special incentives, compensation or treatment 1005
through participation in this trial. 1006
1007
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1008 12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 1009
12.1 Handling and storage of data and documents 1010
Data will be handled confidentially and anonymously. To ensure data security and to 1011
protect the subjects privacy, data on individual subjects will be encoded according to 1012
a subject identification code list. Patient data will be entered by way of an eCRF in a 1013
central GCP proof internet based database to facilitate on-site data-entry. All patients 1014
will be addressed to the interventions with a random patient identification code. 1015
Security is guaranteed with login names, login codes and encrypted data transfer. 1016
The executive investigator safeguards the code and has access to the source data at 1017
any time. All other investigators will have access to source data as well. When 1018
necessary for monitoring of the study, access will be granted to the Health Inspectors 1019
of the Dutch Government (Inspectie voor de Gezondheidzorg) and the members of 1020
the sponsors of this study; the Academic Medical Center in case of an internal audit. 1021
Data will be stored in a secure place during a period of 20 years, in the archives of 1022
the Academic Medical Center, Amsterdam. 1023
1024
12.2 Monitoring and Quality Assurance 1025
The study will be monitored according to ICH-GCP guidelines throughout its duration 1026
by a GCP-certified monitor according to the Monitoring Plan (K6. Monitoringplan 1027
Nebulae, versie 1). 1028
On-site monitoring will be conducted to evaluate the progress of the study, ensure 1029
the rights and wellbeing of the subjects are protected, check that the reported clinical 1030
study data are accurate, complete and verifiable from source documents, and the 1031
conduct of the study is in compliance with the approved protocol and amendments, 1032
GCP and applicable national regulatory requirements. A monitoring visit will include a 1033
review of the essential clinical study documents as well as discussion on the conduct 1034
of the study with the investigator and staff. Every participating center will be visited 1035
at least once every year. 1036
1037
12.3 Amendments 1038
Amendments are changes made to the research after a favorable opinion by the 1039
accredited METC has been given. All amendments will be notified to the METC that 1040
gave a favorable opinion. 1041
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A ‘substantial amendment’ is defined as an amendment to the terms of the METC 1042
application, or to the protocol or any other supporting documentation, that is likely to 1043
affect to a significant degree: 1044
• the safety or physical or mental integrity of the subjects of the trial; 1045
• the scientific value of the trial; 1046
• the conduct or management of the trial; or 1047
• the quality or safety of any intervention used in the trial. 1048
All substantial amendments will be notified to the METC and to the competent 1049
authority. 1050
Non-substantial amendments will not be notified to the accredited METC and the 1051
competent authority, but will be recorded and filed by the sponsor. 1052
1053
12.4 Annual progress report 1054
The investigator will submit a summary of the progress of the trial to the accredited 1055
METC once a year. Information will be provided on the date of inclusion of the first 1056
subject, numbers of subjects included and numbers of subjects that have completed 1057
the trial, serious adverse events, other problems, and amendments. 1058
1059
12.5 End of study report 1060
The investigator will notify the accredited METC of the end of the study within a 1061
period of 8 weeks. The end of the study is defined as the last patient’s last visit. In 1062
case the study is ended prematurely, the investigator will notify the accredited METC 1063
within 15 days, including the reasons for the premature termination. Within one year 1064
after the end of the study, the investigator will submit a final study report with the 1065
results of the study, including any publications/abstracts of the study to the 1066
accredited METC. 1067
1068
12.6 Public disclosure and publication policy 1069
The study protocol and analysis plan will be published before start of the study on 1070
Clinicaltrials.gov and trialregister.nl. The results of the study will find their way into 1071
(inter-)national scientific journals and guidelines. We will submit analyses to scientific 1072
journals in the field of intensive care medicine as well as anesthesiology, since both 1073
ICU physicians and anesthesiologists apply ventilation in the ICU setting.1074
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1075
13. STRUCTURED RISK ANALYSIS 1076
13.1 Synthesis 1077
Nebulisation solution for both acetylcysteine and salbutamol are registered in The 1078
Netherlands for disorders of the respiratory tract. In this study both drugs will only be 1079
applied within this indication. Standard ICU care will be provided in both groups and 1080
procedures will be performed by experienced trained ICU physicians and nurses. An 1081
independent Data Safety Management Board (DSMB) will be installed to monitor 1082
safety parameters and the overall conduct of the study. 1083
1084
1085
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1086
14. REFERENCES 1087
1. Zandstra DF, Stoutenbeek CP, Miranda DR, Care I. Effect of mucolytic and 1088 bronchodilator aerosol therapy on airway resistance in mechanically ventilated 1089 patients. Intensive Care Med. 1985;11:316–318. 1090
2. Grivans C, Lindgren S, Aneman a, Stenqvist O, Lundin S. A Scandinavian survey of 1091 drug administration through inhalation, suctioning and recruitment maneuvers in 1092 mechanically ventilated patients. Acta Anaesthesiol Scand. 2009;53(6):710–6. 1093 doi:10.1111/j.1399-6576.2009.01957.x. 1094
3. Jelic S, Cunningham JA, Factor P. Clinical review: airway hygiene in the intensive care 1095 unit. Crit Care. 2008;12:209. doi:10.1186/cc6830. 1096
4. Houtmeyers E, Gosselink R, Decramer M. SERIES “ CHEST PHYSIOTHERAPY ” 1097 Effects of drugs on mucus clearance. 1999;(1):452–467. 1098
5. Kollef MH, Von Harz B, Prentice D, et al. Patient transport from intensive care 1099 increases the risk of developing ventilator-associated pneumonia. Chest. 1100 1997;112:765–773. doi:10.1378/chest.112.3.765. 1101
6. Beaty CD, Ritz RH, Benson MS. Continuous in-line nebulizers complicate pressure 1102 support ventilation. Chest 96, 1360–1363 (1989). doi:10.1378/chest.96.6.1360. 1103
7. Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and Therapeutics of 1104 Bronchodilators. Pharmacol Rev. 2012;64:450–504. doi:10.1124/pr.111.004580. 1105
8. Nelson HS, Gross NJ, Levine B, Kerwin EM, Rinehart M, Denis-Mize K. Cardiac safety 1106 profile of nebulized formoterol in adults with COPD: a 12-week, multicenter, 1107 randomized, double- blind, double-dummy, placebo- and active-controlled trial. Clin 1108 Ther. 2007;29:2167–2178. doi:10.1016/j.clinthera.2007.10.007. 1109
9. Cazzola M, Imperatore F, Salzillo A, et al. Cardiac effects of formoterol and salmeterol 1110 in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia.; 1111 1998:411–415. doi:10.1378/chest.114.2.411. 1112
10. Chang LH, Honiden S, Haithcock JA, et al. Utilization of bronchodilators in ventilated 1113 patients without obstructive airways disease. Respir Care. 2007;52:154–158. 1114
11. Hodgson CL, Berney S, Harrold M, Saxena M, Bellomo R. Clinical review: Early 1115 patient mobilization in the ICU. Crit Care. 2013;17:207. doi:10.1186/cc11820. 1116
12. Ruokonen E, Parviainen I, Jakob SM, et al. Dexmedetomidine versus 1117 propofol/midazolam for long-term sedation during mechanical ventilation. Intensive 1118 Care Med. 2009;35:282–290. doi:10.1007/s00134-008-1296-0. 1119
13. Suzukawa M, Usada Y NK. The effect of sputum characteristics of combining an 1120 unheated humidifier with a heat-moisture exchanging filter. Resp Care. 1989;34::976–1121 84. 1122
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14. Young D, Harrison DA, Cuthbertson BH, Rowan K. Effect of early vs late tracheostomy 1123 placement on survival in patients receiving mechanical ventilation: the TracMan 1124 randomized trial. JAMA. 2013;309:2121–9. doi:10.1001/jama.2013.5154. 1125
15. Narang S. Use of ventilator bundle to prevent ventilator associated pneumonia. Oman 1126 Med J. 2008;23(2):96–9. Available at: 1127 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3282421&tool=pmcentrez&r1128 endertype=abstract. 1129
16. Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients 1130 receiving mechanical ventilation: a randomised trial. Lancet. 2010;375(9713):475–80. 1131 doi:10.1016/S0140-6736(09)62072-9. 1132
17. Jacobi J, Fraser GL, Coursin DB, et al. analgesics in the critically ill adult. 1133 2002;30(1):119–141. 1134
18. Honiden S, Siegel MD. Analytic reviews: managing the agitated patient in the ICU: 1135 sedation, analgesia, and neuromuscular blockade. J Intensive Care Med. 1136 2010;25(4):187–204. doi:10.1177/0885066610366923. 1137
19. Gélinas C, Fillion L, Puntillo K a, Viens C, Fortier M. Validation of the critical-care pain 1138 observation tool in adult patients. Am J Crit Care. 2006;15(4):420–7. Available at: 1139 http://www.ncbi.nlm.nih.gov/pubmed/16823021. 1140
20. Gélinas C, Fortier M, Viens C, Fillion L, Puntillo K. P AIN A SSESSMENT AND M 1141 ANAGEMENT IN C RITICALLY. 2004;(800):126–136. 1142
21. Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill sedated patients by 1143 using a behavioral pain scale. Crit Care Med. 2001;29(12):2258–63. Available at: 1144 http://www.ncbi.nlm.nih.gov/pubmed/19697008. 1145
22. Plaschke K, von Haken R, Scholz M, et al. Comparison of the confusion assessment 1146 method for the intensive care unit (CAM-ICU) with the Intensive Care Delirium 1147 Screening Checklist (ICDSC) for delirium in critical care patients gives high agreement 1148 rate(s). Intensive Care Med. 2008;34(3):431–6. doi:10.1007/s00134-007-0920-8. 1149
23. CBG. Fluimucil 100mg/ml http://db.cbg-meb.nl/IB-teksten/h06742.pdf. :1–4. 1150
24. CBG. Ventolin 2.5 Nebules http://db.cbg-meb.nl/IB-teksten/h12587.pdf. :3–10. 1151
25. Decramer M, Rutten-van Mölken M, Dekhuijzen PNR, et al. Effects of N-acetylcysteine 1152 on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on 1153 NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 1154 2005;365(9470):1552–60. doi:10.1016/S0140-6736(05)66456-2. 1155
26. Reinero CR, Lee-Fowler TM, Dodam JR, Cohn LA, DeClue AE, Guntur VP. 1156 Endotracheal nebulization of N-acetylcysteine increases airway resistance in cats with 1157 experimental asthma. J Feline Med Surg. 2011;13:69–73. 1158 doi:10.1016/j.jfms.2010.09.010. 1159
27. Chiang C-H, Chuang C-H, Liu S-L, Chian C-F, Zhang H, Ryu JH. N-acetylcysteine 1160 attenuates ventilator-induced lung injury in an isolated and perfused rat lung model. 1161 Injury. 2012;43(8):1257–63. doi:10.1016/j.injury.2011.12.026. 1162
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28. Zingarelli B. Ethyl pyruvate: A simple solution?*. Crit Care Med. 2004;32(7):1603–1163 1604. doi:10.1097/01.CCM.0000130819.84296.93. 1164
29. Matthay M a, Brower RG, Carson S, et al. Randomized, placebo-controlled clinical trial 1165 of an aerosolized β₂-agonist for treatment of acute lung injury. Am J Respir Crit Care 1166 Med. 2011;184(5):561–8. doi:10.1164/rccm.201012-2090OC. 1167
30. Dhand R. Inhalation therapy with metered-dose inhalers and dry powder inhalers in 1168 mechanically ventilated patients. Respir Care. 2005;50:1331–1334; discussion 1344–1169 1345. 1170
31. Dhand R, Tobin MJ. Bronchodilator delivery with metered-dose inhalers in 1171 mechanically-ventilated patients. Eur Respir J. 1996;9(3):585–595. 1172 doi:10.1183/09031936.96.09030585. 1173
32. Holland A, Smith F, Penny K, Mccrossan G, Veitch L, Nicholson C. Metered dose 1174 inhalers versus nebulizers for aerosol bronchodilator delivery for adult patients 1175 receiving mechanical ventilation in critical care units ( Review ) SUMMARY OF 1176 FINDINGS FOR THE MAIN COMPARISON. 2013;(6). 1177
33. Kory RC, Hirsch SR, Giraldo J. Nebulization of N-acetylcysteine combined with a 1178 bronchodilator in patients with chronic bronchitis. A controlled study. Dis Chest. 1179 1968;54(6):504–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/4881157. 1180
34. Henke MO, Ratjen F. Mucolytics in cystic fibrosis. Paediatr Respir Rev. 2007;8(1):24–1181 9. doi:10.1016/j.prrv.2007.02.009. 1182
35. Ferguson ND, Fan E, Camporota L, et al. Erratum to: The Berlin definition of ARDS: 1183 an expanded rationale, justification, and supplementary material. Intensive Care Med. 1184 2012;38:1731–1732. doi:10.1007/s00134-012-2698-6. 1185
36. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult 1186 respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–723. 1187 doi:10.1164/ajrccm/138.3.720. 1188
37. Ortiz RM, Cilley RE BR. Extracorporeal membrane oxygenation in pediatric respiratory 1189 failure. Pediatr Clin North Am. 1987;34:39–46. 1190
38. Vincent J-L, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the 1191 incidence of organ dysfunction/failure in intensive care units. Crit Care Med. 1192 1998;26:1793–1800. doi:10.1097/00003246-199811000-00016. 1193
39. R Development Core Team. R: A language and environment for statistical computing. 1194 R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL 1195 http://www.R-project.org/. R Found Stat Comput Vienna, Austria. 2012. 1196
40. Tan SS, Hakkaart-van Roijen L, Al MJ, et al. A microcosting study of intensive care 1197 unit stay in the Netherlands. J Intensive Care Med. 2008;23(4):250–7. 1198 doi:10.1177/0885066608318661. 1199
41. Mauskopf JA, Sullivan SD, Annemans L, et al. Principles of good practice for budget 1200 impact analysis: report of the ISPOR Task Force on good research practices--budget 1201
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impact analysis. Value Heal. 2007;10:336–347. doi:VHE187 [pii]\n10.1111/j.1524-1202 4733.2007.00187.x [doi]. 1203
1204
1205 Appendix 1. 1206 1207 CDC criteria for Clinically defined Ventilator Associated Pneumonia (2014) One or more serial X-rays with one of the following (two or more serial X-rays in patients
with underlying disease): - New or progressive and persistent infiltrate - Consolidation - Cavitation - Pneumatoceles, in ≤1 y.o. AND At least one of the following: - Fever (>38°C/100.4°F) - Leukopenia (<4,000 WBC/mm³) OR leukocytosis (>12,000 WBC/mm³) - Altered mental status with no other cause, in >70 y.o. AND
At least two of the following: - New onset of purulent sputum OR change in character of sputum OR ↑respiratory secretions OR ↑suctioning requirements - New onset or worsening cough OR dyspnea OR tachypnea - Rales OR bronchial breath sounds - Worsening gas exchange (e.g., O2desats [e.g., PaO2/FiO2<240],7↑O2req, OR ↑ventilation demand) 1208 1209 1210 1211 1212
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1213 1214
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1215 Appendix 2 1216
1217 1218
1219
1220
1221
1222
1223
1224
1225
1226
1227
1228
1229
1230
1231
1232
1233
1234
1235
1236
1237
1238
1239
1240
1241
1242
1243
1244
1245
1246
1247
1248
1249
1250
1251
Data collection
Baseline
(<24 hr)
At
randomization
Daily
(day 0-28)
Day
90
Baseline Gender x
Age x
High x
Weight x
BMI x
Reason admission icu x
Reason ventilation x
Cause respiratoir failure x
APACHE II score x
SAPS score x
Cardiac comorbidity x
Pulmonal comorbidity x
Medication x
Respiratory parameters x x
MV parameter MV parameters x x
Location ICU/hospital/facility/home x x
Life status Alive/deceased x x
Pulmonary complications x
Medication use x
Other Cumulative fluid balance x
Cumulative urine output x
SOFA score x
Blood transfusions x
Colloid infusion x
Side effects Nebulisation x
Acetylcysteine x
Salbutamol x
Abbreviations: BMI: body mass index; MV: mechanical ventilation;NIV: non-invasive mechanical ventilation;
APACHE II: Acute Physiology and Chronic Health Evaluation II;SAPS II: Simplified acute physiology score II;PEEP:
positive end expiratory pressure; IE ratio: inspiratory expiratory ratio; Fi02: Fraction inspired oxygen; MV: minute
volume; SOFA score: sequential Organ Failure Assessment
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1252
1253
Appendix 3. 1254 1255 Protocol: Nebulisation in the “nebulisation on clinical indication only” arm: 1256
1257
Nebulisation is performed incidentally in case of a clinical indication according to the 1258
same procedure applied in the routine nebulisation group. 1259
1260
Clinical indications are defined as: 1261
1262
Mucolytics: 1263
In case of ccurrence of persistent thick and tenacious secretions, following the 1264
Suzakawa criteria* observed during daily care by nurse or physician, the 1265
attending ICU-physician starts the following protocol: 1266
1. Start active humidification of the ventilator circuit 1267
2. In case of persistent tick and tenacious secretions prescribe four times daily 1268
nebulization of 3 mL-solution of acetylcysteine (fluimucil 100mg/ml) and record 1269
indication in the medical chart. 1270
3. Reconsider daily whether this indication is still present or whether nebulisation 1271
can be withdrawn again and record in the medical chart. 1272
1273
Bronchodilators: 1274
In case of occurrence of bronchospasm, defined as occurrence of at least one of 1275
following signs and symptoms of bronchospasm: wheezing, increased airway 1276
pressures, increasing airway resistance, up sloping curve of de end tidal CO2 1277
monitoring, the attending ICU-physician starts the following protocol: 1278
1. Prescribe four times daily nebulization of 2.5 mL solution of salbutamol (Ventolin 1279
2.5 Nebules 2.5mg/2.5 ml) and record indication in the medical chart. 1280
2. Reconsider daily whether this indication is still present or whether nebulisation 1281
can be withdrawn again and record in the medical chart. 1282
1283
*Suzukawa criteria secretion : 1284
Class 1- aqueous: no secretion remains behind on the inside of the suction catheter 1285
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Class 2- sticky: some secretion remains behind on the inside of the suction catheter, 1286
simply removable with rinsing fluid 1287
Class 3- thick/tenacious: secretion remains behind on the inside of the suctioning 1288
catheter, which cannot be flushed away after two times of rinsing with fluid 1289
1290
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