Relationship Between Asynchronies and Sleep Disruption in Mechanically Ventilated Patients: a Prospective Cohort Study
Conditions: Sleep
Sponsor: Althaia Xarxa Assistencial Universitària de Manresa

1 
 
Relationship between Asynchronies and Sleep Disruption in Mechanically Ventilated 
Patients: a prospective cohort study. 
 
NCT05847374 
 
 
 
Investigators: Rafael Fernandez Fernandez, Carles Subira Cuyas 
 
Center: Critical Care Department. Althaia Xarxa Assistencial Universitaria de Manresa. 
Address: Dr. Joan Soler 1. 08243 Manresa. Spain. 
Collaborators: 
- 
BetterCare. Sabadell. Spain. 
- 
CerebraHealth. Winnipeg. Canada. 
 
Keywords: Sleep disruption, Patient-ventilator asynchronies, Delirium 
 
First version: December 1, 2018 
Current version for Clinical Trials: May 5, 2023 
 
 

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INDEX 
Abstract …………………………………………………………………………………………………….   2 
Background ……………………………………………………………………………………………… 
  3 
Study design ………………………………………………………………………………………………   3 
Study subjects and recruitment …………………………………………………………………..   3 
Data collection and management …………………………………………………………………   4 
Primary and secondary outcomes ………………………………………………………………..   4 
Statistical plan …………………………………………………………………………………………..   4 
Trial organization ……………………………………………………………………………………….   5 
Ethical aspects …..……………………………………………………………………………………….   5 
Funding …………….……………………………………………………………………………………….   5 
Experience of the investigator team .…………………………………………………………….   5 
Strategic Framework and Applicability of the results……………………………………….   5 
References ...........................................................................................................   6 
Appendix 1. CRF of the study ...............................................................................   7 
Appendix 3. Logbook for confidential identification of enrolled patients ………….. 12 
Appendix 4. Eligible patients not enrolled in the study ....................................... 
14 
 
 
Abstract 
 
Mechanically ventilated (MV) patients in the Intensive Care Unit (ICU) are highly 
susceptible to sleep disruption. Several studies in the last 15 years have demonstrated an 
extremely poor sleep quality and abnormal sleep pattern evaluated by polysomnography (PSG) 
devices (the gold standard method for evaluating sleep quality and quantity). 
Patient-ventilator interaction is frequently poor leading to asynchronies of varied type 
and consequences. Moderate-to-severe asynchronies are associated with longer mechanical 
ventilation, weaning failure and mortality.  
The goal of this study is to look for an association between poor sleep quality and 
patient-ventilator asynchronies. 
This study is an observational, physiological study investigating sleep quality and 
quantity in 50 MV patients by recording modified PSG (Prodigy. CerebraHealth) at night while 
continuously monitoring 24h/day of patient-ventilator interaction (BetterCare system).  
 
 

3 
 
Background: 
 
Sleep is a natural condition that humans need for homeostasis maintenance. 
Hospitalized patients frequently suffer sleep disruption due to medical conditions and 
environmental circumstances. Critically ill patients, and specifically mechanically ventilated 
patients, exhibit severe sleep disruption patterns. Some factors predisposing to sleep 
disturbances are non-modifiable (age, cerebrovascular disease, but others can be improved 
(noise, excessive light, sedatives, hypotension). Studies on sleep in ICU patients are scarce 
due to the cumbersome and technical difficulties of polysomnographic tests. The recent 
validation of automated sleep studies are a promising field of research. 
  
Delirium is an acute mental disturbance characterized by confused thinking and 
disrupted attention usually accompanied by disordered speech and hallucinations. Hospitalized, 
and mostly ICU, patients develop delirium at a variable incidence between 5% and 40% 
depending on case-mix and individual predisposing factors. Development of delirium during 
hospitalization is associated with higher mortality and long-term neuropsychological sequela. 
Because treatment of delirium is very poor, the research agenda is mostly focused in delirium 
prevention. 
  
The role of mechanical ventilation (MV) on sleep disturbances is not fully understood, 
but international guidelines recently suggest the use of assist-control modes during sleep. In 
the MV field, patient-ventilator interaction has gained wide interest after the association of 
asynchronies with longer MV, weaning failure, and mortality. Nowadays, the availability of 
systems of continuous monitoring of ventilator waveforms allows the 24-h surveillance of 
asynchronies in MV patients.  
 
Therefore, our hypothesis is that patient-ventilator asynchronies at night, but also 
during the day, may be associated with sleep disruption and the secondary development of 
delirium in critically ill patients.  
 
 
Study design 
 
This is a prospective observational cohort study involving 50 patients under mechanical 
ventilation in the Intensive Care Unit. 
 
Study subjects and recruitment 
Inclusion criteria:  
- 
Age >18 yr. 
- 
Patients who have survived the initial critical admission phase (severe hypoxemia or 
shock) and before approaching weaning. 
- 
Consent to participate. 
Exclusion Criteria: 
- 
Presence of recent major central nervous system disease impairing consciousness with 
Glasgow Coma Scale ≤ 8T 
- 
Patients with a sleep breathing disorder when it is predominantly central sleep apnea; 
patients with predominantly obstructive sleep apnea can be included. 
- 
Severe hemodynamic instability (high dose of vasopressors). 
- 
Receiving muscle paralysis. 
- 
Withholding and/or withdrawal of life support treatments. 
Patients will retain the possibility to abandon the study at any step without restrictions. 

4 
 
 
Data collection and management 
After enrolment, every night, sleep architecture will be recorded using modified PSG 
(Prodigy. Cerebra-Health. Canada) (electroencephalography, right and left electrooculography, 
submental electromyography and electrocardiography) from 24:00 to 8:00. Pulse oximetry 
(SpO2) and heart rate will be recorded continuously during the PSG. 
Mechanical ventilation will be continuously monitored by Better-Care system with specific 
algorithms for detection of asynchronies (ineffective efforts during expiration, double-cycling, 
short cycle, long-cycle, and asynchrony index), with additional capabilities (trapped gas, 
presence of secretions, pulse pressure variation,…). 
Analgo-sedation will be administered as per local protocol. Dosage of continuous analgo-
sedation will be recorded hourly by electronic surveillance. Level of sedation will be assessed 
by Ramsay score, whereas pain will be assessed by Campbell score or Visual Analog Scale 
when appropriate every 8 hours, or more frequently if deemed appropriate.   
Delirium will be assessed by using the Confusion Assessment Method for the Intensive Care 
Unit (CAM-ICU) every 8 hours (at 08:00, 16:00 and 24:00) from day 0 until discharge. 
Sleep protective measures (earplugs, eye mask, avoidance of nocturnal feeding, light and 
noise reduction) will be routinely administered as per local protocol. 
When feasible, sleep studies may be recorded in subsequent days to account for technical 
losses in the first study, and to get some insights about the trend in sleep disruption during 
ICU stay. 
 
 
 
Outcome Measures 
 
Primary Outcome Measures: 
Correlation between sleep architecture (total sleep time, % of rapid eye movement sleep, 
sleep quantity (or efficiency), slow wave sleep and circadian sleep ratio, % of 
"pathological/atypical" sleep patterns, and sleep continuity) and asynchronies [Time Frame: 24 
hours] 
Secondary Outcome Measures: 
 
1. Comparison of sleep disturbances between diurnal and nocturnal asynchronies [Time 
Frame: 24 hours] 
2. Correlation between asynchronies and delirium [Time Frame: Up to 28 days]. Assessed 
using the Confusion Assessment Method for the Intensive Care Unit each day until ICU 
discharge. 
3. Correlation between sleep disruption and delirium. [Time Frame: Up to 28 days]. 
Assessed using the Confusion Assessment Method for the Intensive Care Unit each day 
until ICU discharge. 
4. Correlation between heart rate variability, asynchronies and sleep disturbances. [Time 
Frame: Up to 28 days].  
 
Statistical plan 
 
Sample size:  
Based on the exploratory nature of the study, there is no strict sample size calculation, and 
higher sample size only will reduce the uncertainty of the estimation. Then, we decided a 
convenience sample of 50 patients. 
 

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Analysis:  
Continuous variables will be described as mean and standard deviation when normally 
distributed and by median and interquartile range otherwise. Categorical variables will be 
described as frequency and percentages. 
 
Continuous variables will be compared by ANOVA test when normally distributed and by 
Kruskall-Wallis test otherwise. Categorical variables will be compared by chi-square test. 
 
The association of delirium with clinical variables will be analyzed by logistic multivariable 
regression analysis. 
 
 
Trial organization 
Acceptance by Ethics Committee: December 1, 2018 
Actual Study Start Date: 
 
January 1, 2019 
Actual Primary Completion Date:  January 1, 2020 
 
 
Ethical aspects 
The study will follow the legal standards for clinical research in Spain. Specifically, the 
project needs the approval of the Ethics Committee of the “Unió Catalana d’Hospitals” and 
informed consent should be obtained from the patient’s closest relatives. 
 
The available evidence supports that patients will not be harmed in any way by the 
participation in this study. Then, no extra insurance coverage is needed. 
 
 
 
Funding 
This is an investigator-lead study without funding from external sources. 
 
Sleep studies materials will be supplied by CerebraHealth free of charge as a research 
agreement with Althaia Xarxa Assistencial Universitaria de Manresa. 
 
Asynchronies monitoring is already part of the routine ICU monitoring after an 
agreement between BetterCare and Althaia Xarxa Assistencial Universitaria de Manresa. 
 
 
Experience of the investigator team 
 
The investigator team has a wide experience in clinical and physiologic studies in 
critically ill patients, frequently supported by grants from public agencies.  
 
 
Both collaborators (CerebraHealth and BetterCare) also have extensive experience in 
research projects. 
 
 
Strategic Framework and Applicability of the results 

6 
 
 
The study is framed in a vibrant field of research, the interplay between mechanical 
ventilation and sleep either as co-factors or cause-and-effect, with delirium as the most 
important patient-oriented outcome. 
 
 
The results of the study, if positive, may have direct application in a wide population of 
critically ill patients in any ICU. 
 
 
References 
1. Drouot X, Cabello B, d'Ortho MP, Brochard L. Sleep in the intensive care unit. Sleep Med 
Rev. 2008 Oct; 12(5):391-403. http://dx.doi.org/10.1016/j.smrv.2007.11.004 . 
Review. 
 
2. Roche Campo F, Drouot X, Thille AW, Galia F, Cabello B, d'Ortho MP, Brochard L. Poor 
sleep quality is associated with late noninvasive ventilation failure in patients with acute 
hypercapnic respiratory failure. Crit Care Med. 2010; 38 (2):477-85. 
http://dx.doi.org/10.1097/CCM.0b013e3181bc8243  
 
3. Subirà C, de Haro C, Magrans R, Fernández R, Blanch L. Minimizing asynchronies in 
mechanical ventilation: Current and future trends. Respir Care 2018, 63 (4): 464-478 
http://dx.doi.org/10.4187/respcare.05949 PMID: 29487094 
 
4. Blanch Ll, Villagra A, Sales B, Montanya J, Lucangelo U, Lujan M, Garcia-Esquirol O, 
Chacon E, Estruga A, Oliva JC, Hernandez-Abadia A, Albaiceta GM, Fernandez-Mondejar 
E, Fernandez R, Lopez-Aguilar J, Villar J, Murias G, Kacmarek RM. Asynchronies during 
mechanical ventilation are associated with mortality. Intensive Care Med 2015; 41: 
633-641.  http://dx.doi.org/10.1007/s00134-015-3692-6 PMID: 25693449. 
 
5. Younes M, Soiferman M, Thompson W, Giannouli E. Performance of a New Portable 
Wireless Sleep Monitor. J Clin Sleep Med. 2017 Feb 15;13(2):245-258. PMID: 
27784419 http://dx.doi.org/10.5664/jcsm.6456  
 
6. Younes M, Younes M, Giannouli E. Accuracy of automatic polysomnography scoring 
using frontal electrodes. J Clin Sleep Med. 2015;12(5):735–746. 
http://dx.doi.org/10.5664/jcsm.5808 PMID: 26951417 
 
7. Younes M, Ostrowski M, Soiferman M, Younes H, Younes M, Raneri J, Hanly P. Odds 
ratio product of sleep EEG as a continuous measure of sleep state. Sleep. 2015 Apr 
1;38(4):641-54. http://dx.doi.org/10.5665/sleep.4588 PMID: 25348125 
 
8. Stein PK, Pu Y. Heart rate variability, sleep and sleep disorders. Sleep Med Rev. 2012 
Feb;16(1):47-66. http://dx.doi.org/10.1016/j.smrv.2011.02.005 PMID: 21658979  
 
 
 
 
 
 

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Appendix 1. CRF of the study 
 
 

8 
 
 
Study Number:  
 
 _ _ 
 
ICU Admission: 
 
Date  _ _ / _ _ / _ _ _ _ 
Hour: _ _ / _ _ 
Age:   
 
 
_ _ years 
Sex:   
 
 
Male [ ]   Female [ ] 
Weight: 
 
 
_ _ _ kg 
Height:   
 
 
_ _ _ cm 
 
COMORBIDITIES:   HEART FAILURE 
 
  
YES [ ] 
NO [ ] 
 
 
 
NEUROMUSCULAR  DISEASE 
YES [ ] 
NO [ ] 
 
 
 
 
COPD  
 
 
 
YES [ ] 
NO [ ] 
 
 
 
 
DIABETES 
 
 
 
YES [ ] 
NO [ ] 
 
 
 
 
CANCER  
 
 
 
YES [ ] 
NO [ ] 
 
 
 
 
RENAL FAILURE 
 
 
YES [ ] 
NO [ ] 
 
 
 
 
LIVER CIRRHOSIS  
 
YES [ ] 
NO [ ] 
 
 
ADMISSION DIAGNOSIS: __________________________________________ 
 
APACHE II ON ADMISSION:   _ _ (sum up the worse values within 24 h of admission) 
 
 
CASE REPORT FORM (CRF)
Relationship between Asynchronies and Sleep Disruption in Mechanically 
Ventilated Patients: a prospective cohort study.  
CHECKLIST FOR ENROLLMENT 
BetterCare software OK: 
 
[ ] YES 
[ ] NO 
Prodigy available:  
 
 
[ ] YES 
[ ] NO 
Informed Consent obtained: 
[ ] YES 
[ ] NO 

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DAY OF THE STUDY 
 
Data: _ _ / _ _ / _ _ _ _ 
 
 
 
 
 
 
 
 
 
 
 
 
 
FiO2: ___ 
VT: ___ ml 
Mode: ______ 
PEEP: ___ 
PeakPaw: ___ 
Resp Rate: ___ 
SpO2: ____ 
Heart rate: ____ 
Systolic blood pressure: ____ 
Diastolic blood pressure: _____ 
Continuous sedatives: 
NO [ ]  
YES [ ] Daily dose: ________ 
Continuous opioids:  
NO [ ]  
YES [ ] Daily dose: ________ 
Ramsay: 
 
 
0-8 h: ___ 
8-16 h: ___ 16-24 h: ___  
Campbell [ ] VAS [ ]  
0-8 h: ___ 
8-16 h: ___ 16-24 h: ___  
CAM-ICU:  
 
 
0-8 h: ___ 
8-16 h: ___ 16-24 h: ___  
NIGHT SURVEILLANCE 
 
Light reduction: 
YES [ ] 
NO [ ] Reason: ____________________ 
Noise reduction: 
YES [ ] 
NO [ ] Reason: ____________________ 
Critical incident: 
NO [ ]  
YES [ ] Describe: ____________________ 
Extra-sedation: 
NO [ ]  
YES [ ] Describe: ____________________ 

10 
 
 
 
 
 
 
 
 
 
Days after enrollment 
 
0 
1 
2 
3 
4 
5 
6 
7 
14 
21 
28 
Respiratory 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
Liver 
 
 
 
 
 
 
 
 
 
 
 
Cardiovasc. 
 
 
 
 
 
 
 
 
 
 
 
CNS 
 
 
 
 
 
 
 
 
 
 
 
Renal 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
SOFA Assessment (only during ICU stay) 

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OUTCOME:
 DELIRIUM: 
[ ] NO  
 
 
 
 
[ ] YES   
Start:  _ _ / _ _ / _ _ _ _ 
 Hour:  _ _:_ _ 
 
 
 
 
End:      _ _ / _ _ / _ _ _ _ 
 Hour:  _ _:_ _ 
WEANING FAILURE:  
[ ] NO  
[ ] YES   
TRACHEOSTOMY:  
[ ] NO  
[ ] YES    
  
ICU discharge (date):   
_ _ / _ _ / _ _ _ _ 
ALIVE:    YES [ ]   NO [ ]  
 Hospital discharge (date):  
_ _ / _ _ / _ _ _ _ 
ALIVE:    YES [ ]   NO [ ]  

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Appendix 2. Logbook for confidential identification of enrolled patients. 
 
Relationship between Asynchronies and Sleep Disruption in Mechanically Ventilated Patients: a 
prospective cohort study. 
REGISTRY OF ENROLLED PATIENTS (LOGBOOK) 
(CONFIDENCIAL AT ENROLLMENT CENTER) 
Nº of 
study 
patient 
Data 
Family name/First name 
Chart Number 
 
1
_ _/_ _/_ _
2
_ _/_ _/_ _
3
_ _/_ _/_ _
4
_ _/_ _/_ _
5
_ _/_ _/_ _
6
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7
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8
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9
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10
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11
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12
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13
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14
_ _/_ _/_ _
15
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16
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17
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18
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19
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20
_ _/_ _/_ _
21
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22
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23
_ _/_ _/_ _
24
_ _/_ _/_ _
25
_ _/_ _/_ _
26
_ _/_ _/_ _
27
_ _/_ _/_ _
28
_ _/_ _/_ _
29
_ _/_ _/_ _
30
_ _/_ _/_ _
31
_ _/_ _/_ _
32
_ _/_ _/_ _
33
_ _/_ _/_ _
34
_ _/_ _/_ _
35
_ _/_ _/_ _
36
_ _/_ _/_ _
37
_ _/_ _/_ _

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38
_ _/_ _/_ _
39
_ _/_ _/_ _
40
_ _/_ _/_ _
41
_ _/_ _/_ _
42
_ _/_ _/_ _
43
_ _/_ _/_ _
44
_ _/_ _/_ _
45
_ _/_ _/_ _
46
_ _/_ _/_ _
47
_ _/_ _/_ _
48
_ _/_ _/_ _
49
_ _/_ _/_ _
50
_ _/_ _/_ _
 
 
 

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Appendix 3. Eligible patients not enrolled in the study.