Clinical trial NCT02219659
Conditions: Acute Respiratory Failure
Keywords: sedation strategy mechanical ventilation ventilator weaning
Sponsor: MemorialCare Health System
Start date: 2014-12-01; Completion date: 2017-05-01
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A three-arm, randomized, pilot feasibility, study to assess the effect three validated sedation strategies on outcomes of patient on mechanical ventilation.

Detailed description:
A three-arm, randomized, pilot feasibility, study to assess the effect three validated sedation strategies on outcomes of patient on mechanical ventilation.

A significant proportion of patients admitted to the intensive care unit (ICU) require mechanical ventilation (MV). To maintain comfort and facilitate quality care, large quantities of sedatives and analgesics are often administered either by continuous infusion, with or without daily interruption (DI) of sedation, or as intermittent doses of analgesics. Three validated sedation strategies are currently available. A recently published study ( trial has shown that instituting protocol-directed sedation in patients requiring continuous infusion of sedatives and analgesics, whether or not daily interruption (DI) of the sedative occurs, will improve MV outcomes, specifically the duration of MV. Girard et al performed a randomized, multicenter, clinical trial (ABC- Awakening and Breathing Controlled trial) evaluating the pairing of a spontaneous awakening trial (SAT) with an SBT. Most recently, a Danish study by Strom et al. investigated whether an analgesia-first approach to patient comfort that consisted of intermittent doses of intravenous opioids, and the initiation of IV sedation for short periods only when acute agitation was present, would be superior to a protocol similar to the ABC trial. While the three above mentioned approaches are accepted and currently implemented in the critical care community there is no comparative study or evaluation on the optimal timing to conduct a spontaneous breathing trial (SBT) for assessing weaning readiness with each of these strategies. It is possible that a SAT strategy, where sedative and opioid infusions are interrupted, may lead to more agitation and anxiety than a strategy in patients managed with a sedation protocol where intravenous sedative and analgesic therapy is regularly titrated to maintain patients in a lightly sedated state. Moreover, it remains unclear whether there are advantages of an analgesia-first sedation strategy over either an SAT or sedation protocol strategy in terms of the time it takes to wean patients from MV. However, it is noteworthy to mention that the analgesia-first strategy was associated with more delirium episodes, which were attributed to the ability to assess for it in a more awake patient. However, comparing delirium occurrence in studies with different sedation goals and methodologies may be inaccurate.

The investigators therefore propose a three-arm, randomized, pilot feasibility, study to assess the effect of these three (3) validated strategies for sedation and pain management

Arms: arm 1: Continuous infusion of fentanyl and midazolam is started per protocol. Both drugs are titrated to target pain score (0 to 3) using Critical Care Pain Observation Tool (CPOT) and target sedation score (0 to -3) using Richmond Agitation Sedation Scale (RASS). Every morning both drugs are stopped (Daily Interruption) and patient's wakefulness is assessed per protocol. If patient's pain and RASS score stays within the target, both drugs are kept off. If patient shows any signs and symptoms of pain or agitation (described in the study protocol), both drugs are restarted at a half dose of the previous dose and titrated to target pain and RASS score. Every morning both drugs are stopped and when patient is awake and met the SBT safety screen, 120-min continuous positive airway pressure (CPAP) trial is performed. arm 2: Continuous infusion of fentanyl and midazolam is started per protocol. Both drugs are titrated to target pain score (0 to 3) using Critical Care Pain Observation Tool (CPOT) and target sedation score (0 to -3) using Richmond Agitation Sedation Scale (RASS). Daily interruption of fentanyl and midazolam is not performed. Every morning 120-min CPAP trial is performed as long as the patient's RASS score is 0 to -2 and the patient passes the SBT safety screen. arm 3: This arm attempts to manage patient's pain and agitation with analgesia first. Fentanyl intravenous (IV) pushes are administered every 5 minutes as needed to target pain and sedation score, up to 4 doses per hour. Every morning 120-min CPAP trial is performed as long as patient's RASS score is 0 to -2 and patient passes the SBT safety screen. If fentanyl IV push doses alone cannot manage patient's pain and agitation (could not reach the target score), notify the study team. Fentanyl infusion is started and titrated to target pain and sedation score up to 6 hours. If fentanyl infusion is titrated up twice consecutively and target pain and sedation score are not met, notify the study team. Propofol infusion is started and titrated to target RASS score up to 6 hours.
Interventions: intervention 1: Sedation Protocol with Daily Interruption intervention 2: Sedation Protocol Without Daily Interruption intervention 3: Fentanyl Push First
Intervention descriptions: intervention 1: Continuous infusion of fentanyl and midazolam is started and titrated to target pain and RASS score: Fentanyl started at 25 mcg/hr titrated by 25 mcg/hr every 30 minutes to goal pain score; Midazolam started at 1 mg/hr titrated by 1 mg/hr every hour to goal RASS score for the study design duration (28 days) or for the duration of mechanical ventilation. Every morning both infusions are stopped and when the patient is awake and met the SBT safety screen, 120-min CPAP trial is performed. If the patient meets the CPAP passing criteria, arterial blood gas (ABG) is done and the patient is placed back to the previous ventilator setting. ABG result is notified to the physician for determination for extubation. If the patient does not pass the CPAP trial it is repeated next morning. intervention 2: Continuous infusion of fentanyl and midazolam is started and titrated to target pain and RASS score: Fentanyl started at 25 mcg/hr titrated by 25 mcg/hr every 30 minutes to goal pain score; Midazolam started at 1 mg/hr titrated by 1 mg/hr every hour to goal RASS score for the study design duration (28 days) or for the duration of mechanical ventilation. Every morning when the patient's RASS score is 0 to -2 and the patient passes the SBT safety screen, 120-min CPAP trial is performed. If the patient meets the CPAP passing criteria, arterial blood gas (ABG) is done and the patient is placed back to the previous ventilator setting. ABG result is notified to the physician for determination for extubation. If the patient does not pass the CPAP trial it is repeated next morning. intervention 3: Fentanyl 25 mcg intravenous push (IVP) every 5 min up to 4 doses hourly as needed to target pain score for the study design duration (28 days) or for the duration of mechanical ventilation. Every morning when patient's RASS is 0 to -2 and passes the SBT safety screen, 120-min CPAP trial is performed. If patient meets CPAP passing criteria, the physician will be notified for determination of extubation. If patient does not pass, it is repeated next morning. If target RASS is not achieved with fentanyl IV push alone, study team is notified and fentanyl infusion at 50 mcg/hr titrated by 25 mcg/hr every 30 min to target pain score (max 6 hrs). If target RASS score is not achieved with the fentanyl IV, propofol infusion is started at 5 mcg/kg/hr titrated by 5 mcg/kg/hr every 15 min to target RASS score (max 6 hrs).

Protocol documents:
Prot_SAP_000.pdf: 
Pilot Study on Pairing Sedation Strategies and Weaning 
Protocol
Principal Investigator: 
Maged A. Tanios MD, MPH 
Associate Professor of Medicine 
David Geffen School of Medicine at UCLA 
Director, Intensive Care Unit 
Long Beach Memorial Medical Center 
Long Beach, CA 90806 
562-424-8000
Sub-Investigator / Study Coordinator: 
Hyunsoon Park, CNS, MN, CCRN 
Clinical Nurse Specialist, Intensive Care Unit 
Long Beach Memorial Medical Center 
Long Beach, CA 90806 
562-933-7176
Data and Safety Monitoring Board: 
TBD 
Protocol advisors: 
John W. Devlin, Pharm.D., FCCM, FCCP 
Department of Pharmacy Practice 
Bouve College of Health Science; Northeastern University 
360 Huntington Ave R218F, Boston, MA 02115 
Sangeeta Mehta, MD, FRCPS 
Research Director, Medical/Surgical ICU 
Associate Professor of Medicine, University of Toronto 
Mount Sinai Hospital Room 18-216  
600 University Ave  
Toronto, Ont M5G 1X5 
Huan Mark Nguyen, Pharm.D. 
Assistant Professor, Western University of Health Sciences 
309 E. Second Street, Pomona, CA 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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TABLE OF CONTENTS 
1. Synopsis
2. List of Abbreviations and Definition of Terms
3. Background and summary
4. Study design
a.
Trial interventions
b.
Patient Population
c.
Inclusion criteria
d.
Exclusion criteria
e.
Duration of treatment period
f.
Frequency and duration of follow-up
g.
Recruitment
5. Outcome measurement
a.
Primary outcomes
b.
Secondary outcomes
6. Randomization and stratification methods
7. Patient safety
8. Statistics
9. Study compliance
a.
Study management
b.
Study coordinator
c.
Confidentiality and study data storage
d.
Principal Investigator
10. Relevance and value
11. Consent
12. References
13. Appendix
a.
Education material (appendix A, B & C)
14. Tables


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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1. SYNOPSIS: 
Pilot studies are important initial step in exploring a new trial protocol.  This is a 
pilot to assess feasibility of recruitment, randomization, retention, and assessment 
procedures of implementation of a three different sedation protocols in a 
randomized controlled trial (RCT) design.  The purpose is to examine the 
feasibility of the protocol that is intended to be used in a larger scale study.  This is 
not a hypothesis testing study. The future large RCT will compare the effect of 
three different validated ICU sedation strategies, each paired with a validated 
weaning protocol, on outcomes of mechanical ventilation.   
 
2. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS: 
Abbreviation  
 
Term 
DI 
 
 
 
Daily interruption  
SAT 
 
 
 
Spontaneous awakening trial 
SBT 
 
 
 
Spontaneous breathing trial 
ICU 
 
 
 
Intensive Care Unit 
PDS 
 
 
 
Protocol-directed sedation   
MV 
 
 
 
Mechanical ventilation 
SAT-SBT 
 
 
Paired SAT and SBT 
NSD-SBT  
 
 
Paired Analgesia first and SBT 
PDS-SBT 
 
 
Paired PDS and SBT 
ABC   
 
 
Awakening and breathing controlled trial 
 
3. BACKGROUND AND SUMMARY:   
A significant proportion of patients admitted to the intensive care unit (ICU) 
require mechanical ventilation (MV).[1]  To maintain comfort and facilitate quality 
care, large quantities of sedatives and analgesics are often administered either by 
continuous infusion, with or without daily interruption (DI) of sedation, or as 
intermittent doses of analgesics.[2-7]  The recently published SLEAP trial has 
shown that instituting protocol-directed sedation in patients requiring continuous 
infusion of sedatives and analgesics, when daily interruption (DI) of the sedative 
occurs, will improve MV outcomes, specifically the duration of MV.[8-13] 
Similarly, studies have shown that use of a weaning protocol for mechanically 
ventilated ICU patients reduces the time to mechanical ventilation liberation.[14-
16]    
 
The Consensus Conference on Intensive Care Medicine in 2007 recommended 
using weaning protocols with the spontaneous breathing trial (SBT) as the major 
diagnostic test to determine if a patient can be successfully extubated.[14, 16-18]  
Girard et al performed a randomized, multicenter, clinical trial (ABC- Awakening 
and Breathing Controlled trial) evaluating the pairing of a spontaneous awakening 
trial (SAT) with an SBT.  The study did not require use of a specific protocol- 
directed sedation approach in the control arm.  In the intervention group the authors 
conducted a spontaneous awakening trial (SAT) by holding sedatives, followed by 
a spontaneous breathing trial (SBT) to assess for weaning readiness.  Subsequently, 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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this strategy of incorporating a daily interruption of sedation was challenged by 
Mehta et al who conducted a randomized controlled study comparing a PDS with 
DI and PDS without DI.  Their findings suggested that there was no added value 
for incorporating a daily interruption of sedation among patients managed with a 
protocol-directed sedation approach. Most recently, a Danish study by Strøm et al. 
went a step further to investigate whether an analgesia-first approach to patient 
comfort that consisted of intermittent doses of intravenous opioids, and the 
initiation of IV sedation for short periods only when acute agitation was present, 
would be superior to a protocol similar to the ABC trial.  The intervention arm 
received intermittent intravenous opioids for pain and sedation only if the 
analgesia-first approach fails.  The intervention arm had significantly more days 
without ventilation (13.8 days ± 11.0 vs. 9.6 ± 10.0; p=0.0191) and fewer ICU days 
and hospital days.  There was no difference was recorded in the occurrences of 
accidental extubations.   
 
While the three above mentioned approaches are accepted and currently 
implemented in the critical care community the optimal time to conduct an SBT 
during each of these sedative approaches remains unknown.  It is possible that a 
SAT strategy, where sedative and opioid infusions are interrupted, may lead to 
more agitation and anxiety than a strategy in patients managed with a sedation 
protocol where intravenous sedative and analgesic therapy is regularly titrated to 
maintain patients in a lightly sedated state. Moreover, it remains unclear whether 
there are advantages of an analgesia-first sedation strategy over either an SAT or 
sedation protocol strategy in terms of the time it takes to wean patients from MV.  
However, it is noteworthy to mention that the analgesia-first strategy was 
associated with more delirium episodes, which were attributed to the ability to 
assess for it in a more awake patient. However, comparing delirium occurrence in 
studies with different sedation goals and methodologies may be inaccurate.   
We therefore propose a three-arm, randomized, pilot feasibility, study to assess the 
effect of these three (3) validated strategies for sedation and pain management on 
time to liberation of mechanical ventilation and other related outcomes.  
 
Literature review 
Protocol-directed sedation and daily interruption studies:  
Brook AD et al. performed a randomized, single-center, clinical trial comparing 
protocol-directed sedation versus non-protocol-directed sedation in 321 
mechanically ventilated patients.  They included patients greater than the age of 17 
who were admitted to the medical intensive care unit.  162 patients received 
protocol-directed sedation and 159 patients received the non-protocol-directed 
sedation.  The primary outcome was the duration of mechanical ventilation and 
secondary outcomes included lengths of ICU and hospital stay.  The results 
revealed a reduction in the mean duration of mechanical ventilation for the 
protocol-directed sedation group (89.1 ± 133.6 hrs. vs. 124.0 ± 153.6 hrs. p = 
0.003); as well as a reduced length of stay in the ICU and hospital [5.7 ± 5.9 days 
vs. 7.5 ± 6.5 days (p = 0.013) and 14.0 ± 17.3 days vs. 19.9 ± 24.2 days (p < 
0.001); respectively][1].  The intervention group had a reduced duration of 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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continuous intravenous sedation (3.5 ± 4.0 days vs. 5.6 ± 6.4 days; p = .003).  
Brook’s study demonstrated the clinical benefits of having protocol-directed or 
nurse-directed sedation in the medical ICU.  Since the study only involved patients 
in the medical ICU, it is uncertain if the results are applicable to surgical patients. 
 
 
Kress JP, et al [11] performed a randomized, single-center, clinical trial to evaluate 
daily interruption of continuous infusions of sedation in 128 mechanically 
ventilated adult patients.  Notable exclusion criteria were patients who were already 
receiving sedative agents upon transfer to the ICU and admission due to 
resuscitation from cardiac arrest.  The primary end points of the study included: 
duration of MV, and lengths of stay in the ICU and hospital. Secondary outcomes 
included total doses of sedative (i.e. midazolam, propofol) and analgesic agents (i.e. 
morphine).  Results from the study reveal a reduction in the median duration of 
mechanical ventilation for the daily interruption group (4.9 vs. 7.3 days, p=0.004).  
In addition, there was a reduction in the median length of stay in the ICU and 
hospital (6.4 vs. 9.9 days, p=0.02 and 13.3 vs. 16.9 days, p=0.19; respectively).  
The total dose of midazolam was lower in the daily interruption group (229.8 vs. 
425.5 mg; p=0.05).   The study found no difference in regards to the incidence of 
self-extubation.  Kress’ study showed positive clinical outcomes with DI in the 
medical ICU.  The study was limited to a single-center and was only for patients 
that were admitted to the medical intensive care unit.  It is not clear if the results 
can be reproduced in other centers or in critically ill surgical patients.  In addition, 
there was no mention of the use of PDS-SBTs.  These are some of the limitations of 
the study.  In addition many clinicians are concerned about potential complications 
of sedation interruption (i.e. posttraumatic stress disorder, enhance catecholamine 
response leading to cardiac complications).   
 
Does DI of sedative increase the risk of developing posttraumatic stress 
disorder (PTSD) or acute myocardial ischemia?   
 
Kress et al addressed the concerns raised that daily interruption of sedation may 
precipitate PTSD or cardiac events in subsequent studies.[12, 19]  One study 
evaluated the long-term psychological outcomes (minimal of 6 months after 
discharge), in 32 patients from the initial study (19 control 13 who received DI).   
The study did not find a statistical difference between the DI patients versus the 
patients who did not receive DI (0% vs. 32%, p = 0.06).[19]  In a separate 
observational study,  74 patients with two established risks for CAD were evaluated 
for cardiac ischemia with continuous three-lead Holter monitoring, during a  
DI.[12]  Of the 74 patients, 18 had an ischemic event.  A comparison between 
periods of being awake versus sedation found no difference in the fraction of 
ischemic time between the two groups (0% vs. 0%, p=0.17).  Further controlled 
studies are needed to identify and evaluate the risk of DI (i.e. sedative withdrawal, 
PTSD, CAD), especially studies to identify who is not eligible for DI. 
 
Which patients should not receive DI of sedative? 
 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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Literature is not completely supportive of the implementation of DI of sedative in 
mechanically ventilated patients.  de Wit et al. performed a randomized clinical 
study evaluating DI versus PDS.[20]  The study was terminated prior to completion 
due to a higher incidence of hospital mortality in the DI group (13 patients vs. 7 
patients, p=.04).  The authors speculate that the high number of patients with drug 
and alcohol use disorders (39%) had an adverse impact on patient outcome.   
Further studies are warranted to evaluate the safety of DI in patients with a history 
of alcohol and other illicit drug abuse. 
 
 
 
 
 
 
 
 
Pairing of DI with mechanical ventilator weaning protocol:   
 
Girard TD, et al. performed a randomized, multicenter, clinical trial (ABC trial) 
evaluating the pairing of SAT with SBT.[9]  The study involved 336 MV patients; 
one group was managed with a paired SAT and SBT and the other received usual 
care.  The study included adult patients (≥18 years) who required MV beyond 12 
hrs.  Notable exclusion criteria included: admission due to cardiopulmonary arrest, 
continuous MV for ≥2 weeks, profound neurological deficit (i.e. stroke, dementia).  
The primary outcome was breathing without assistance.  Other measured outcomes 
included: time to discharge from the ICU or hospital, total dose of sedative agents, 
and self-extubation.  The result of the study revealed that the SAT-SBT group spent 
more days without breathing assistance (mean 14.7 vs. 11.6 days, p=0.02), and less 
time in the ICU and hospital (9.1 vs. 12.9 days, p=0.01 and 14.9 vs. 19.2, p=0.04; 
respectively).  The intervention group received less total dose of benzodiazepine 
(20 vs. 39 mg, p=0.02).  However, they had a higher incidence of self extubation 
(10 vs. 4%, p=0.03), but the incidence of self-extubation requiring reintubation was 
comparable (3 vs. 2 %, p=0.47).  Girard’s study revealed positive clinical outcomes 
with the pairing of SAT with SBTs, but it was not designed to evaluate whether 
patients actually need to be fully awake for initiation of ventilator weaning or 
whether it is safe to initiate weaning with a PDS while RASS is maintained at 0 to -
3.   
 
Can an analgesia-first approach effectively facilitate mechanical ventilation 
weaning for critically ill patients? 
 
Strøm T et al evaluated an analgesia-first approach with avoidance of sedatives in 
critically ill patients requiring mechanical ventilation.  In this randomized 
controlled trial, 140 patients were assigned in a 1:1 ratio to no sedation with 
analgesia (analgesia-first) group or to sedation with DI.  The analgesia-first group 
or intervention arm received analgesics for pain control and sedation only if the 
analgesia first approach failed.  The intervention arm had significantly more days 
without ventilation (13.8 days ± 11.0 vs. 9.6 ± 10.0; p=0.0191) and shorter ICU and 
hospital stays.  No difference was recorded in accidental extubation, but delirium 
was significantly higher in the analgesia-first group (20% vs. 7%, p=0.04).  The 
study questions if patients need to be manage with SAT with PDS during 
mechanical ventilation. 
 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
7 
 
Is the pairing of SAT with PDS necessary? 
 
Mehta S, et al. perform a randomized controlled trial, multicenter clinical trial of 
mechanically ventilated patients in the ICU.  The study compared the use of PDS 
versus PDS plus SAT.  The primary outcome measure was time to successful 
extubation and additional outcomes included duration of ICU and hospital stay, 
unintentional endotracheal tube removal, and incidence of delirium.  The median 
time to extubation was comparable in PDS versus PDS plus SAT [7 vs. 7 days, 
respectively (p=0.52)].  In addition, the duration of ICU (10 vs. 10 days, 
respectively) and hospital stay (20 vs. 20 days, respectively) were not significantly 
different (p>0.05).  Unintentional endotracheal tube removal was not significantly 
higher in the PDS group (12 vs. 10, p=0.064).  The incidence of delirium was 
54.1% in the PDS group and 53.3% in the PDS plus SAT group (p=0.83).  In 
conclusion, when protocol-directed sedation for critically patients requiring 
mechanically ventilation is paired with daily interruption of sedatives, there is no 
additional benefit over the use of protocol-directed sedation alone but the patients 
in the DI group recived higher doses of sedatives and opioids and had a higher 
nurse workload 
 
4. STUDY DESIGN 
A prospective randomized, unblinded single-center clinical trial.   
We will enroll patients admitted into the ICU at Long Beach Memorial Medical 
Center who require continuous intravenous administration of sedatives and/or 
opioids, and are anticipated to require MV for ≥ 48 hours.   
Study Objectives: This pilot study is to compare the efficacy and safety between 
three (3) validated sedation strategies (i.e., ABC, SLEAP, or Analgesia-first 
protocol) paired with a SBT in mechanically ventilated adults.  
 
a. Trial interventions 
i. SAT-SBT arm (Sedation infusion protocol with DI): Appendix A 
ii. PDS-SBT arm (sedation infusion protocol without DI): Appendix B 
iii. NSD-SBT arm (No sedation analgesia-first protocol): Appendix C 
 
b. Patient Population: 
ICU patients in a mixed medical-surgical ICU will be evaluated to 
determine if they meet the inclusion and exclusion criteria.  Informed 
consent (from the patient or substitute decision maker) will be required 
prior to enrollment. 
 
c. Inclusion criteria:  
1. ≥ 18 years of age 
2. Mechanically ventilated with an expected duration of MV ≥ 48 hours 
3. ICU team has initiated continuous sedative and/or /analgesic infusions 
 
d. Exclusion criteria: 
i. Admission after resuscitation from cardiac arrest 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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ii. Admission with traumatic brain injury or another acute neurologic event 
(e,g. stroke, uncontrolled seizures).  
iii. History of severe dementia 
iv. Admission because of acute alcohol withdrawal or acute drug 
intoxication 
v. Administration of more than 24 hours of continuous sedation   
vi. Allergy to fentanyl, midazolam, and/or propofol 
vii. Lack of informed consent 
e. Duration of treatment period: All specific study interventions will cease at 28 
days following enrollment into the study, but Patients will continue to receive 
standard of care throughout their hospitalization. 
 
f. Frequency and duration of follow-up: All study interventions will cease at 28 
days, but data relevant to the study will be collected until the patient is 
discharged or dies.   
 
g. Recruitment: The principle investigator and study coordinators will perform 
patient recruitment.  
5. OUTCOMES 
a. Outcomes measurement   
i. Primary outcome 
i. Protocol feasibility  
1. Time to randomization 
2. Proportion of time in target sedation in the first 
48 hours (RASS 0 to -3)  
3. Protocol compliance 
ii. Days in deep sedation or coma: Number of days with 
RASS score of -4 or deeper 
iii. Mechanical ventilation free days: This is the number of 
days where patients were breathing without assistance 
during the 28-day study period.  This began at the time of 
enrolment. Patients who die during the study period will 
be assigned 0 ventilator-free days. 
b. Secondary outcomes 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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i. Duration of weaning: Time from initiation of weaning 
until successful extubation 
ii. ICU length of stay: The number of days from ICU 
admission to ICU discharge with admission day being 
ICU day 0 
iii. Hospital length of stay: The number of days from 
hospital admission to hospital discharge with admission 
day being hospital day 0 
iv. Mortality: 28 day hospital mortality 
v. Total amount of sedatives and analgesics used: Total 
dosage in mcg (fentanyl) or mg (midazolam) 
administered      
vi. Occurrence and duration of delirium. The occurrence of 
adverse events will be noted by the nurse on a case report 
form.  Delirium assessment will be based on the CAM-
ICU and will be done daily by the clinical managing 
team and/or study investigators.  
 
vii. Time at the desired sedation goal: percent of time while 
on protocol at desired sedation goal.  
viii. Time spent without pain: based on assessment by non-
verbal pain scale (CPOT) 
ix. Nursing assessment on perceived workload 
x. Extubation failure: If patient required reintubation within 
48 hours of extubation  
xi. Self-extubation: Inadvertent removal of an endotracheal 
tube during the course of the study by the patient 
6. RANDOMIZATION AND STRATIFICATION METHODS 
The randomization numbers generated with a 1:1:1 ratio and put into sealed 
opaque, not re-sealable envelopes. Each subject will have a unique identification 
number and keep that number throughout the study.  
This pilot study will assign 30 patients to each arm of the trial, based on a 
convenience of sample.  No power analysis will be conducted at this phase.  .   
 
7. PATIENT SAFETY:  
a. Serious Adverse Event Reporting: All adverse outcomes will be reported to 
the IRB according to guidelines.  The principle investigator or managing ICU 
physician will determine if a serious adverse events (SAE) is study-related.  A 
detailed submission of the event should be reported within 72 hours.  Relevant 
progress notes from the nurses and physician will be reviewed as well as 
laboratory and diagnostic results, and procedure notes.  Complete 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
10 
 
documentation of these findings will be done by the principle investigator or 
managing ICU physician. 
8. STATISTICS: 
Continuous variables will be presented as the mean and median with standard deviation 
(SD). Discrete variables will be presented as frequencies and percentages. Student’s t-
test (adjusted for unequal variances when necessary) or Mann-Whitney U test will be 
used for continuous data where appropriate. Categorical data will be evaluated using 
the Pearson’s chi-squared test or Fisher’s exact test where appropriate.  Time to 
extubation will be evaluated using the Kaplan-Meier survival estimate with censored 
data.  In the matched-pair analysis, paired t-test or Wilcoxon signed-rank test will be 
used to evaluate continuous data where appropriate.  Two-tailed statistical significance 
will be defined as a p<0.05. 
 
9.  STUDY COMPLIANCE:  
a. Study Management: Study compliance will be maintained with the following 
steps:  
i. Training session(s) for all health care providers involved in the care of 
the patient; 
ii. Project coordinators will provide all necessary training and study aids; 
iii. A telephone number will be made available at all times to answer 
questions and concerns;  
iv. Daily reminders form the project coordinators regarding compliance to 
all protocols;  
v. Audit of study compliance will be routinely performed. 
 
b. Study coordinator: The study coordinator (HP) will be responsible for the day 
to day management of the study and will provide guidance and support to all 
participants. 
 
c. Confidentiality and data storage 
i. The confidentiality of all patient identifiable information will be 
maintained throughout the research and thereafter.  The research 
involves the collection or the study of existing data in such a manner 
that the patient cannot be identified directly or through identifiers.  Only 
the patient’s identification numbers will be used to classify patients as 
necessary for the study.   


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
11 
 
ii. The patient’s identification numbers used in the study will be created 
with the separate keys.  All data pertaining to the study will only be 
accessible to the investigators and will be stored in a locked room and 
cabinent.  
 
d. Principal investigator (PI): The PI (MT) will oversee the entire study and will 
prepare and submit reports of SAE. 
 
10.  RELEVANCE AND VALUE:  
The results of this study are clinically and economically relevant.  The clinical data 
will provide information on what is the preferred sedation practice during 
mechanical ventilation weaning.  In addition, the study will support a multi-
disciplinary approach to managing mechanical ventilated patients.  The measured 
outcomes from the study will generate further research to improve patient 
outcomes, specifically mechanically ventilated patients.  The economic 
implications can be potentially derived from the length of ICU or hospital stay 
 
11. 
CONSENT: The consent form will be prepared according to the MHS guidelines 
and the IRB approved version will be presented to the patient or surrogate decision 
maker and discussed by the study PI or representative. 
 
12. 
REFERENCES 
 
1. 
Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, Davidson JE, Devlin 
JW, Kress JP, Joffe AM et al: Clinical Practice Guidelines for the Management 
of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit. 
Critical care medicine 2013, 41(1):263-306 
210.1097/CCM.1090b1013e3182783b3182772. 
2. 
De Jonghe B, Bastuji-Garin S, Fangio P, Lacherade JC, Jabot J, Appere-De-
Vecchi C, Rocha N, Outin H: Sedation algorithm in critically ill patients without 
acute brain injury. Crit Care Med 2005, 33(1):120-127. 
3. 
Gommers D, Bakker J: Medications for analgesia and sedation in the intensive 
care unit: an overview. Crit Care 2008, 12 Suppl 3:S4. 
4. 
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, 
Masica MF, Bjerke HS, Coplin WM et al: Clinical practice guidelines for the 
sustained use of sedatives and analgesics in the critically ill adult. Crit Care 
Med 2002, 30(1):119-141. 
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Schweickert WD, Kress JP: Strategies to optimize analgesia and sedation. Crit 
Care 2008, 12 Suppl 3:S6. 
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Sessler CN, Varney K: Patient-focused sedation and analgesia in the ICU. 
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overview of the issues. Crit Care 2008, 12 Suppl 3:S1. 
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Effect of a nursing-implemented sedation protocol on the duration of 
mechanical ventilation. Crit Care Med 1999, 27(12):2609-2615. 


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9. 
Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, 
Taichman DB, Dunn JG, Pohlman AS, Kinniry PA et al: Efficacy and safety of a 
paired sedation and ventilator weaning protocol for mechanically ventilated 
patients in intensive care (Awakening and Breathing Controlled trial): a 
randomised controlled trial. Lancet 2008, 371(9607):126-134. 
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APPENDIX A 
 
SAT-SBT ARM (SEDATION INFUSION PROTOCOL WITH DI FOLLOWED BY SBT) 
1. Start 
 
Fentanyl 25 mcg/hr 
 
Midazolam 1 mg/hr 
 
Goal pain score: ≤ 3 
 
Goal sedation score: 0 to -3 
 
2. Titration 
 
Fentanyl increase or decrease by 25 mcg/hr every 30 minutes 
 
Midazolam increase or decrease by 1 mg/hr every 60 minutes 
Fentanyl is titrated to goal pain score 
Midazolam is titrated to goal RASS score 
 
If RASS -4 to -5, DC midazolam.  If RASS remains -4 to -5, then wean fentanyl and  
 
DC to achieve target RASS 
 
 
 
If RASS -4 to -5, yet patient shows an episode of agitation, bolus doses are used 
 
before increasing infusion: 
 Fentanyl 25 mcg Q 5 minutes  
 Midazolam 1 mg Q 5 minutes  
3. Daily interruption (SAT) 
Do not perform SAT if any of the following present: 
a. Active seizures or increased ICP 
b. Use of continuous neuromuscular blockade (NMB) 
c. Active myocardial ischemia 
d. Refractory hypotension requiring ≥ 2 vasopressors 
e. Use of high frequency oscillatory ventilation 
f. Open chest or abdomen 
 
Perform SAT by stopping both fentanyl and midazolam (if acute pain is present or  
 
suspected, fentanyl may continue) 
 
 
 
Assess for wakefulness during sedative/analgesic interruption.  If able to perform  
 
At least 3 out of 4 activities below, patient is awake: 
o Open eyes to voice 
o Use eyes to follow nurse upon request 
o Squeeze hand upon request 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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o Wiggle toes upon request 
 
Leave them off if no agitation (RASS at 0 to -5) and proceed to SBT safety screen  
 
 
Resume fentanyl and/or midazolam at ½ dose and titrate to goal pain score and  
 
goal RASS score, respectively, if agitated (RASS +1 to +4) 
4. Spontaneous Breathing Trial (SBT) 
 
Daily Screening 
 
Respiratory Care Practitioners (RCP) conduct a daily screen every morning to  
 
assess readiness to wean:  
o adequate oxygenation (SpO2 ≥90% on FIO2 ≤40% and PEEP ≤5) 
o No evidence of myocardial ischemia in the previous 24 hours evidenced by 
ST changes and elevated troponin 
o Hemodynamically stable (dopamine or dobutamine ≤ 5 mcg/kg/min, 
norepinephrine ≤ 2 mcg/min, or absence of vasopressin or milrinone at any 
dose) 
o No evidence of increased intracranial pressure 
 
 
If pass the screening, place on CPAP of 5 and PS of 6 for a 120-min trial 
 
 
The patient’s RN and RCP will observe the patient for failure criteria.  Patients fail  
 
The SBT if they develop any of the following: 
o RR > 35 or < 8 for ≥ 5 min 
o SpO2 < 88% for ≥ 5 min 
o Altered mental status 
o Acute cardiac dysrhythmia 
o HR > 130 or < 60  
o Use of accessory muscles 
o Abdominal paradox 
o Diaphoresis 
o Marked dyspnea 
 
 
Patients who fail the SBT will be placed back on the ventilator settings used before 
 
The trial. If the SBT was successful, the patients’ physicians will be notified to  
 
decide on extubation 
 
 
 
 
 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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APPENDIX B 
 
PDS-SBT ARM (SEDATION INFUSION PROTOCOL WITHOUT DI FOLLOWED BY SBT) 
 
1. Start 
 
Fentanyl 25 mcg/hr 
 
Midazolam 1 mg/hr 
 
Goal pain score: ≤ 3 
 
Goal sedation score: 0 to -3  
 
2. Titration 
 
Fentanyl increase or decrease by 25 mcg/hr every 30 minutes 
 
Midazolam increase or decrease by 1 mg/hr every 60 minutes 
Fentanyl is titrated to goal pain score 
Midazolam is titrated to goal RASS score 
 
If RASS -4 to -5, DC midazolam.  If RASS remains -4 to -5, then wean fentanyl and  
 
DC to achieve target RASS 
 
 
If RASS -4 to -5, yet patient shows an episode of agitation, bolus doses are used 
before increasing infusion: 
 Fentanyl 25 mcg Q 5 minutes  
 Midazolam 1 mg Q 5 minutes  
3. Do not perform daily interruption (SAT) 
 
4. Spontaneous Breathing Trial (SBT) 
 
Daily Screening 
 
Respiratory Care Practitioners (RCP) conduct a daily screen every morning to 
 
assess readiness to wean:  
o adequate oxygenation (SpO2 ≥90% on FIO2 ≤40% and PEEP ≤5) 
o No evidence of myocardial ischemia in the previous 24 hours 
o Hemodynamically stable (dopamine or dobutamine ≤ 5 mcg/kg/min, 
norepinephrine ≤ 2 mcg/min, or absence of vasopressin or milrinone at any 
dose) 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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o No evidence of increased intracranial pressure 
 
 
If pass the screening, place on CPAP of 5 and PS of 6 for a 120-min trial 
 
 
The patient’s RN and RCP will observe the patient for failure criteria.  Patients fail  
 
The SBT if they develop any of the following: 
o RR > 35 or < 8 for ≥ 5 min 
o SpO2 < 88% for ≥ 5 min 
o Altered mental status 
o Acute cardiac dysrhythmia 
o HR > 130 or < 60  
o Use of accessory muscles 
o Abdominal paradox 
o Diaphoresis 
o Marked dyspnea 
 
 
Patients who fail the SBT will be placed back on the ventilator settings used before  
 
The trial. If the SBT was successful, the patients’ physicians will be notified to 
 
decide on extubation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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APPENDIX C 
 
NSP-SBT ARM (NO SEDATION PROTOCOL: ANALGESIA-FIRST SEDATION FOLLOWED BY 
SBT) 
 
1. Fentanyl 25 mcg IVP Q 5 min PRN pain 
Goal pain score: ≤ 3 
Goal sedation score: 0 to -3 
 
2. If fentanyl IVP cannot relieve pain after 4 doses, notify the study team for: 
 Fentanyl infusion (start at 25 mcg/hr and titrate every 30 minutes to goal 
pain score)  
 If fentanyl infusion was titrated up X2 and goal pain and sedation score not 
achieved, start propofol infusion (start at 5 mcg/kg/min and titrate to goal 
RASS score.  Use propofol 6 hours only)    
 
3. Spontaneous Breathing Trial (SBT) 
 
Daily Screening 
 
Respiratory Care Practitioners (RCP) conduct a daily screen every morning to  
 
assess readiness to wean:  
o adequate oxygenation (SpO2 ≥90% on FIO2 ≤40% and PEEP ≤5) 
o No evidence of myocardial ischemia in the previous 24 hours 
o Hemodynamically stable (dopamine or dobutamine ≤ 5 mcg/kg/min, 
norepinephrine ≤ 2 mcg/min, or absence of vasopressin or milrinone at any 
dose) 
o No evidence of increased intracranial pressure 
 
If pass the screening, place on CPAP of 5 and PS of 6 for a 120-min trial 
 
 
The patient’s RN and RCP will observe the patient for failure criteria.  Patients fail  
 
the SBT if they develop any of the following: 
o RR > 35 or < 8 for ≥ 5 min 
o SpO2 < 88% for ≥ 5 min 
o Altered mental status 
o Acute cardiac dysrhythmia 
o HR > 130 or < 60  


Pilot study on Pairing Sedation and Weaning Strategies 1: June 2013 
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o Use of accessory muscle 
o Abdominal paradox 
o Diaphoresis 
o Marked dyspnea 
 
Patients who fail the SBT will be placed back on the ventilator settings used before 
 
the trial. If the SBT was successful, the patients’ physicians will be notified to 
 
decide on extubation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D 
 
Richmond Agitation Sedation Scale (RASS) 
+4 Combative 
Overly combative, violent, immediate danger to staff 
+3 Very agitated 
Pulls or remove tube(s) or catheter(s); aggressive 
+2 Agitated 
Frequent non-purposeful movement, fights ventilator 
+1 Restless 
Anxious but movement not aggressive or vigorous 
0 
Alert and calm 
 
-1 
Drowsy 
Not fully alert but has sustained awakening (eye opening/eye 
contact to voice ≥ 10 seconds) 
-2 
Light sedation 
Briefly awakens with eye contact to voice (< 10 seconds) 
-3 
Moderate 
sedation 
Movement or eye opening to voice but no eye contact 
-4 
Deep sedation 
No response to voice but movement or eye opening to physical 
stimulation 
-5 
Unarousable 
No response to voice or physical stimulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX E 
 
Critical-Care Pain Observation Tool (CPOT) 
Facial expression 
No mussular tension observed 
 
Presence of frowning, brow lowering, orbit 
tightening, & levator contraction 
 
All of the above facial movements plus eyelid 
tightly closed 
Relaxed 
 
Tense 
 
 
Grimacing 
0 
 
1 
 
 
2 
Body movements 
Does not move at all (does not necessarily 
mean absence of pain) 
 
Slow, cautious movements, touching or 
rubbing the pain site, seeking attention 
through movements 
 
Pulling tubes, attempting to sit up, moving 
limbs/thrashing, not following commands, 
striking at staff, trying to climb out of bed 
Absence of 
movement 
 
Protection 
 
 
 
Restless 
0 
 
 
 
1 
 
 
 
2 
Muscle tension 
(passive flexion &  
extension of UE) 
No resistance to passive movements 
 
Resistance to passive movements 
 
Strong resistance to passive movements, 
inability to complete them 
Relaxed 
 
Tense, rigid 
 
Very tense or 
rigid 
0 
 
1 
 
2 
Compliance with  
ventilator 
(intubated) 
OR 
 
 
 
 
 
 
Vocalization 
(extubated) 
Alarms not activated, easy ventilation 
 
 
Alarms stop spontaneously 
 
 
 
Asynchrony: Blocking ventilation, alarms 
frequently activated 
 
Talking in normal tone or no sound 
 
Sighing, moaning 
 
Crying out, sobbing 
Tolerating 
vent 
 
Coughing but 
tolerating 
 
Fighting 
ventilator 
 
 
0 
 
 
1 
 
 
 
2 
 
 
0 
 
1 
 
2 
Total, range 
 
 
0-8 


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