Efficacy of Self-management of Sedative Therapy by Ventilated ICU Patients
Phase: PHASE2
Conditions: Critical Illness, Anxiety, Respiratory Failure
Sponsor: Mayo Clinic

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Clinical Protocol 
 
Efficacy of self-management of sedative therapy by ventilated ICU patients 
(L. Chlan and C. Weinert, MPIs) 
 
 
Funding Sponsor: 
National Heart, Lung & Blood Institute, National Institutes 
of Health, 1 R01 HL130881-01 
 
 
Study Products: 
Dexmedetomidine (Precedex) 
The LifeCare® PCA Infusion System 
The CADD Solis® infusion pump 
 
 
IND Number: 
111693 (E. Wittwer) 
ClinicalTrials.gov number: 
NCT02819141 
 
Version / Date: 
Version 1, February 11, 2016 
Version 2, Revised March 24, 2016 
Version 3, Revised April 12, 2016 
Version 4, Revised June 30, 2016 
Version 5, Revised August 2, 2016 
Version 6, Revised August 29, 2016 
Version 7, Revised October 7, 2016 
Version 8, Revised February 6, 2017 
Version 9, Revised April 11, 2017 
Version 10, Revised May 18, 2017 
Version 11, Revised July 12, 2017 
Version 12, Revised September 1, 2017 
Version 13, Revised December 5, 2017 
Version 14, Revised January 30, 2018 
Version 15, Revised June 14, 2018 
Version 16, Revised August 24, 2018 
Version 17, Revised November 21, 2018 
Version 18, Revised January 17, 2019 
Version 19, Revised April 29, 2019 
Version 20, Revised September 17, 2019 
Version 21, Revised January 13, 2020 
Version 22, Revised December 13, 2021 
Version 23, Revised October 4, 2022 
Version 24, Revised August 22, 2023 
Version 25, Revised October 23, 2023 

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Study Summary 
Title 
Efficacy of self-management of sedative therapy by ventilated 
ICU patients 
Short Title 
Patient-controlled sedation (PCS). 
IND Number 
111693 
Phase 
Phase II 
Methodology 
Study Design is an open label, randomized comparison of Patient 
self-management of sedative therapy compared to Usual Sedation 
Practice. 
Study Duration 
Estimated duration for the study is 5 years. 
Study Center(s) 
The study will involve three sites: 
University of Minnesota/Fairview Medical Center 
500 Harvard Street, Minneapolis, MN 55455 
Fairview Ridges Hospital 
201 E. Nicollet Boulevard 
Burnsville, MN 55338 
Fairview Southdale Hospital 
6401 France Avenue South, Edina, MN 55435 
Mayo Clinic 
1216 2nd St, SW 
Rochester, MN 55902 
Objectives 
The primary objective of the study is to assess the efficacy of patient 
controlled sedation (Self-management of sedative therapy) using 
dexmedetomidine  to  reduce  anxiety,  delirium  incidence  and 
duration of mechanical ventilation compared to usual sedation 
practices in mechanically ventilated subjects. 
Number of Subjects 
N = 190; Mayo Clinic n=111; University of Minnesota Medical 
Center, Fairview 
Southdale Hospital, and Fairview Ridges Hospital n=79 subjects 
combined. 
Diagnosis and Main 
Inclusion Criteria 
Study subjects will be recruited from ICUs with intubated patients 
with respiratory failure who are able willing and able to operate the 
PCS push-button device and do not have conditions that could be 
worsened by dexmedetomidine (e.g., bradycardia, high degree 
heart block, or hypotension). 
Study Product, 
Dose, Route, 
Regimen 
Dexmedetomidine (Precedex®) 
Dexmedetomidine basal maintenance infusion rate of 0.2 to 0.7 
mcg./kg/hr by the LifeCare® PCA Infusion System (Mayo Clinic) 
or the CADD Solis® infusion pump (University of Minnesota). 
Study patients may self-administer up to 3 mini-doses (0.25mcg/kg) 
per hour (every 20 minutes maximum with pump lock-out). The 
basal infusion rate will be titrated (up or down) every 2 hours based 
on the published algorithm [22]. 

3 
 
 
Duration of 
administration 
Up to 7 days of PCS. Subjects will be evaluated prior to hospital 
discharge for recall of ICU experiences, and again at 3- and 6- 
month post-ICU for recall of ICU experiences, functional status, 
well-being and quality of life 
 
Reference therapy 
Usual Sedation Practice (Nurse Administered) 
Statistical 
Methodology 
Duration of mechanical ventilation after enrollment, total sedative 
exposure and anxiety levels over time between groups will be 
assessed using linear mixed models and competing risk approach. 
Analysis of the CAM-ICU scores (delirium present/absent) over 
time between groups will be accomplished with mixed models using 
general estimating equations (GEE). Post-ICU outcomes 
will be analyzed with bivariate and limited multivariate analyses. 
 
1. Introduction 
This document is a protocol for a human research study. This study will be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 
part 312 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures. 
 
1.1 
Background 
Each day approximately 55,000 patients are treated in U.S. adult ICUs [1]. 
Mechanical ventilation therapy is the major reason for ICU admission. While 
life-saving, intubation and mechanical ventilation cause unpleasant, distressful 
symptoms for patients such as anxiety, discomfort, fear, and dyspnea [2,3]. 
Numerous intravenous (IV) sedative and opioid medications are routinely 
administered by ICU nurses to ameliorate these symptoms and promote 
breathing synchrony with ventilators. While sedative therapy for ventilated 
ICU patients is a necessary, near-universal practice [4-7] the major issue is that 
patients are exposed to multiple, potent IV medications at high doses for 
prolonged periods leading to adverse outcomes such as prolonged ventilatory 
support and altered mental status. Since the 1970’s researchers have tested new 
drugs; developed methods to measure the effects of sedation [8]; shortened the 
duration of mechanical ventilation by minimizing excessive drug exposure 
while maintaining patient comfort [9]; and documented the post-ICU effects of 
sedative exposure on mental health outcomes [10]. However, one belief 
underlying 30 years of ICU practice has never been challenged: the assumption 
that clinicians are the only ones who can judge sedation adequacy and make 
dose adjustments to achieve a subjective clinician-desired sedation goal. It is 
important to challenge this assumption because a large body of evidence shows 
that in both in-patient and out-patient surgery and diagnostic procedures, 
patients manage symptoms of anxiety and pain better than clinicians and are 
more satisfied with self-management of these symptoms as compared to 
clinician-managed [11-15]. 
 
Until recently, sedation practice was driven by the belief that ICU symptom 
management and enhancement of post-ICU psychological recovery required 
that patients receive enough medications to “sleep through” their severe illness. 
But research has demonstrated the deleterious effects of sedation 

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such as delayed time to spontaneous breathing trials, [16] an association 
between periods of blunted awareness and worse post-ICU psychological 
recovery [17] and an association of sedatives with delirium. [18] In fact, 
ventilated patients randomized to a light sedation regimen required one day 
less of ventilatory support and had fewer disturbing memories of the ICU 
compared to those patients given a deeper sedation regimen [19]. Furthermore, 
a recent trial showed that it was feasible to not sedate patients at all during 
mechanical ventilation (analgesics were given) and that non- sedation was 
associated with a shorter ICU stay [20]. Research has clearly demonstrated that 
sedative use can be tailored to specific patient symptoms and behaviors; many 
ventilated ICU patients can be awake or only lightly sedated if they are 
comfortable [21]. An analogous clinical scenario is management of post- 
operative pain for which pain and opioid requirements can vary substantially 
among patients. Rather than nurses administering “as needed” medications 
after responding to patient complaints or behaviors indicating pain, patient- 
controlled analgesia with IV pumps control pain better while requiring less 
medication [11-15] and is a preferred method of pain control by patients in the 
post-operative period which also decreases their anxiety [13]. 
 
1.2 
Investigational Agents 
Dexmedetomidine (Precedex®) is a selective alpha-2 adrenergic agonist with 
both sedative and analgesic properties. The pharmacokinetic profile has a rapid 
onset and short duration of action, producing light sedative properties. 
Dexmedetomidine has no active metabolites, does not diminish respiratory 
drive, and has minimal effects on cognitive function. Subjects receiving 
dexmedetomidine for sedation can be easily awakened without stopping the 
infusion. Precedex® was approved in 1999 (NDA 021038) for sedation of 
initially intubated and mechanically ventilated patients during treatment in an 
intensive care setting, not to exceed 24 hours; or non-intubated patients prior 
to and/or during surgical and other procedures. 
 
The LifeCare PCA® Infusion System with Hospira MedNet™ Software is an 
electromechanical infusion pump that uses a stepper motor that exerts pressure 
on an inserted drug vial to control the infusion of analgesic into a patient. The 
infuser is pole-mounted and includes an attached patient pendant that allows 
a patient to self-administer analgesia within physician- prescribed, 
programmed parameters that include delivery mode, PCA dose, lockout 
interval (5-120 min in 1 min increments) and/or 1 or 4 hour dose limits. The 
LifeCare PCA® Infusion System with Hospira MedNet™ Software is 
indicated for accurate, volumetric, infusion of analgesic drugs by continuous 
or patient-demanded (PCA) intravenous administration. The LifeCare PCA® 
Infusion System allows patients to self-administer drug within clinician 
programmed limits and/or hospital-defined medication limits. Safety features 
include the bar code reader that is designed to enhance patient safety and 
automate drug identification and concentration. The system allows the device 
to recognize pharmacy-generated bar codes and apply 

5 
 
hospital-defined medication limits. The LifeCare PCA® infusion pump is used 
in practice at the Mayo Clinic site. The CADD Solis® infusion pump is used in 
practice at the University of Minnesota site. 
 
1.3 
Clinical Data to Date 
A review of short term (≤ 24 hour) patient controlled sedation by seventeen 
patients provided proof of principle that mechanically ventilated patients can 
use this technology [22]. While sedation level was appraised by the nurses as 
adequate, 70% of subjects received supplemental sedative and/or opiate 
medications. There were no self-extubations and 5 subjects experienced mild 
hemodynamic alterations known to be associated with the drug (persistent 
bradycardia or hypotension). Patient controlled sedation was discontinued for 
four subjects who developed hypotension. Patients rated dexmedetomidine for 
sedation favorably for self-management of anxiety and, relaxation level 
attained, and were comfortable in self-administration of a sedative agent. ICU 
nurses were generally satisfied with patient controlled sedation as a method for 
sedation, including satisfaction with dexmedetomidine as a sedative and with 
patients’ responses to the drug. 
 
In a small randomized trial pilot study conducted by Linda Chlan and Craig 
Weinert, MPIs (results submitted for publication), it was shown that intubated 
patients could be efficiently identified, consented, enrolled and treated with 
patient-controlled sedation using dexmedetomidine for up to 5 days. 
Hemodynamic effects were similar to that seen when dexmedetomidine is 
delivered by the usual nurse-managed method, there were no serious adverse 
events, daily anxiety assessments could be made and that patients rated the 
patient-controlled dexmedetomidine delivery method favorably. We did not 
find a shorter length of mechanical ventilation duration (although the study was 
not powered for that) or a reduction in anxiety compared to usual sedation 
method but there was an intriguing finding that no patient on PCS- 
dexmedetomidine developed delirium after enrollment whereas as 4 usual care 
patients did (p =.058, post-hoc analysis). 
 
2. Study Objectives 
2.1 
Primary Objective: 
The primary objective of the study is to assess the efficacy of patients’ self- 
management of sedative therapy (SMST) using dexmedetomidine compared to 
usual sedation practices in mechanically ventilated subjects. Efficacy will be 
defined by statistically significant differences compared to usual sedation care 
comparator for: 
a). 
Duration of mechanical ventilation after randomization 
b). 
Incidence of delirium after randomization as assessed by the CAM-ICU 
tool. 
c). 
Anxiety level over time after randomization. 
 
2.2 
Secondary Objectives: 
Secondary objectives for the study include comparing PCS to a usual sedation 
comparator for the following variables: 
a). 
Level of alertness over time after randomization as assessed by the 

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Richmond Agitation-Sedation Scale (RASS) scale. 
b). 
Total sedative drug exposure after randomization assessed by two 
previously methods we have published—an aggregate sedative exposure 
(combining 9 possible sedative-analgesics) and a sedation dose 
frequency method [25]. 
c). 
Ventilator-free days defined as the number of days between successful 
weaning from mechanical ventilation and Day 28 after study enrollment. 
 
2.3 
Exploratory Aim: 
The first exploratory aim is to compare post-ICU outcomes (physical/functional 
status, psychological well-being, and health-related quality of life) between 
MVPs randomized to SMST and those receiving nurse-administered sedative 
therapy. Statistically significant differences compared to usual sedation care 
comparator will be explored with the following: 
 
a). Physical and Functional Status: Physical status will be assessed by the 
Katz Activities of Daily Living Scale (KADL), a widely used instrument 
that assesses basic physical abilities such as bathing, feeding, etc., with 6 
questions. 
b). Psychological Well-Being: We will use two instruments to measure 
psychological well-being. The first is the: (1) Patient Health Questionnaire 
(PHQ-9) a brief, 9-item tool that has been successfully administered via 
telephone to post-ICU patients, and the items closely track the cardinal 
symptoms of major depression. The second is the: (2) Posttraumatic Stress 
Disorder Checklist Event Specific (PCL) which will be used to measure 
symptoms of PTSD. The tool contains 17 event-specific items associated 
with PTSD; higher scores indicate PTSD. 
c). Health-Related Quality of life: The Short Form-36 (SF-36) will be used 
to assess post-ICU quality of life. It contains 36 questions across 8 domains, 
with raw domain scores of 0-100; composite scores of “physical” and 
“mental health” can be compared to population norms. 
 
The second exploratory aim is to compare immediate post-extubation recollections 
of ICU and to explore any relationship among cognitive experiences (CAM-ICU) 
and awareness (RASS scores) with mechanical ventilation complications (device 
disruption, self-extubation) and sedative exposure between MVPs randomized to 
SMST and those receiving nurse-administered sedative therapy. Statistically 
significant differences compared to usual sedation care comparator will be explored 
following 24-48 hours after extubation prior to discharge, and then again at 3- and 
6-months after ICU discharge in accordance with the data collection points noted 
in exploratory aim #1: 
a). The Intensive Care Experience (ICE) questionnaire will be used to assess 
patient recall, awareness of surroundings, satisfaction of care, and self- reported 
frightening cognitive experiences post-extubation prior to hospital discharge, and 
then again at 3- and 6-months. ICE questionnaire contains a total of 31 questions in 
four main categories: awareness of surroundings, frightening experiences, recall of 
experiences, and satisfaction with care. Previous investigations using the ICE 
questionnaire have administered 24-31 items, depending on the domains for 
assessment. We will administer 25 items at the three data collection time points. 

7 
 
3. Study Design 
3.1 
General Study Design 
The study design will be an open label two-group randomized design with 
repeated measures and subjects randomly allocated to either: 1) Patient 
controlled, self-management of sedative therapy using dexmedetomidine or 
2) nurse-administered sedative therapy (usual care). The protocol will last up 
to seven days or until the patient exits the study. After 7 days the sedative 
regimen reverts to usual care with drug choice by the attending consultant 
physician. We will obtain from all participants who are alive and living in their 
own homes data on post-ICU physical and functional status, psychological 
well-being, and health-related quality of life. These assessments will be 
obtained over the telephone at 3- and 6-months post-ICU discharge. A member 
of the research team will contact the individual at the designated time period 
and ascertain a convenient time to obtain the data. We will request a home 
phone number for this follow-up prior to hospital discharge or obtain it from 
the electronic health record. 
 
 
3.2 
Primary Study Endpoints 
a) Duration of mechanical ventilation after randomization 
b) Incidence of delirium for up to 7 days after randomization 
c) Anxiety level over time by the visual analog scale (VAS-A) measure for up 
to 7 days 
 
3.3 
Secondary Study Endpoints 
The secondary endpoints to be analyzed in this study include 
a) Level of alertness of subjects after randomization and for up to 7 days 
b) Total sedative exposure for up to 7 days after randomization 
c) Ventilator-free days after randomization 
 
4. Subject Selection and Withdrawal 
4.1 
Inclusion Criteria 
Subjects may be included in the study if all of the following conditions exist: 
1. 
Subject is acutely mechanically ventilated during the current 
hospitalization 
 
2. 
Subject is currently receiving a continuous intravenous infusion of a 
sedative/opioid medication(s) or has received at least one intravenous 
bolus dose of a sedative/opioid medication in the previous 24 hours 
(fentanyl, hydromorphone, ketamine, morphine, midazolam, diazepam, 

8 
 
lorazepam, propofol, haloperidol, dexmedetomidine). 
3. 
Subject must pass pre-PCS screening test (see below 4.4) and be 
assessed RASS -2 to +1 
4. 
Subject Age ≥ 18 years 
5. 
Subject or their proxy is capable of providing informed consent 
 
4.2 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following conditions 
exist: 
1. 
Aggressive ventilatory support or prone ventilation. 
2. 
Hypotension (systolic blood pressure < 85 mmHg) requiring a 
vasopressor at a dose greater than norepinephrine or epinephrine 0.15 
mcg/kg/min or vasopressin > 2.4 units per hour. Subjects will be 
excluded if they require more than one continuous infusion of a 
catecholamine vasopressor medication simultaneously. Subjects will be 
excluded if the vasopressor dose was higher than norepinephrine or 
epinephrine 0.15 mcg/kg/min, vasopressin > 2.4 units per hour, 
phenylephrine >3 mcg/kg/min, dopamine >10 mcg/kg/min or 
dobutamine at any dose in the prior 6 hours. If dopamine is being used 
to increase heart rate, rather than as a vasopressor for hypotension, 
subject will be excluded. 
3. 
Second or third degree heart block or bradycardia (heart rate < 50 
beats/min). 
4. 
Paralysis or other condition preventing the use of push button device 
5. 
Positive pregnancy test or lactation 
6. 
Acute hepatitis or acute liver failure (direct bilirubin >5 mg/dL) 
7. 
Acute stroke or uncontrolled seizures. 
8. 
Acute myocardial infarction within 48 hours prior to enrollment. 
9. 
Severe cognition or communication problems (such as coma, deafness 
without signing literacy, physician-documented dementia) 
10. 
Assessed RASS -3, -4, -5 or RASS +2, +3, +4 
11. 
Chronic ventilator support in place of residence prior to current 
hospitalization. 
12. Imminent extubation from mechanical ventilator support. 
 
4.3 
Study Exit Criteria 
Subjects will exit from the study if any of the following conditions exist: 
1. Subject completes protocol 
2. Subject (or proxy giving initial consent) voluntarily withdraws from 
the study 
3. Subject death 
4. Subject is extubated and remains free of invasive ventilation for 24 
hours 
5. Subject transfers from the ICU 

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6. Subject experiences a serious persistent adverse event such as 
unexplained rash or sustained hemodynamic instability as defined in 
the SEDCOM [23] trial (e.g., systolic blood pressure < 80 or > 180 
mmHg, diastolic < 50 or > 100mmHg despite the use of a vasopressor 
at dose greater than norepinephrine or epinephrine 0.15 mcg/kg/min, 
vasopressin > 2.4 units per hour, phenylephrine >3 mcg/kg/min, 
dopamine >10 mcg/kg/min, dobutamine at any dose, or two 
catecholamine vasopressors at any dose, or heart rate < 40 or > 120 
beats/min) 
7. Pregnancy 
 
4.4 
Subject Recruitment and Screening 
Subjects will be recruited from three facilities located 90 miles apart. Research staff will 
ask attending physician consultants each screening day about approaching potential study 
eligible patients. Inclusion and exclusion criteria will be reviewed; only those patients 
approved for the study by the primary medical care team will be approached for potential 
study participation. 
 
The University of Minnesota Medical Center (UMMC) Fairview, Medical and Surgical 
ICUs in Minneapolis, MN. UMMC is the primary teaching hospital of the University of 
Minnesota Medical School. Combined, these adjacent ICUs have 47 staffed beds; admit 
about 1500 patients annually of which approximately 900 require mechanical ventilation. 
 
Fairview Southdale Hospital has a single mixed med-surgery/Neuro/CV surgery ICU with 
22 bed capacity with approximately 720 ventilated patients annually. Their physician/NP 
intensivist providers are drawn from the same ICU program as UMMC thereby ensuring 
that the general ICU practice regarding sedation and mechanical ventilation is similar to 
that of UMMC. Southdale uses the same PCS drug delivery machines as UMMC and the 
drug will be dispensed by the Fairview Investigational Drug Service in the same manner 
as UMMC. 
 
Fairview Ridges Hospital has a medical-surgical ICU with 12 beds. Their physician 
intensivist providers are drawn from the same ICU program as UMMC thereby ensuring 
that the general ICU practice regarding sedation and mechanical ventilation is similar to 
that of UMMC. Ridges uses the same PCS drug delivery machines as UMMC and the drug 
will be dispensed by the Fairview Investigational Drug Service in the same manner as 
UMMC. 
 
St Mary’s Campus is the main hospital for patients at the Mayo Clinic Hospital-Rochester 
and has 80 adult ICU beds. The Methodist Campus has 21 adult ICU beds. The MICUs (24 
total beds) average 2900 patient admissions per year with approximately 880 mechanically 
ventilated patients/year from which to enroll participants. 
 
Our previous experience with recruiting mechanically ventilated subjects for PCS studies 
shows a 45% consent yield rate, which should easily permit enrolling 190 patients over the 
study period —111 at Mayo Clinic and 79 at UMMC. 
 
The three facilities utilize electronic medical records systems, physician-order entry and 
have Research Investigational Drug Pharmacies that can dispense and monitor study 
medications. The Mayo Clinic site uses the Hospira LifeCare® pump in routine clinical 
use so RN staff will be familiar with it when used in study patients. The University of 

10 
 
Minnesota sites use the CADD Solis® infusion pump. RN staff at the University of 
Minnesota sites are familiar with the infusion pump operations. 
 
Informed Consent will be obtained from either the patient or via proxy consent of the 
patient’s legally authorized representative (LAR). 
 
Subjects will be screened for participation with a pre-PCS screening test to evaluate 
motor abilities, alertness, and presence of delirium (Uploaded to Section 47, Supporting 
Documents). Motor abilities and alertness level will be evaluated by a trained research 
staff that will consist of the following: Motor ability will be assessed by placing the 
medication push-button activation device button in the patient’s hand and asking them to 
depress the button or click a ball-point pen. An audible tone is emitted after the device is 
engaged, which will verify the patient has enough strength to depress the button. The 
alertness screen will consist of the trained research staff assessing the subject’s ability to 
communicate and appropriately follow commands, including direction to depress the 
actual PCS button and following verbal instructions accurately to do so. The two-step 
process of the Confusion Assessment Method-ICU (CAM-ICU uploaded to Section 47, 
Supporting Documents) will also be administered to determine a patient’s alertness and 
for the presence of delirium. Step one of the assessment process consists of arousal and 
alertness assessment using the Richmond Agitation-Sedation Scale (RASS). Any patient 
will need to be assessed as RASS level of -2 to +1 ( -1 indicates drowsy, easily 
arousable and wakens with eye-opening/eye contact to voice; -2 indicates light 
sedation awakens with eye contact to voice) to be eligible for study participation. 
Step two of the assessment process includes administration of the Confusion Assessment 
Method for the ICU (CAM-ICU) which consists of the delirium assessment component. 
The dichotomous result is either delirium absent (CAM-ICU negative) or delirium 
present (CAM-ICU positive). Potential participants must be RASS -1 to +1 AND CAM- 
ICU negative to provide their own informed consent. 
 
Procedures for Proxy Consent 
If a potential participant passes the pre-screening test, is RASS -2 to +1 except is found to 
be CAM-ICU positive (delirium present), proxy consent must be pursued as detailed. 
Presence of delirium will not automatically exclude any potential participants. Given 
delirium is a transient syndrome, if a patient can follow commands, rate his/her anxiety, 
and follow commands to independently depress the PCS push-button device, she/he will 
be considered for enrollment by proxy after the research personnel discusses the pre- 
screening results with the attending consultant physician and Dr. Gajic (or his designate) 
at Mayo Clinic or Dr. Weinert (or his designate) at UMMC, Fairview Southdale, and 
Fairview Ridges. 
 
We estimate that some patients who are otherwise eligible (RASS -2 to +1), pass the pre- 
screening test but are CAM-ICU+ (delirium present) will not be able to provide their own 
informed consent. In this case, we will use proxy consent for any patient who is willing 
and able to self-medicate with dexmedetomidine by verbal assent with an affirmative 
head nod “yes”. We are an experienced research team that is familiar with the sometimes 
limited capacities of mechanically ventilated patients and the need for obtaining proxy 
consent, such as patients too fatigued or weak to actively participate in a lengthy consent 
process, decreased ability to maintained focused concentration, or may be more heavily 
sedated for a short duration such as for a bedside procedure. 
 
We will obtain consent for participation from a family member or legally authorized 

11 
 
representative (LAR) if an eligible patient is unable to participate in a lengthy consent 
process and/or CAM-ICU+ yet is deemed to be a promising candidate for the protocol. 
Patients must be reasonably alert (RASS -2 to +1), follow commands appropriately and 
consistently, and be able to depress the push- button activation device to be considered for 
study participation with consent via proxy. A member of the research team will approach 
the designated proxy LAR and explain the study and what is being asked of the proxy if 
consent is provided to participate in the study. Each proxy will then read the consent form 
and be asked to re-phrase to a member of the research team what the study aims are, how 
long the patient will remain in the study, and if payment will be received. Opportunity will 
be provided for asking questions concerning the protocol. If the LAR is not available at the 
bedside, and not expected to be for the rest of the day, study personnel will contact him/her 
by telephone and explain the study and what is being asked of the LAR if consent is 
provided to participate in the study. A DocuSign email will be sent to the LAR with a link 
to the consent form. The consent form will be reviewed with the LAR. The LAR will be 
asked to rephrase to the study team member what the study aims are, how long the patient 
will remain in the study, and if payment will be received. If the LAR agrees to provide 
consent verbally, the study team member will direct the LAR to electronically sign the 
consent form. 
 
Females less than 50 years old and who are of unknown fertility (pregnancy) status after 
review of the medical record including documentation of surgical procedure or medical 
condition that would make pregnancy unlikely and/or recent serum or urine pregnancy test, 
have to consent to a urine or serum pregnancy test to be performed in the hospital lab at no 
cost to the patient. If the test is positive, the patient and her doctor will be informed and the 
subject then will be withdrawn from the study BEFORE randomization. 
 
If the female is > 50 years old or has clear documentation of a surgical procedure or medical 
condition that would make pregnancy unlikely or has a recent serum or urine pregnancy 
test that is negative, then they can proceed to randomization. 
 
4.5 
Subject Randomization 
Subjects (n =228 total accounting for 20% attrition to attain a target sample of 
n = 190) will be assigned to either the Usual Sedation Practice or Patient 
Controlled Sedation arms of the study based on a block randomization plan 
developed by the Mayo Clinic study statistician and administered by the 
Research Pharmacy Investigational Drug Service at both hospitals. For patients 
randomized to the experimental arm, dexmedetomidine will be prepared and 
dispensed with Research Pharmacy prepared, bar-coded medication cartridges. 
Randomization will occur after written consent is received. 
 
4.6 
Early Withdrawal of Subjects 
Subjects will be withdrawn if any of the Exit Criteria listed in Section 4.3 are 
present. If subjects are withdrawn prior to extubation, they will be transitioned 
to usual sedation practice per the primary medical care team. For any subject 
who completes the 7-day PCS protocol and is still receiving mechanical 
ventilatory support, Dr. Weinert at UMMC or Dr. Gajic at Mayo 
(or their designates) will consult with the subject’s attending physician for the 
transition to primary care team sedation management. All data will be 
considered for analysis regardless of length of time on protocol. 
 
5. Study Drug 

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5.1 
Description 
Dexmedetomidine (Precedex®) is a selective alpha-2 adrenergic agonist with 
both sedative and analgesic properties. The pharmacokinetic profile has a rapid 
onset and short duration of action, producing light sedative properties. 
Dexmedetomidine has no active metabolites, does not diminish respiratory 
drive, and has minimal effects on cognitive function. 
 
5.2 
Treatment Regimen 
We will use a continuous basal infusion (0.2-0.7 mcg/kg/hr) with 3 allowable 
patient-controlled self-boluses per hour (0.25 mcg/kg) each with a 20-minute 
lock-out. The Lifecare PCA® Infusion System is the infusion pump used at 
Mayo Clinic and the CADD Solis® infusion pump is used at the University of 
Minnesota sites; infusion pumps will be set up by the patient care nurse. The 
pump will be utilized in the PCA + continuous mode. Intermittent doses are 
delivered in 1 ml over 35 seconds. Delivery accuracy is ± 5% for continuous 
delivery rates > 1 ml/hour. Settings, dose delivery times and aggregate dosing 
are recorded by the pump for later retrieval. 
 
5.3 
Preparation and Administration of Study Drug 
Dexmedetomidine will be stored, prepared and dispensed from the Central 
Pharmacy at Mayo Clinic and from the Investigational Drug Service Pharmacy 
at UMMC, Fairview Southdale, and Fairview Ridges. When study drug is 
requested for a subject, the respective pharmacy will obtain the study 
dexmedetomidine and complete the required paperwork documenting the lot 
number and vials utilized for the specific study subject. 
 
For patients weighing between 50 and 164 kg at the time of study enrollment, 
under strict aseptic technique, 720 µg/7.2 ml will be added to 52.8 ml of 0.9% 
sodium chloride; this will yield a concentration of 720 µg/60 ml (or 12 
µg/ml). Two 30 ml syringes will be drawn up from the bag each containing 
360 µg/30 ml of dexmedetomidine. Dexmedetomidine will be delivered via a 
pharmacy-prepared bar-coded cartridge syringe manufactured for use with the 
LifeCare PCA® infusion device as described above. Preparation date and time 
will be recorded. Within 48 hours of initial preparation, the volume of the 
remaining preparation will be recorded and a fresh drug preparation will be 
supplied for the subject. 
 
For patients weighing between 165 and 260 kg at the time of enrollment, under 
strict aseptic technique, 1200 µg/12 ml will be added to 48 ml of 0.9% sodium 
chloride; this will yield a concentration of 1200 µg/ 60 ml (or 20 
µg/ml). Two 30 ml syringes will be drawn up from the bag each containing 
600 µg/30 ml of dexmedetomidine. Each syringe will be clearly labeled “FOR 
> 165 kg patients ONLY.” Dexmedetomidine will be delivered via a 
pharmacy-prepared bar-coded syringe manufactured for use with the LifeCare 
PCA® infusion device as described above. Preparation date and time will be 
recorded. Within 48 hours of initial preparation, the volume of the remaining 
preparation will be recorded and a fresh drug preparation will be supplied for 
the subject. 
 
 
6. Study Procedures 

13 
 
Usual Care: Subjects will receive standard care for the respective ICU which 
consists of nurse-administered sedative therapy as ordered by the primary care team. 
 
Anxiety and mental status/alertness assessments will be performed by a member of 
the research team three times each day, up to 7 days or until the ICU phase of the 
protocol is completed (i.e., extubation, transfer out of ICU, patient withdraws or is 
withdrawn from study), for subjects in both groups. 
 
Self-management of Sedative Therapy (SMST) with Dexmedetomidine PCS 
Protocol: The PCS dosing algorithm will consist of a continuous basal infusion (0.2- 
0.7 mcg/kg/hr) with 3 allowable patient-controlled self-boluses per hour (0.25 
mcg/kg) each with a 20-minute lock-out. Dr. Weinert or his designate at UMMC, 
Fairview Southdale, and Fairview Ridges or Dr. Gajic or his designate at Mayo Clinic 
will write the PCS medication orders; each study patient on dexmedetomidine will 
begin the study with a continuous, basal infusion of 0.2 mcg/kg/hr; set up by the 
patient care nurse. Patient-care nurses will increase or decrease the basal infusion 
rate based on the number of mini-bolus doses self-administered from the subject in 
the prior two hours. Subjects can receive bolus supplemental sedative medications 
(benzodiazepines and/or opioids) as ordered by Dr. Weinert or Dr. Gajic (or their 
designate) if needed in the judgment of the patient-care nurse. Subjects will be 
monitored closely by research personnel during the first 4 hours on protocol. Every 
4-hour heart rate and blood pressure recordings will be abstracted from the medical 
record daily during each subject assessment visit. Alert adverse events will be 
reported by research personnel or the patient-care nurse to first the attending 
physician and then to the safety monitor. 
 
Nurse alert parameters to notify the attending physician consultant and study 
physicians (Drs. Gajic, Weinert or their designate) include: heart rate (HR) < 55 beats 
per min for > 5 min; systolic BP < 90 mm Hg; diastolic BP < 55 mm Hg; or mean 
arterial pressure < 60 mm Hg on two measurements 10 min apart.; persistent inability 
to understand rationale for triggering the PCS device despite education and 
demonstration; or marked worsening of respiratory status requiring aggressive 
ventilatory support with deep sedation and/or chemical paralysis. 
 
Data Collection Measures and Procedures 
Study entry demographic and descriptive data: Data to be recorded includes: 
age, gender, race, ethnicity, admission and enrollment weight, medical diagnoses, 
indication for ventilatory support, medications including sedative medications in 
the prior 24 hours, ventilator settings, and severity of illness measured by 
APACHE III score. The APACHE III is used to stratify patients during the first 24 
hours of ICU admission to determine severity of illness and predict mortality; a 
higher score is associated with an increased risk of death. Data to determine illness 
severity will be abstracted by a member of the research team from the medical 
record. For daily illness severity, Sequential Organ Failure Assessment (SOFA) 
will be scored each day from the medical record for the length of study enrollment. 
In order to describe this sample of ICU patients, data to calculate the length of ICU 
stay as well as length of mechanical ventilation will be collected. Any differences 
in illness severity, SOFA scores, age, or sex will be considered as covariates in 
subsequent analyses. 
 
Daily Measures on Protocol. 

14 
 
Sedative exposure. For all subjects, we will measure exposure to 9 commonly 
administered intravenous sedative and analgesic medications (lorazepam, midazolam, 

15 
 
propofol, morphine, hydromorphone, fentanyl, dexmedetomidine, haloperidol, ketamine) 
for up to 7 days after enrollment (primary drug endpoint for analysis). We have developed 
a method (the sedation intensity score) [25] to aggregate dose frequency and dosing of 
intravenous medications from disparate drug classes by day. The 9 possible intravenous 
drugs tracked are summarized individually over all subjects and time periods to obtain 
estimates of their medians and quartiles. Each drug during each 4-hr period is then assigned 
a ranking as follows: 0 for drug not used, 1 for the bottom quartile, 2 for the second quartile, 
3 for the third and 4 for the fourth. These scores are then summed for the day over the six 
4-hour blocks to produce a daily sedation intensity score. Our analysis will compare the 
mean sedation intensity scores between the PCS and usual care group. For the PCS group, 
the patient care nurse will record every two hours the basal infusion rate, number of patient 
triggers, and actual doses delivered. 
 
We will also use a dose-frequency analysis based on recent trials that suggest the 
mechanism by which sedation protocols result in more rapid weaning from ventilatory 
support is by reducing the time exposure to sedatives [9,26]. We will divide a 24-hr day 
into six, 4-hour time blocks and, for each of the 9 intravenous drugs, sum the occurrences 
in which a non-PCS drug was administered at least once during that interval. The amount 
of drug, count of doses above one, and type of administration (bolus vs. infusion) are not 
influential in this approach. 
 
Alertness and Delirium. Level of arousal will be assessed three times each day (07:00, 
13:00, 19:00; +/- 2 hours) by research study staff with the Richmond Agitation- Sedation 
Scale (RASS). The RASS is based on a 10-point scale, with four levels of agitation 
ranging from +1 (restless) to +4 (combative), one level representing an alert and calm 
state (0), and five levels of sedation ranging from -5 (unarousable) to -1 (drowsy). These 
assessments will be completed by a member of the research team ( (investigator, study 
coordinator or member of the CRTU (Mayo Clinic only)) at 07:00,13:00, and 1900 (+/- 
2hours). The RASS scores obtained at 07:00, 13:00 and 19:00 (+/- 2 hours) will be 
compared between groups and correlated with sedative exposure and dosing by drug 
class (benzodiazepine midazolam equivalents, morphine equivalents for opioids, 
propofol, and dexmedetomidine) to address our secondary aim. 
 
The Confusion Assessment Method-ICU (CAM-ICU) [24] will be used as a pre- 
enrollment delirium screening tool and to measure level of alertness and presence of 
delirium three times each day in both groups. The pre-enrollment delirium screening will 
be obtained by a member of the research team (investigator or study coordinator). These 
assessments will be completed by a member of the research team (investigator, study 
coordinator or member of the CRTU (Mayo Clinic only)) at 07:00, 13:00, and 1900 (+/- 2 
hours). Any positive delirium findings will be reported by the research staff to the primary 
care team. Research personnel will be trained by Dr. Tracy at UMMC and Dr. Chlan at 
Mayo Clinic in assessment with the CAM-ICU using free web resources 
(www.icudelirium.org). 
 
Anxiety rating. Anxiety, defined as a state marked by apprehension, agitation, increased 
motor activity, arousal, and fearful withdrawal [27] will be obtained from subjects by a 
member of the research team (investigator, study coordinator, or member of CRTU 
(Mayo Clinic only)) prior to randomization and at 07:00,13:00, and 1900 (+/- 2 hours). 
This will be the primary symptom endpoint for analysis. Subjects will be asked three 
times daily to rate their current level of anxiety on the visual analog scale-anxiety (VAS- 
A) in response to, “How are you feeling right now?” A 100-millimeter vertical line will 

16 
 
be anchored on each end by statements ‘not anxious at all’ to ‘the most anxious I have 
ever been’. The VAS-A will have a vertical orientation, as it is more sensitive and easier 
for subjects to use, particularly for those with a narrowed visual field or when under 
stress [28,29]. Subjects will be asked to mark their current anxiety level on the vertical 
line. Scores will be derived by the distance in millimeters from the bottom anchor to the 
mark placed by the subject, yielding interval level data [30,31]. Reason(s) for not 
obtaining any of the anxiety assessments will be recorded by the research staff. 
 
Duration of mechanical ventilatory support. This will be calculated from the time of 
study enrollment to clinician-ordered extubation, withdrawal of ventilatory support or 
death for the incident ICU admission. Patients will be required to remain free from 
mechanical ventilatory support for 24 hours to be considered liberated from mechanical 
ventilation. Unplanned self-extubations and re-intubations and timing and frequency of 
tracheostomy will be recorded. 
 
Mechanical Ventilator-Related Outcomes. We will obtain data on the following 
important mechanical ventilator-related outcomes. These data will be used to describe the 
clinical course for all study participants: tracheostomy placement, reintubation rates, time 
to first and successive weaning trials (initiation of pressure support or t-piece weaning), 
extubation, ICU discharge destination (step-down, long-term acute care hospital, 
rehabilitation or skilled nursing facility, death), ICU or hospital readmission at any time 
from transfer/discharge during the 6-month follow-up period. 
 
Protocol adherence. A checklist will be completed daily by the research staff to monitor 
the number of days subjects are able to use the PCS device for up to 7 days. A checklist 
will also be used to monitor the ability of the ICU nurses to adjust and adhere to the PCS 
infusion protocol per instructions. 
 
Daily adverse event monitoring. A member of the research team will record and report 
the presence of hypotension, bradycardia (known adverse effects of dexmedetomidine), 
delirium, self- extubations, and protocol deviations related to drug, pump or both. Heart 
rate and blood pressure will be abstracted from the medical record. Research staff or ICU 
nurses caring for PCS subjects will alert the attending physician and the safety monitor for 
sustained (lasting > 30 min.) systolic blood pressure < 80 or > 180 mmHg, diastolic < 50 
or > 100 mmHg; heart rate < 40 or > 120 beats/min for any necessary intervention or 
protocol withdrawal. 
 
Post-PCS Satisfaction Survey. Upon completion of the SMST PCS protocol, we will 
query subjects about their satisfaction with self-administration of medication to manage 
anxiety, ease of medication administration, and the resulting level of relaxation. 
 
Post-Extubation ICU Recall Prior to Hospital Discharge and at 3 and 6 months 
The Intensive Care Experience (ICE) questionnaire will be administered to all subjects 
24-48 hours after extubation and prior to hospital discharge or transfer out of ICU, and 
then again at 3 and 6 months after ICU discharge in accordance with the Post-ICU 
Outcomes data collection points noted below. The ICE questionnaire contains 31 total 
questions in four main categories: awareness of surroundings, frightening experiences, 
recall of experiences, and satisfaction with care. We will administer 25 questions to 
subjects at the three assessment time points. Subjects who are not extubated prior to ICU 
transfer or hospital discharge will not be assessed for ICU recall with the ICE 
questionnaire. 

17 
 
 
Post-ICU Outcomes at 3- and 6-months 
 
Telephone follow-up will be completed at 3 and 6 months after date of study 
randomization. 
 
Physical and Functional Status: Physical status will be assessed by the Katz Activities 
of Daily Living Scale (KADL), a widely used instrument that assesses basic physical 
abilities such as bathing, feeding, etc., with 6 questions. The Functional Activities 
Questionnaire (FAQ) contains 10 questions that assess instrumental activities of daily 
living that require higher-order abilities, such as cooking, driving, managing finances, 
medications, etc. 
Psychological Well-Being: We will use two instruments to measure psychological well- 
being. The first is the: (1) Patient Health Questionnaire (PHQ-9) a brief, 9-item tool that 
has been successfully administered via telephone to post-ICU patients, and the items 
closely track the cardinal symptoms of major depression. The second is the: (2) 
Posttraumatic Stress Disorder Checklist Event Specific (PCL) which will be used to 
measure symptoms of PTSD. 
 
Health-Related Quality of life: The Short Form-36 (SF-36) will be used to assess post- 
ICU quality of life. It contains 36 questions across 8 domains, with raw domain scores of 
0-100; composite scores of “physical” and “mental health” can be compared to 
population norms. 
 
7. Statistical Plan 
 
Estimates of Effect Sizes, Sample Size, and Statistical Power. Our primary 
outcomes are anxiety, duration of mechanical ventilation, and delirium. In our previous 
study, overall, anxiety decreased over time for the PCS group by 5 points from 58.1 to 
53.1 (0-100 visual analog scale), whereas it increased by 15.5 points from 43.7 to 53.9 for 
the UC group. The delta change for anxiety = .45 for an effect size = .11 with a sample 
size of 95 per group (190 total). We base our target sample size on these anxiety data for 
our efficacy RCT. During the study, no patients randomized to DEX-PCS became 
delirious, while four patients randomized to UC group developed delirium. Because of 
small numbers, the p value was .058. A sample of 35 subjects per group would be 
required (70 total). The power calculation for duration of mechanical ventilatory support 
after study enrollment (Mann-Whitney U) with an effect size of .41 would = 43 per group 
(86 total). 
Using Optimal Design software, we estimated the power for multilevel models 
approximating our study design. A sample size of 95 patients per arm, 190 total (at a 
minimum 7 data collection points for each, resulting in ~1,050 observations) will have 
greater than 80% power to detect small to moderate effects (i.e., 0.11 or greater) in 
between-group differences in anxiety, delirium, and duration of mechanical ventilation at 
alpha = .05 for all proposed models. 
 
Preliminary Analyses. In initial analyses, we will screen to identify and, if necessary, 
correct outliers, data entry errors, or other logical inconsistencies. After data cleaning, we 
will calculate descriptive statistics to ensure the quality of the data (check distributions, 
examine outliers) and describe the sample. Where necessary, we will consider variable 
collapsing or power transformations. We will evaluate the psychometric qualities 
(reliability, convergent and discriminant validity) of the scales, employing both exploratory 

18 
 
factor analyses and SEM measurement models. We will identify potential effects of 
respondent attrition. The bivariate analyses will include independent and dependent t tests, 
correlations, one-way ANOVAs, and repeated measures ANOVAs. Analyses will include 
both Intention-to-treat and per-protocol. 
 
Analysis by Aims. Our primary aim is to determine the efficacy of PCS compared to 
nurse-administered sedative therapy on anxiety, duration of mechanical ventilation 
after enrollment, and presence of delirium in ventilated patients. All three outcomes will 
be assessed with multilevel models. We will conduct multilevel growth curve analyses, to 
model the trajectories of anxiety as predicted by group in 190 patients, while controlling 
for illness severity, age, sex, or sedative exposure. The level 1 sub-model will estimate how 
each patient’s stress changes over one week. The level 2 sub-model will relate the inter- 
individual differences to intervention group and other time-invariant predictors (such as 
biological sex) and will estimate a subject’s initial anxiety level and rate of change in 
anxiety over the week. Anxiety will be modeled in terms of random subject effects 
(intercept and time trends) to account for individual differences in how patients change 
over time. We will begin with a linear model for time but will investigate nonlinear effects 
as suggested by the data. Subsequent models will contain time-varying covariates (i.e., 
sedative exposure and acuity (APACHE III)) and thus will be able to focus on within- 
subjects effects, that is, whether within-subject differences in the covariates are associated 
with within-subject differences in anxiety. The most appropriate covariance structure for 
the residuals will be determined after data collection and the correlation of responses over 
time is estimated. Several covariance structures will be examined and the resulting models 
compared for fit using the quasi-likelihood independence model information criterion 
(QIC). 
 
Statistical analysis for the duration of mechanical ventilation outcome will be time (days) 
from study enrollment to first ventilation free day (24 hours free of mechanical ventilation 
support after extubation) as an outcome will be performed using competing risk approach 
as referenced in Fine and Gray (1999). In this analysis, death will be considered as a 
competing event. When delirium is operationalized as a dichotomy (present vs. absent) 
over time we will fit the models using general estimating equations (GEE). For binomial 
data, the most appropriate link function is the logit (logistic regression model) and, for 
incidence, the log (Poisson regression in Log-Linear Model). 
 
Withdrawal of mechanical ventilatory support is not considered equivalent to death but 
the same as a medically planned extubation (i.e., patient who is determined to be ‘ready’ 
for extubation by the medical care team). For those enrolled patients who undergo 
terminal withdrawal of ventilatory support, we will ascertain their vital status up to 30 
days after enrollment in the study ended. 
 
Our first secondary aim is to: (1) Examine level of alertness (RASS) and sedative 
exposure (frequency and intensity) in patients randomized to SMST compared to those 
patients receiving nurse-administered sedative therapy. We hypothesize that SMST 
patients will be more alert and be exposed to less sedation than those who receive nurse- 
administered sedative therapy. After bivariate tests, such as repeated measures ANOVAs, 
we will fit multilevel models as described in our primary aim. Similar analyses will be used 
for the exploratory aim data. 
 
Our second secondary aim is to: (2) compare ventilator-free days in patients randomized 
to SMST to those patients receiving nurse-administered sedative therapy. Ventilator-free 

19 
 
days are defined as the number of days between successful weaning from mechanical 
ventilation and day 28 after study enrollment. A score of zero will be assigned to any 
patient who dies within 28 days or remains on the ventilator for 28 days or more. For other 
patients that are alive and successfully weaned from mechanical ventilation, a score of 28 
minus number of days on ventilation will be assigned. Ventilator-free days will be analyzed 
using Wilcoxon rank sum test. 
 
Our first exploratory aim is to compare post-ICU outcomes (physical/functional and 
psychological well-being; health-related quality of life) between patients randomized to 
SMST and those receiving nurse-administered sedative therapy. We anticipate conducting 
bivariate and limited multivariate analyses for these data. 
 
Our second exploratory aim is to compare immediate post-extubation recollections of ICU 
and to explore any relationships among cognitive experiences (CAM-ICU) and awareness 
(RASS scores) with mechanical ventilation complications (device disruption, self- 
extubation) and sedative exposure between MVPs randomized to SMST and those 
receiving nurse-administered sedative therapy. Statistical comparisons between the two 
study groups will be carried out for total scores on the 25-item ICE questionnaire as a 
whole, as well as and its 4 main categories, will be performed using two sample t-test or 
Wilcoxon rank sum test as appropriate. In an event there are baseline imbalances between 
the two groups, we will use linear regression approach to adjust for those variables with 
imbalances. Analysis will be performed separately for each of the three time points (24- 48 
hours, 3 months, 6 months). 
 
 
8. Safety and Adverse Events 
8.1 
Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens in severity during the course of the study. Intercurrent 
illnesses or injuries will be regarded as adverse events. Abnormal results of 
diagnostic procedures are considered to be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse 
event is any AE that is: 
• 
fatal 
• 
life-threatening 
• 
requires or prolongs a hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
Important medical events are those that may not be immediately life 
threatening, but are clearly of major clinical significance. They may jeopardize 
the subject, and may require intervention to prevent one of the other serious 

20 
 
outcomes noted above. For example, drug overdose or abuse, a seizure that did 
not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious. 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of 
the study treatment follow-up. For this study, the study treatment follow-up is 
defined as 24 hours following extubation, study withdrawal, transfer out of 
ICU or 24 hours after completing 7 days on protocol from the time of 
randomization. Refer to Data and Safety Monitoring Plan (DSMP) for 
additional details. 
 
 
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on 
adverse events by specific questioning and, as appropriate, by examination. 
Information on all adverse events will be recorded immediately in the source 
document, and also in the appropriate adverse event module of the case report 
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic 
procedures results will be recorded in the source document, though should be 
grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded. The 
clinical course of each event will be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not the 
cause. Serious adverse events that are still ongoing at the end of the study 
period must be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly 
related to the study treatment or study participation should be recorded and 
reported immediately. 
 
8.3 
Reporting of Serious Adverse Events. Refer to the Data Safety 
Monitoring Plan and the Data and Safety Monitoring Board charter. 
 
8.4 
Stopping Rules 
Initial protocol suspension rules are as follows for an individual subject’s 
participation in the study: 
• 
Persistent (>30 min.) adverse hemodynamic effects as in the SEDCOM 
[23] trial including systolic blood pressure < 80 or > 180 mmHg, 
diastolic blood pressure < 50 or > 100 mmHg; heart rate < 40 or > 120 
beats/min.; 
• 
Persistent inability to understand rationale for triggering the PCS device 
despite education and demonstration; or 
• 
Marked worsening of respiratory status requiring aggressive ventilatory 
support with deep sedation and/or chemical paralysis. 
 
Any subject who experiences any of the above will first be evaluated by the 
attending physician consultant (or his/her designate). He/she will communicate 
their findings to Dr. Weinert at UMMC or Dr. Gajic at Mayo Clinic (or their 
designate) and their opinion of any event(s) regarding the suitability of an 

21 
 
individual subjects to continue on the study protocol. Dr. Weinert or Dr. Gajic 
(or their designate) will review the circumstances and will decide whether to 
restart the protocol or withdraw the subject from the protocol. 
 
The study does not have any pre-planned interim analysis. Our study team will 
monitor adverse and serious adverse events on a monthly basis. If there is 
clinically meaningful imbalance in such event related to the experimental 
intervention irrespective of statistical significance, DSMB members will be 
notified. Decision of continuation versus stopping the study will be made in 
consultation with DSMB members. 
 
8.5 
Medical Monitoring 
It is the responsibility of the Principal Investigators to oversee the safety of the 
study at his/her site. This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the 
construction and implementation of a site data and safety- monitoring plan. 
Medical monitoring will include a regular assessment of the number and type 
of serious adverse events. In addition, a blinded adverse event attribution 
adjudication committee comprised of clinicians independent of the research 
team is in place at each site. It is the responsibility of the adjudication 
committee to judge the relatedness of any adverse events (AE) or serious 
adverse events (SAE) relatedness to the study protocol, and then report back to 
the responsible PI or their designate. If any AE or SAEs occur, the respective 
site principal investigator (or her/his designate) will alert the committee 
members to the need for review and assignment of relatedness/not related to 
the protocol. 
 
 
8.6 
Independent Data and Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will be established for 
this study by the Midwest Area Research Consortium for Health (MARCH) 
which is comprised of Midwest CTSA institutions, inclusive of the Mayo 
Clinic, University of Minnesota and Fairview Southdale. The Board will 
consist of a minimum of 5 individuals, including a statistician, mental health 
professional and expertise in critical care and pharmacology. All members will 
be independent of the study and the research team members from the 
University of Minnesota, Fairview Southdale, Fairview Ridges and the Mayo 
Clinic. 
 
The Board will be asked to: 
• 
Meet in face-to-face or conference call meetings at a frequency to be 
determined by the DSMB, based on the accrual rate, data complexity, 
and frequency of adverse events. 
• 
Review all Serious Adverse Events (SAEs) pursuant to immediate 
notification by the Principal Investigator. Data and information will be 
provided by study staff. 
• 
Review summaries of selected cases and review study data. 
• 
Recommend changes in the protocol that are consistent with their 
findings concerning safety and or clinical practice. 

22 
 
• 
Issue a written summary of finding and recommendations for each 
meeting. 
 
Potential Risks to Human Subjects 
Physiological Risks 
There are several potential risks associated with participation in this study for 
subjects randomized to the SMST group. Known side-effects of dexmedetomidine 
include hypotension and bradycardia, which will be included in the study consent 
form. We anticipate that this will occur in 10% of subjects. 
 
Another risk is that SMST subjects may not be able to self-administer the study 
medication, possibly due to confusion about using the push button device or, less 
likely, because of severe weakness. This might result in inadequate control of 
symptoms. Similarly, a SMST subject might activate the device appropriately but 
remain subjectively anxious. In both situations, our study protocol minimizes 
these risks by permitting supplemental medications to be administered by the 
subject’s bedside nurse. Based on our prior work, we estimate that supplemental 
sedatives will be administered at least once during the 7 day study interval to > 
50% of SMST subjects. Because this intervention can be given quickly, we 
estimate that the subject’s risk of experiencing uncontrolled anxiety or other 
significant symptoms is very low (< 5%). 
 
Based on prior work, we estimate that unselected patients requiring more than 48 
hours of mechanical ventilation have a 2 month mortality of 30%, most of that 
occurring within the first three weeks. Our entry criteria will select a more stable 
sample but these patients will remain quite ill and will have the potential to 
worsen regardless of study participation. We estimate the 5% will die from their 
acute and chronic medical conditions during the study interval which may last up 
to 7 days. Another 5-10% will complete the study interval but die from the acute 
and chronic medical conditions in the 4 weeks after study enrollment. No study 
that has randomized intubated patients to dexmedetomidine versus another 
sedative medication has shown an increase in mortality rate. 
 
Pregnant (confirmed by a positive pregnancy test documented in the medical 
record) or lactating women will be omitted from the study. For women of 
potentially fertile age, it is standard medical practice on the participating ICUs to 
rule out pregnancy early in the course of respiratory failure; this information is 
available in the medical record during the enrollment screening process. If no 
documentation is present, we will perform a urine or blood test prior to any 
consent procedures. 
 
Psychological Risks 
There is a risk to maintaining confidentiality of any study participant. This risk is 
thought to be low because Mayo Clinic number and names will only be contained 
on the written signed consent forms, a data collection form for a home telephone 
number for follow up contact at 3 and 6 months when discharged from the ICU, 
and a Health Survey (SF-36) that is electronically scored. 
 
Subjects may perceive an invasion of their privacy when approached for study 
participation by a member of the research team. This risk is thought to be low 
given that we will first discuss appropriateness of any potential subject with the 

23 
 
patient-care nurse. There is risk for invasion of privacy when being contacted 
twice in a 6-month time frame for the post-ICU instrument administration. This 
risk is thought to be low as participants will be asked to complete the 
questionnaires over the phone in the convenience of their homes at a time that is 
convenient for them. 
 
Subjects may feel burdened by responding to the three times daily anxiety 
assessment via the visual analog scale-anxiety (VAS-A) and the alertness/arousal 
assessment using the RASS and for the presence/absence of delirium with the 
Confusion Assessment Method-ICU (CAM-ICU) three times each study day for 
up to 7 days. This risk is thought to be low given that our experienced study 
personnel all are well-aware of the energy limitations of ICU patients and will 
approach them in a gentle, un-hurried manner. 
 
Although post-ICU depression symptoms are common (approximately 25%) the 
risk of severe depression and self-harm is very low. Since the PHQ-9 can be 
scored in real-time, if a subject has a score > 10 (indicating moderate depression 
symptoms), or verbalizes self-harm (PHQ-9 item #9), the phone interviewer will 
be trained by the investigators to do the following: (1) Acknowledge to the 
subject that they have some symptoms that might indicate significant depression 
and were they aware of that. (2) Ask if they have discussed these symptoms with 
family members or his/her physician. (3) If there are responses indicating serious 
intent of self-harm and access to lethal instruments, then responses may range 
from contacting family members (contact numbers will be obtained on subject 
enrollment) to further intervention such as notifying the subject’s primary 
physician or making a referral call to the county mental health agency. Dialing 
911 is always an option in the unlikely event that immediate care is needed. 
 
 
Alternative Treatments/Procedures 
Any subject (or their proxy who enrolled them in the study) enrolled from the 
participating ICUs is free to withdraw from the study at any time. The alternative 
treatments/procedures associated with this study for those mechanically ventilated 
patients who choose not to participate is to continue to receive the standard ICU 
care for the respective unit, which consists of sedative and opioid therapy 
administered by and at the discretion of the bed side ICU nurses with medications 
selected and ordered by the attending ICU physician. 
Potential Benefits of the Proposed Research to Human Subjects and Others 
Subjects randomized to the SMST group may receive more individually tailored, 
better control of anxiety through the self-management of anxiety symptoms 
without over-sedation than those subjects randomized to the usual care group of 
nurse-administered sedative therapy (NAST). Subjects randomized to the usual 
care group of NAST may not receive any benefit from participating in this study. 
 
The findings from this study have the future potential to benefit the thousands of 
patients who receive mechanical ventilatory support each year in the U.S. 
Potential benefits include greater control of anxiety, fewer days receiving 
mechanical ventilation, less delirium, and shorter ICUs stays realized from 
receiving less sedative medication through the self-administration of a sedative 
medication controlling symptoms and promoting comfort while receiving 
ventilatory support. Other potential benefits for SMST participants include 

24 
 
better post-ICU physical and functional status, psychological well-being, and 
health-related quality of life. These potential benefits would parallel the 20 years 
of research findings surrounding patient-controlled analgesia whereby patients 
report greater control with pain and high satisfaction when provided the 
opportunity to self-manage symptoms in many in-patient and out-patient surgical 
and diagnostic procedures settings. 
 
9. Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). Those regulations require a signed 
subject authorization informing the subject of the following: 
• 
What protected health information (PHI) will be collected from 
subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of 
their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected 
prior to the revocation of subject authorization. For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e., that the subject is alive) at the 
end of their scheduled study period. 
 
 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source 
documents; examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept 
at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
 
Data generated by the methods described in the protocol will be recorded in 
the subjects' medical records and/or study progress notes. Data may be 
transcribed legibly on CRFs supplied for each subject or directly inputted into 
an electronic system or any combination thereof. The Mayo Clinic will be the 
primary data storage site for the study and will serve as the coordinating center. 
 
9.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for 
the study. All data requested on the CRF must be recorded. All missing data 
must be explained. If a space on the CRF is left blank because the procedure 

25 
 
was not done or the question was not asked, write “N/D”. If the item is not 
applicable to the individual case, write “N/A”. All entries should be printed 
legibly in black ink. If any entry error has been made, to correct such an error, 
draw a single straight line through the incorrect entry and enter the correct data 
above it. All such changes must be initialed and dated. DO NOT ERASE OR 
WHITE OUT ERRORS. For clarification of illegible or uncertain entries, print 
the clarification above the item, then initial and date it. 
 
9.4 
Records Retention 
The Investigator will retain study records including source data, copies of case 
report forms, consent forms, HIPAA authorizations and all study 
correspondence for at least 6 years after the study file has been closed with the 
IRB. 
 
10. Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study was monitored quarterly at both sites by the University of 
Minnesota Clinical and Translational Science Institute’s Clinical Monitoring 
Service (CTMS). As of October 2023, Mayo Office of Research Regulatory 
Support (ORRS) will complete semiannual monitoring at the Mayo Clinic 
site only, as study enrollment has been completed at the University of 
Minnesota. The investigators will allocate adequate time for such monitoring 
activities. The Investigator will also ensure that the monitor or other 
compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring 
visit. 
 
10.2 Auditing and Inspecting 

26 
 
The investigators will permit study-related monitoring, audits, and inspections 
by the IRB, the sponsor, government regulatory bodies, and University and 
Mayo Clinic compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable University and 
Mayo Clinic compliance and quality assurance offices. 
 
11. 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct. The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator and a 
copy of this decision will be provided to the sponsor before commencement of this 
study. The investigator should provide a list of IRB members and their affiliate to the 
sponsor. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects or his /her legally authorized 
representative (LAR) to make an informed decision about their participation in this 
study. The consent form will be submitted with the protocol for review and approval 
by the IRB for the study. The formal consent of a subject or LAR, using the IRB- 
approved consent form, must be obtained before that subject is submitted to any study 
procedure. This consent form must be signed by the subject or LAR and the 
investigator-designated research professional obtaining the consent. 
 
12. Study Finances 
12.1 
Funding Source 
This study is financed through a (pending funding) grant from the U.S. 
National Institutes of Health, National Heart, Lung & Blood Institute 1- 
R01HL130881-01 Efficacy of self-management of sedative therapy by 
ventilated ICU patients (L. Chlan and C. Weinert, MPIs). 
 
12.2 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent 
ownership, royalties, or financial gain greater than the minimum allowable 
by their institution, etc.) must refer to the Regents Policies on Individual 

27 
 
Conflict of Interest Policy or the Mayo Clinic Institutional Conflict of 
Interest Policy. These policies require University Faculty and staff to report 
external professional activities and business and significant financial 
interests related to his or her University activities by submitting a REPA 
(Report of External Professional Activities) at least once per year. Faculty 
and staff should also file a REPA when substantial changes in business or 
financial interests occur, when an activity that presents a potential conflict 
of interest is anticipated, or when submitting an application for research 
support or technology transfer, submitting research protocols to the IRB, or 
receiving financial contributions. All University of Minnesota investigators 
will follow the University conflict of interest policy. All Mayo Clinic 
investigators will follow Mayo Clinic conflict of interest policy. 
 
12.3 
Subject Stipends or Payments 
Subjects will receive no payment or stipend for participation in this study. 
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