Clinical trial NCT01739933
Conditions: Sepsis Delirium Impaired Cognition
Keywords: Delirium Delirium/coma-free days Long term cognitive impairment Sedation Intensive care Mechanical Ventilation Dexmedetomidine Propofol Coma-free days Sepsis Organ dysfunction Acute Respiratory Distress Markers of inflammation
Sponsor: Vanderbilt University Medical Center
Start date: 2013-05-15; Completion date: 2019-07-01
Enrollment: 438 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Ventilated ICU patients frequently have sepsis and the majority have delirium, a form of brain dysfunction that is an independent predictor of increased risk of dying, length of stay, costs, and prolonged cognitive impairment in survivors. Universally prescribed sedative medications-the GABA-ergic benzodiazepines-worsen this brain organ dysfunction. The available alternative sedation regimens, the shorter acting GABA-ergic propofol, and the alpha2 agonist, dexmedetomidine, have both been shown to be superior to benzodiazepines, and yet are different with regard to their effects on innate immunity, bacterial clearance, apoptosis, cognition and delirium. The MENDS2 study will compare propofol and dexmedetomidine, and determine the best sedative medication to reduce delirium and improve survival and long-term brain function in our most vulnerable patients- the ventilated septic patient.

Detailed description:
The need for mechanical ventilation (MV) secondary to sepsis is the leading cause of admission to the intensive care unit, often necessitating sedation for patient safety and comfort. Recently, we have learned that these sedative medications contribute to iatrogenic injury, such as prolonging ventilator time and ICU length of stay and exacerbating acute brain dysfunction. This acute brain dysfunction, manifested as delirium and coma, occurs in 50%-70% of MV septic patients and is a significant contributor not only to death but also to functional and cognitive decline, which can persist for years after recovery of lung and other organ function, levying significant costs to patients and society. Despite advances in the management of acute respiratory failure and sepsis, few clinical trials have examined the effects that supportive therapies, like sedation, may have on both short- and long-term outcomes in this vulnerable population. The gamma-aminobutyric acid (GABA)-ergic benzodiazepines, in particular, have been shown to increase brain dysfunction, promote infection, and prolong MV. Therefore, the short-acting GABA-ergic sedative propofol and the alpha2 agonist dexmedetomidine are becoming widely used to sedate septic MV patients. There are only a few randomized trials, however, to guide clinicians when selecting between these and other sedatives, and none have explored the mechanisms underlying the differences in outcomes, though some data indicate that GABA-ergic and alpha2 agonist agents have very different effects on innate immunity, apoptosis, arousability, and respiratory drive. In early animal and human studies, dexmedetomidine had more anti-inflammatory effects than the GABA-ergic agents; dexmedetomidine improved bacterial clearance, whereas propofol impaired it. In addition, sedation with dexmedetomidine instead of benzodiazepines reduces delirium by 20%-30% and improves arousability, cognition, and attentiveness in ventilated patients. Alpha2 agonists induce unconsciousness at the brainstem-more akin to natural sleep-which may improve autonomic function and immunity. All these factors converge to suggest that sedation with an alpha2 agonist rather than a GABAergic agent may improve outcomes, including brain function, MV, and survival, for septic MV patients. We therefore propose the MENDS2 (Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure) study, in which we will test the hypotheses that sedation of MV severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will (Aim 1A) increase days alive without delirium or coma, (Aim 1B) increase ventilator-free days, (Aim 2A) improve 90-day survival, (Aim 2B) decrease long-term cognitive impairment, and (Aim 3) reduce the pro-inflammatory cytokine cascade following sepsis. We will randomize 420 ventilated, severely septic patients requiring goal-directed sedation with dexmedetomidine or propofol, giving the study 85% power to detect a difference of 1.5 delirium/coma-free days and an absolute difference in mortality of 12% between the two groups.

Arms: arm 1: Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.

Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. arm 2: Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.

Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
Interventions: intervention 1: Dexmedetomidine intervention 2: Propofol
Intervention descriptions: intervention 1: For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee. intervention 2: For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.

Protocol documents:
SAP_002.pdf: 
 
 
 
 
 
 
 
 
 
1 
Statistical analysis plan for the Maximizing the Efficacy of Sedation and 
Reducing Neurological Dysfunction and Mortality in Septic Patients with 
Acute Respiratory Failure trial 
Administrative Information 
Full Study Title 
Maximizing the Efficacy of Sedation and Reducing Neurological 
Dysfunction and Mortality in Septic Patients with Acute Respiratory 
Failure
Acronym 
MENDS2 
Trial Registration
https://clinicaltrials.gov/ct2/show/NCT01739933  
Protocol Version 
1.12 (October 1st, 2018) 
Principal 
Investigators 
Pratik P. Pandharipande, MD, MSCI 
Christopher G. Hughes, MD, MS 
E. Wesley Ely, MD, MPH
Biostatistician 
Rameela Chandrasekhar, PhD 
Onur M Orun, MS
Date of version 
October 10th, 2019 
SAP Version 
1.1 
SAP Revision 
History
Version 1.0 - January 4th, 2019  
SAP Revision 
Justification
To modify content for clarity; to reduce number of covariates based on 
limited sample size for mortality outcome.
 
 
 


 
 
 
 
 
 
 
 
 
2 
TRIAL REGISTRATION:  
Clinicaltrials.gov (NCT01739933) 
1. INTRODUCTION 
This serves as the formal Statistical Analysis Plan (SAP) for the Maximizing the Efficacy of 
Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute 
Respiratory Failure (MENDS2) study, written before closure of the database and unblinding of 
the treatment groups. The trial is registered at https://clinicaltrials.gov/ct2/show/NCT01739933. 
This SAP is written based on guidelines in Gamble et al.1 and will be the guiding document for 
the analyses that will be conducted in the primary manuscript. Any changes to this SAP will be 
presented as an addendum in the future. 
1.1 Background and Rationale 
The need for mechanical ventilation (MV) secondary to sepsis is the leading cause of admission 
to the intensive care unit, often necessitating sedation for patient safety and comfort. Sedative 
medications contribute to iatrogenic injury, such as prolonging ventilator time and intensive care 
unit (ICU) length of stay and exacerbating acute brain dysfunction. This acute brain dysfunction, 
manifested as delirium and coma, occurs in 50%-70% of MV septic patients and is a significant 
contributor not only to death but also to functional and cognitive decline, which can persist for 
years after recovery of lung and other organ function, levying significant costs to patients and 
society. The gamma-aminobutyric acid (GABA)-ergic benzodiazepines, in particular, have been 
shown to increase brain dysfunction, promote infection, and prolong MV. Therefore, the short-
acting GABA-ergic sedative propofol and the alpha2 agonist dexmedetomidine are becoming 
widely used to sedate septic MV patients. There are only a few randomized trials, however, to 


 
 
 
 
 
 
 
 
 
3 
guide clinicians when selecting between these and other sedatives, and none have explored the 
mechanisms underlying the differences in outcomes, though some data indicate that GABA-ergic 
and alpha2 agonist agents have very different effects on innate immunity, apoptosis, arousability, 
and respiratory drive. The MENDS2 study will determine whether sedation of mechanically 
ventilated severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a 
GABAergic agent (propofol) will increase days alive without delirium or coma and increase days 
alive and free from mechanical ventilation (ventilator-free days or VFDs). 
1.2 Study Objectives 
The MENDS2 study is a multicenter, double-blind, randomized trial investigating the effects of 
sedatives—the alpha2 agonist dexmedetomidine and the GABAergic propofol—in mechanically 
ventilated severely septic patients. The study evaluates the following aims: 
● Aim 1: To determine whether sedation of mechanically ventilated severely septic patients 
with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) 
will (Aim 1A) increase days alive without delirium or coma (delirium/coma-free days or 
DCFDs) and (Aim 1B) increase days alive and free from mechanical ventilation 
(ventilator-free days or VFDs). 
● Aim 2: To determine whether sedation of mechanically ventilated severely septic patients 
with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) 
will (Aim 2A) improve 90-day survival and (Aim 2B) decrease incidence and severity of 
long-term cognitive impairment (LTCI). 
● Aim 3: To determine whether sedation of mechanically ventilated severely septic patients 
with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) 
will reduce pro- and anti-inflammatory cytokines (CRP, interleukin-1 [IL-1], IL-6, IL-10, 


 
 
 
 
 
 
 
 
 
4 
sTNFR1, HMGB1). We intend to present the results of Aim 3 in a subsequent 
manuscript. 
2. STUDY METHODS 
2.1 Trial Design 
This is a multicenter, double-blind, randomized trial. The two treatment arms comprise an alpha2 
agonist (dexmedetomidine) and a GABAergic agonist (propofol). Upon meeting inclusion and 
none of the exclusion criteria, patients were consented, enrolled and then randomized to either of 
the two treatment arms.  
2.2 Inclusion and Exclusion criteria 
Consecutive patients were eligible for inclusion in the MENDS2 study if they were: [1] an adult 
patient (≥18 years old) [2] in a medical or surgical ICU and [3] on MV, requiring sedation and 
[4] have a suspected or known infection. Patients were excluded if they met any of the exclusion 
criteria listed in Table 1. 
2.3 Randomization 
Randomization to dexmedetomidine and propofol was conducted in 1:1 ratio using a computer-
generated permuted-block randomization scheme, stratified by study site and age (<65 vs ≥ 65 
years). The randomization scheme was created by a biostatistician external to the study and 
distributed directly to each site’s investigational pharmacy as a set of randomization lists 
stratified by study site and age (<65 vs ≥ 65 years). Once a consented patient entered the 
Interventional Trial Phase, an order for blinded study drug was placed, and the investigational 
pharmacist referred to the appropriate randomization list (determined by patient’s age) to 


 
 
 
 
 
 
 
 
 
5 
establish that patient’s treatment assignment. The lists were only accessible to investigational 
pharmacists so that treatment assignments were known only by the investigational pharmacists. 
Unblinding of the treatment groups (and subsequent data lock) will be performed after data 
cleaning and will be documented. Any unlock of the database will be performed only to correct 
serious data entry errors and will be documented in a detailed manner. 
2.4 Power and Sample Size  
Power analyses and sample size calculations for Aim 1A (DCFDs): Based on the demographic 
data from our NIH-sponsored Bringing to Light the Risk Factors and Incidence of 
Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) cohort, we assumed patients 
in the MENDS2 control group (sedation with propofol) to have a mean±SD of 6.8±5.2 DCFDs 
during the 14-day study period. The study was repowered/resized due to concerns about the 
feasibility of completing study enrollment. Our initial sample size of 530 patients provided us 
with > 90% power to detect a difference of 1.5 delirium/coma-free days between the two groups 
and an absolute difference in mortality of 10%. With approval from the Data Safety Monitoring 
Board (DSMB), we re-sized to enroll 420 patients, which assuming a 2-sided alpha of 0.05 will 
provide >80% power to demonstrate a difference of 1.5 DCFDs between dexmedetomidine and 
propofol (primary outcome), which we believe has face validity as a clinically meaningful 
difference in the duration of acute brain injury. Importantly, this sample size also provides 80% 
power to detect a 10% absolute improvement in 90-day survival with dexmedetomidine, 
assuming the 90-day mortality in patients receiving propofol to be 30% (which is conservative 
given the 25% mortality at 28 days in the both the recent PROWESS-Shock control group and 
MENDS [dexmedetomidine vs lorazepam] study lorazepam group).  


 
 
 
 
 
 
 
 
 
6 
Power Analyses for Long-Term Cognitive Impairment (Aim 2B): We assumed to follow ≥80% 
of survivors for evaluation of LTCI. Based on the expected mortality rates (see above), we 
expected an overall 25% mortality across the two groups and planned to test 252 
(=420x0.75x0.80) patients for LTCI at 6 months. With 252 patients, we will have up to 17 
degrees of freedom in our multivariable linear regression to account for potential confounders. 
The proposed study will have adequate—indeed abundant—ability to assess the independent 
effect of the intervention on cognitive impairment while controlling for confounders. 
2.5 Study treatments and interventions 
Study treatment and interventions are summarized in the study aids provided in Supplement 1. 
 
3. STATISTICAL PRINCIPLES 
Statistical analysis will be conducted in accordance to the plan outlined in this SAP. Statistical 
analysis will abide by these general statistical principles below. 
3.1 Descriptive statistics 
Patient flow information as recommended by CONSORT guidelines will be presented for 
patients randomized and receiving study intervention, including screening, exclusions, refusal of 
consent, withdrawals, deaths, and hospital discharge status. Demographics, baseline clinical 
status and ICU characteristics will be described overall as well as by treatment using medians 
and interquartile ranges for continuous variables and frequency (%) for categorical variables. 
Significance testing of baseline differences between treatment groups will not be performed in 
keeping with CONSORT 2010 guidelines for reporting parallel group randomized clinical trials.  


 
 
 
 
 
 
 
 
 
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3.2 Confidence Intervals and P-Values 
Our protocol a priori specified one interim analysis at N=300 before the final analysis for early 
stopping due to safety and efficacy based on DCFD and 90-day mortality. To maintain the 
overall study wise alpha level at 0.05, with interim analysis, it was specified that the level of 
statistical significance for the final analyses for the primary outcome would be adjusted to 0.044 
(based on O'Brien Fleming method). The level of statistical significance for all other outcomes 
will be at the 0.05 level. 95% confidence intervals will be reported along with all effect estimates 
due to it being the standard in which confidence intervals are typically reported and how 
statistical software outputs are constructed. Presentation of results will emphasize clinical 
significance, effect sizes and confidence intervals over statistical significance. 
3.3 Modeling Principles 
Whenever possible (based on variable distribution), we will not assume linear associations 
between covariates and outcomes; rather, nonlinear associations between continuous covariates 
and outcomes will be permitted by inclusion of restricted cubic splines with 3 knots. To account 
for correlation among patients within a given site, we will adjust standard errors using Huber-
White sandwich estimate2. 
3.4 Multiple Comparisons 
Regarding the analyses of all a priori-defined secondary and exploratory outcomes, no 
adjustments will be made for multiple comparisons, in keeping with standard practice when 
analyzing multiple, prospectively defined outcomes in a clinical trial. For all secondary and 
exploratory outcomes and subgroup analyses, caution will be exercised in the interpretation of 


 
 
 
 
 
 
 
 
 
8 
results by noting the number of nominally significant tests that would be expected to occur by 
chance alone3.  
 
3.5 Missing Data 
Data for missing in-hospital variables will be imputed using simple imputation or clinical 
imputation rules when appropriate; details on these rules and the imputation process for 
summary variables (e.g., days alive and free of delirium and coma) are detailed in the Definitions 
and Derived Variables section in Supplement 2. Simple imputation of completely missing 
baseline covariates will be performed using available baseline covariates.  
In adjusted analyses for the long-term Telephone Interview for Cognitive Status (TICS) 
outcome, model-based multiple imputation strategies will be used. In all cases, decisions and 
processes will be documented both in data management and analysis code and in statistical 
reports. TICS scores from patients that were not available at follow-up will not be imputed, but 
those with partially missing data will be imputed using model-based imputation with covariates 
age at enrollment, gender, BMI, education, first language English, insurance, Charlson 
comorbidities index, Benzodiazepine exposure after ICU admission to the midnight of the day 
before enrollment and long-term assessments (KATZ ADL, FAQ, EQ-5D, Digit Span, Logical 
Memory I, Logical Memory II, Similarities, COWA, Hayling Sentence Completion). 


 
 
 
 
 
 
 
 
 
9 
3.6 Rigor, Transparency and Reproducibility 
To enhance rigor, transparency and reproducibility in research, we will ensure all aspects of this 
study are transparent and easily reproduced by independent investigators. The statistical analysis 
plan will be pre-specified and time-stamped. All the analysis code will be made publicly 
available post publication of the primary manuscript. 
4. ADHERENCE TO THE INTERVENTION AND PROTOCOL NONCOMPLIANCE 
4.1 Definition & assessment of adherence to the intervention 
All analysis will be conducted based on the intention to treat principle (ITT). Patients will be 
considered to be in the intent-to-treat population if they (a) meet all criteria required for 
randomization AND (b) are assigned to and actually receive the treatment drug as indicated on 
the randomization log. If subjects received the study drug and form a part of the intent to treat 
population, they will be analyzed according to the treatment they were randomized to.  
4.2 Presentation of adherence to intervention 
These are process outcomes and statistical significance will not be assessed. We will describe, 
within each treatment group, the following: 
● Patient level: 
○ Days each randomized patient received study treatment 
○ Time from meeting all inclusion criteria and start of study drug  
○ Average daily dose of study drug 
○ Whether study treatment was ever permanently discontinued, and reasons for 
discontinuation 
○ Proportion of patients that withdrew from the study by treatment 


 
 
 
 
 
 
 
 
 
10 
○ Time at target (+/- 1 RASS score) sedation by comparing actual RASS to ordered 
RASS, while on study drug 
○ Average daily fentanyl dose and average dose/kg, while on study drug, among 
users 
○ Proportion of patients receiving antipsychotic medications 
○ Days of antipsychotic medications 
○ Proportion of patients receiving midazolam 
○ Proportion of patients, mean daily dose among those exposed and days of use 
among exposed for open label propofol, dexmedetomidine and rescue midazolam  
○ Open label propofol use (proportion and days among users) 
○ Open label dexmedetomidine use (proportion and days among users) 
4.3 Definition and description of protocol noncompliance 
Any noncompliance that increased safety risk to the patient was considered protocol 
noncompliance. These events will be captured for a variety of causes considered related to 
patient safety and will be described in the final study report, broken down according to a simple 
categorization scheme followed prospectively during the conduct of the MENDS2 study. 
4.4 Analysis Populations 
All analysis will be conducted for all in-hospital outcomes on all randomized patients who 
received study drug in an intent-to-treat manner as defined earlier. Analysis for long-term 
outcomes will include all randomized patients who received study drug and who survived and 
have at least partial data for their assessments.  


 
 
 
 
 
 
 
 
 
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For the primary outcome delirium/coma-free days and for the secondary outcomes ventilator-free 
days and 90-day mortality, we will also perform a sensitivity analysis that will also include 
patients that were randomized to receive treatment drug but never received treatment. 
5. STATISTICAL ANALYSIS 
5.1 Outcome Definitions 
Primary outcome 
The primary outcome is delirium/coma-free days (DCFDs) over a 14-day study period, defined 
as the number of days during the 14-day intervention period (from randomization, which will be 
Study Day 1, until Study Day 14) that the patient was alive and free of delirium and coma. Study 
outcomes are presented in Table 2, and study timelines and assessments are provided in Table 3.  
5.2 Analysis Methods 
All in-hospital outcomes will be analyzed using both univariate methods and multivariable 
regression, adjusting for covariates noted below. Though baseline patient characteristics should 
theoretically be balanced between treatment groups due to randomization, adjustment increases 
our power and precision. Adjusted analyses will be considered the primary analyses. We will 
adjust all coefficient variances using Huber-White sandwich estimation, clustered by study site. 
This will help account for unmeasured variability and correlation among patients within a given 
site. 


 
 
 
 
 
 
 
 
 
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In-Hospital Continuous Outcomes 
We will use proportional odds logistic regression for continuous outcomes that are non-normally 
distributed (e.g., delirium/coma-free days; ventilator-free days) with covariates as listed below; 
this method assumes an ordinal outcome but does not assume that it follows a specific statistical 
distribution. Both adjusted odds ratios as well as adjusted medians will be reported as estimates4.  
Time-to-Event Outcomes 
We will use Cox proportional hazards regression for mortality with covariates as listed below. 
For time-to-event outcomes with competing risks, we will use Fine-Gray5 competing risks 
regression.  
Long-Term Outcomes 
We will analyze the primary long-term outcome, the TICS score, using multivariable regression 
with treatment and adjusting for other covariates mentioned below. Depending on the 
distribution of the outcome, we will use linear regression, or proportional odds logistic 
regression, as appropriate. This will be the primary analysis model for this outcome. 
As a sensitivity analysis, we will also define a patient as being cognitively impaired 
based on whether they are >=2 SD in 1 test OR >=1.5 SD in any two tests, where the tests we 
will consider are the Digit Span, Logical Memory I, Logical Memory II, Similarities, Controlled 
Oral Word Association, and Hayling Sentence Completion. We will analyze this outcome using 
multivariable logistic regression adjusting for covariates mentioned below. 
Since mortality is hypothesized to have an association with treatment, the analysis of 
survivors with assessments may be susceptible to survivor bias. To deal with this potential bias, 
we will conduct a sensitivity analyses using the continuous TICS score. We will use the 


 
 
 
 
 
 
 
 
 
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unadjusted composite endpoint approach described in Lachin6, where the composite endpoint 
will be defined as: 
- 
If the patient dies prior to assessment or is missing assessments days between 
randomization and death/date of last follow-up (for patients who were lost to follow up)/180 
days for those who were assessed but had missing TICS score 
- 
If the patient survives and is successfully assessed: days between randomization and 
planned assessment (180 days) + assessment score.  
Model Assumptions 
Model assumptions will be evaluated graphically. Proportional odds assumptions will be checked 
using multiple cutoffs for proportional odds assumption7, and Schoenfeld residuals will be used 
for proportional hazards. If linear regression is used for long-term outcomes, we will check 
residual vs fitted plots and quantile-quantile plots to ensure assumptions are met. 
Covariates 
Covariates for all multivariable regression models except 90-day mortality include: 
● Age at study enrollment 
● Education  
● Baseline cognitive function, via the Informant Questionnaire on Cognitive Decline in the 
Elderly (IQCODE) (performed via patient or surrogate questionnaire) 
● Preexisting comorbidities, via the Charlson Comorbidities Index 
● Sequential Organ Failure Assessment (SOFA) on the day of enrollment excluding the 
central nervous system (CNS) component since delirium and coma are accounted for 
separately 


 
 
 
 
 
 
 
 
 
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● Level of arousal at randomization via the Richmond Agitation-Sedation Scale (RASS) 
closest to time of randomization - treated as a categorical variable.  
● Propofol, dexmedetomidine, opioids (fentanyl equivalents), antipsychotics (haloperidol 
(iv) equivalents) and benzodiazepines (midazolam equivalents) between ICU admission 
and midnight prior to enrollment. Exposure will be defined as total dose/kg and will be 
cube-rooted in the models to mitigate the influence of extremely high values.  
● Medical vs surgical - Surgical patients are those who have a recorded ICU admission 
reason involving surgery; had surgery between hospital admission and ICU admission; 
and/or went to the operating room between ICU admission and study enrollment. All 
other patients will be considered medical patients.  
● Infection type (from 48 hours before enrollment until end of treatment period-study day 
14, treatment withdrawal, hospital discharge or death.): Confirmed Gram positive 
(yes/no), Gram negative (yes/no), viral (yes/no), fungal (yes/no), or suspected infection 
but culture negative. Patients may have more than one type of infection. These will be 
modeled as separate variables in the model. If there is very limited variability that causes 
convergence issues, we will combine the fungal and viral variables. If the convergence 
issues persist, we will create a single variable with multiple levels: Gram Positive, Gram 
Negative, Culture negative, Viral/Fungal. 
Prior to modeling, we will perform redundancy analyses to ensure that no covariates completely 
explain any of the others (resulting in multicollinearity) using an adjusted R^2 cutoff of 0.7. If 
any covariates are highly correlated, only one of them based on clinical relevance will be kept in 
the model. If there are covariates with very limited variability that cause the model to not 
converge, they will be removed from the model.  


 
 
 
 
 
 
 
 
 
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Covariates for 90-day mortality will include age, baseline cognitive function, Pre-existing 
comorbidities, SOFA on the day of enrollment excluding the CNS component, Medical vs 
surgical and Infection type as specified above.  
Safety Analysis 
In addition to the primary and secondary outcomes detailed above, descriptive analysis of 
specified safety outcomes will be performed as described below. 
The safety endpoints below will be tracked starting from randomization until conclusion of the 
combined Treatment/Post Study Drug Period, hospital discharge, death or withdrawal 
(whichever happens first). For patients who do not have hospital discharge and death time 
available, they will be tracked until their withdrawal date. 
1. Proportion of patients and days with hypotension (defined as systolic blood pressure <80 
mmHg) 
2. Mean daily cardiovascular (CV) SOFA for patients along with proportion of days CV 
SOFA >=2  
3. Proportion of patients with arrhythmias (tachycardia [HR > 100] and/or bradycardia [HR 
< 60]) 
4. Proportion of patients with severe lactate acidosis (as defined by lactate > 5) as well as 
median days with severe lactic acidosis among those with severe lactic acidosis. 
5. Mean triglyceride and cortisol levels at  7- and 14-day assessments 
6. Proportion of patients with triglycerides >500 and cortisol <20 at 7- and 14-day 
assessments  


 
 
 
 
 
 
 
 
 
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7. Proportion of patients showing signs of withdrawal from study agent based on vital signs 
(tachycardia HR >100) and diaphoresis. 
6. SOFTWARE DETAILS 
R version 3.5.2 (2018-12-20) or above will be used for all analyses. Versions of specific 
packages used for analysis will be noted in the analysis report. The checkpoint package will be 
used to preserve R package versions throughout the manuscript submission and review process. 
 
7. CONCLUSION 
This document presents the formal Statistical Analysis Plan for the MENDS2 study. Further 
details regarding variable definitions, unadjusted and exploratory analyses and Database 
Cleaning & Lock Procedures are provided in Supplement 2. 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
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Table 1: Study exclusion criteria 
• Rapidly resolving organ failure, indicated by planned immediate discontinuation of MV, at 
time of screening for study enrollment 
• Pregnant or breastfeeding 
• Severe dementia or neurodegenerative disease, defined as either cognitive impairment that 
makes the patient incapable of living independently at baseline or IQCODE >4.5,123 
measured using a patient’s qualified surrogate. This exclusion also pertains to mental 
illnesses requiring long-term institutionalization, acquired or congenital mental retardation, 
severe neuromuscular disorders, Parkinson’s disease, Huntington’s disease, Alzheimer’s 
and debilitating cerebrovascular disease. It also excludes patients in coma or with severe 
cognitive deficits due to structural brain diseases such as stroke, intracranial hemorrhage, 
cranial trauma, malignancy, anoxic brain injury, or cerebral edema. 
• Present history of 2nd or 3rd degree heart block, or persistent bradycardia < 50 
beats/minute that requires intervention (e.g., atropine, glycopyrrolate). If patient has a 
pacemaker for bradyarrythmias, then patient does not meet this exclusion criterion and may 
be enrolled. 
• Benzodiazepine dependency or history of alcohol dependency based on the medical team’s 
decision to institute a specific treatment plan involving benzodiazepines (either as 
continuous infusions or intermittent intravenous boluses) for this dependency. 
• Active seizures during this ICU admission being treated with intravenous benzodiazepines. 
• Expected death within 24 hours of enrollment or lack of commitment to aggressive 
treatment by family or the medical team (e.g., likely to withdraw life support measures 
within 24 hrs of screening). 


 
 
 
 
 
 
 
 
 
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• Inability to understand English or deafness that will preclude delirium evaluation. The 
inability to understand English (for example in Spanish-only or Mandarin-only speaking 
patients) will not result in exclusion at centers where the research staff is proficient and/or 
translation services are actively available in that particular language; these patients will not 
be followed in the long-term follow-up phase of the trial since the testing materials are 
primarily available only in English. Patients with laryngectomies and those with hearing 
deficits are eligible for enrollment if their medical condition permits them to communicate 
with research staff. 
 
 
 


 
 
 
 
 
 
 
 
 
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Table 2: Primary, secondary and exploratory outcomes 
Variable 
Description 
*Time frame 
Primary outcome 
Delirium/coma-free 
days 
(DCFD) 
Number of days during the 14-day intervention 
period (from randomization, which will be Study 
Day 1, until Study Day 14) that the patient was 
alive and free of delirium and coma
14 days 
Secondary outcomes 
Ventilator-Free Days 
(VFD)
Days alive and free of mechanical ventilation 
28 days 
Survival
Time to death
90 days
Long-term outcomes 
The TICS score will be the primary long-term 
outcome. Descriptive statistics for other long-term 
outcomes such as Katz ADL, Functional 
Activities Questionnaire (FAQ), EQ-5D and a 
validated phone battery for neuropsychological 
function testing (e.g., TICS, Digit Span, Logical 
Memory I, Logical Memory II, Similarities, 
Controlled Oral Word Association, Hayling 
Sentence Completion) will be reported. 
6 months 
Organ Dysfunction 
Will be defined as ever vs never. Kidney, Cr > 2 
mg/dL; Lung, PaO2/FiO2 <300 or SaO2/FiO2 
<315; Liver, total bilirubin > 2 mg/dL; 
Coagulation, Platelet count < 100,000/mm3; and 
Hemodynamic, need for vasopressor. Descriptives 
for this outcome will computed both overall and 
by treatment group and no hypothesis testing will 
be performed.
14 days 
Acute Respiratory 
Distress Syndrome 
Ever had ARDS during intervention phase? 
Descriptives for this outcome will computed both 
overall and by treatment group and no hypothesis 
testing will be performed.
14 days 
Exploratory outcomes 
Delirium duration
Number of days the patient had delirium
14 days
Duration of hyperactive 
delirium 
Number of days the patient had hyperactive 
delirium (defined as CAM-ICU positive and 
RASS +1, +2, +3, or +4)
14 days 
Duration of hypoactive 
delirium 
Number of days the patient had hypoactive 
delirium (defined as CAM-ICU positive and 
RASS -3, -2, -1, or 0)
14 days 
Coma duration 
Number of days the patient had coma (defined as 
RASS -4 or -5 or RASS missing and CAM-ICU 
Unable to Assess)
14 days 
ICU mortality
Death while in the ICU
30 days
Hospital mortality
Death while in the hospital
30 days


 
 
 
 
 
 
 
 
 
20 
ICU-free days
Days alive and free of being in the ICU
28 days
Time to successful ICU 
discharge 
“Successful” is defined as discharge followed by 
at least 48 hours alive.
30 days 
Compliance 
Daily compliance on the first five elements of the 
ICU Liberation ABCDEF Bundle
14 days 
Severity of Shock 
• Mean daily CV SOFA 
• Proportion of patients with at least one CV 
SOFA >= 2 (the definition of organ 
dysfunction) and then >2 and then >3 
14 days plus 2 
days post-study 
drug period (if 
longer than 14 
days)
Heterogeneity of 
treatment effects 
Heterogeneity of treatment effects will be 
assessed for age at enrollment, Baseline cognition 
(measured by the IQCODE; continuous 
covariate), Medical vs surgical patients
- 
*Time frames all begin the day of randomization 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
21 
Table 3: Study timelines and assessments 
*Variable  
Enrollment 
 
Treatment Period & 
Post-Study Drug 
Period 
6 Month 
Follow-up 
12 Month 
Follow-up 
Pre-Hospital Function Assessment (ADL, IADL/FAQ, IQCODE, AUDIT) 
X 
 
 
 
Demographics, Comorbidities,APACHE II 
X 
 
 
 
SOFA 
X 
Daily 
 
 
Rhythm strip assessment for advanced heart block 
X 
Daily 
 
 
Pregnancy test (either urine or serum Beta hCG) 
X 
 
 
 
Blood draw: IL-1, IL-6, IL-10, CRP, sTNFR1, HMGB1 
 
Approximately 
Days 1,3,5,7,14 
 
 
Blood draw: whole blood AChE and BuChE at participating sites 
(Blood draw above will be used when possible) 
 
Approximately 
Days 1,3,5,7,14 
 
 
Hematology/Chemistry, Neuroimaging 
X 
Daily 
 
 
Co-administered sedative/analgesic/antipsychotic medications 
 
Daily 
 
 
RASS (target/actual), CAM-ICU 
 
1-2x daily 
 
 
Bush Francis Catatonia Rating Scale (BFCRS), and Delirium Motor 
Subtype Scale (DMSS) at participating sites   
 
1-2x daily 
 
 
Hospital-acquired infections (blood, urine, sputum) 
 
Daily 
 
 
ABCDE Protocol Compliance & Sepsis/Ventilator tracking   
 
Daily 
 
 
Safety assessments. As part of routine ICU care 
 
Daily 
 
 
Plasma triglycerides & cortisol
 
Approximately 
Days 7,14 
 
 
SaO2/FiO2, PaO2/FiO2 ratio, Chest X-ray to evaluate ARDS 
 
Daily 
 
 
EEG via portable SedLine Sedation Monitor at participating sites   
 
Up to 7 days 
 
 
Delirium Experience Questionnaire and Chronic Pain Questions 
 
X 
 
 
Long-term telephone follow-up: CAM, neuropsychological battery, ADL, 
IADL/FAQ, EuroQOL quality of life (EQ-5D), BPI 
 
 
X 
 
*Abbreviations (alphabetical):  AChE- acetylcholinesterase ADL- activities of daily living, APACHE II- Acute Physiologic 
Chronic Health Evaluation II, AUDIT- Alcohol Use Disorders Identification Test, BPI- Brief Pain Inventory, BuChE- 
butyrylcholinesterase, CAM- Confusion Assessment Method, CAM-ICU- Confusion Assessment Method for ICU, CRP- C-
reactive protein, EEG- Electroencephalograph, FAQ- Functional Activities Questionnaire for IADLs, HMGB1- High-mobility 
group protein 1, IADL- instrumental activities of daily living, IL- interleukin, IQCODE- Informant Questionnaire of Cognitive 
Decline in Elderly, MV-mechanical ventilation, RASS- Richmond Agitation Sedation Scale, SOFA- Sequential Organ Failure 
Assessment, sTNFr1- soluble TNF receptor 1  
 
 
 


 
 
 
 
 
 
 
 
 
22 
Supplement 2 
Exploratory Analyses 
In addition to the primary and secondary outcomes listed on clinicaltrials.gov, the following 
additional analyses will be used to inform specific decisions on missing data and modeling, to 
elucidate findings from primary outcomes, and more fully describe the course of the 
intervention: 
• 
Exploration and description of outcome and covariate missingness 
• 
Distribution of all continuous covariates, to determine ability to use restricted cubic 
splines and knot placement 
• 
To describe patient status from randomization to the end of the assessment period, we 
will create a sankey plot where a patient's’ status would displayed. 
• 
Durations of a) delirium b) hyperactive and c) hypoactive delirium as additional 
outcomes, to describe any relationship between treatment and delirium and specific types 
of delirium. We will use proportional odds logistic regression for these outcomes since 
they are non-normally distributed. Coma duration as an additional outcome, to aid in 
elucidating relationship between treatment and primary outcome of DCFDs; will be 
analyzed in the same manner as delirium duration. 
• 
ICU and Hospital mortality: To model this outcome, discharged alive from hospital will 
be considered a competing event for hospital mortality, and discharged alive from ICU 
will be a competing event for ICU mortality. Patients who withdrew in the hospital with 
no discharge or death information available are censored at the time of withdrawal. 
Cumulative incidences of both the outcome and competing risk along with a modified 
chi-squared test for the difference between groups in the subdistribution of interest will 
be described. For the adjusted analysis, will we use Fine-Gray competing risks 
regression, treating discharge as our competing risk. 
• 
ICU-free days: This outcome will be analyzed similar to VFDs and DCFDs. 
• 
Time to successful ICU discharge in 30-days: Since ICU Discharge has the competing 
risk of death, we will describe the cumulative incidences of both the outcome of interest 
and competing risk, along with a modified chi-squared test for the difference between 
groups in the subdistribution of interest. For the adjusted analysis, will we use Fine-Gray 
competing risks regression, treating death as our competing risk. Patients who withdrew 
in the hospital with no discharge or death information available are censored at the time 
of withdrawal; we censor at x.01 days anyone who has experienced neither death nor the 
outcome of interest by x days (where x is the end of the time frame specified for the 
outcome). We will detail how many and when patients were censored for each analysis. 
• 
Daily compliance on the first five elements (A-E) of the ICU Liberation ABCDEF 
Bundle during the intervention period (number and % of eligible days compliant; 
descriptive statistics only). 
• 
Severity of Shock: Descriptive statistics only 
• 
Heterogeneity of treatment effects: We will assess heterogeneity of treatment effects 
using separate multivariable regression models that include interaction terms between 
treatment group and the following clinical characteristics: 
• 
Age at enrollment (continuous) 
• 
Baseline cognition (measured by the IQCODE; continuous covariate) 


 
 
 
 
 
 
 
 
 
23 
• 
Medical vs surgical patients 
 
Definitions and Derived Variables 
Delirium/Coma-Free Days 
This primary outcome variable is calculated over the intervention period (14 days including and 
immediately following randomization). It is defined as days alive and without delirium and 
coma. This definition makes no assumptions about the sequence in which delirium, coma or 
normal mental states occurred during the 14-day treatment period; all days during which a 
participant was alive and free of delirium and coma will contribute to the total number of 
delirium/coma-free days regardless of whether or not they occurred consecutively. 
Mental Status (Delirium and Coma) 
Determining Mental Status Using CAM and RASS 
We will determine mental status for a given assessment using the following criteria: 
1. Comatose: RASS -4 or -5, or RASS missing and CAM Unable to Assess 
2. Delirious: RASS missing or >= -3, and CAM Positive 
3. Normal: RASS missing or >= -3, and CAM Negative 
 
Patients could have multiple assessments on a given study day. On a given day, a patient will be 
considered delirious if any assessment was considered delirious; comatose if no assessments met 
criteria for delirium and at least one was considered comatose; and normal if no assessments met 
criteria for delirium or coma, and at least one was considered normal. If there are conflicting 
assessments where CAM is ‘Unable to Assess’ and RASS -4 or -5, then patient will be assigned 
a mental status of coma. If RASS is -3 or -2, since prior studies state that this highly correlates 
with delirium, patients will be assigned a mental status of delirium. RASS assessment of 0 to -1 
will be considered to be normal. 
Handling Missing Data 
In order to compute this composite outcome, it is necessary to have a value (alive and normal vs. 
delirious vs. comatose vs. deceased) for every single day during the treatment period; ignoring 
missingness would have the unintended consequence of implying that patients 
were alive and free of brain dysfunction on all missing days. Therefore, for eligible patient-days 
with missing mental status, we will perform simple imputation, including the following variables 
as covariates in the imputation. 
 
• 
Baseline: age at enrollment; gender; BMI; education; first language English?; insurance; 
Charlson comorbidities index; , benzodiazepine exposure after ICU admission and 
midnight of the day before randomization (Yes/No). 
• 
Daily: 


 
 
 
 
 
 
 
 
 
24 
o Medications (antipsychotics, opioids, benzodiazepine) 
o Variables indicating severity of illness (CV SOFA, creatinine, platelets, P/F ratio, 
S/F ratio, bilirubin) 
o Any mental status data available the day of, the day before, and the day after the 
missing day (such as RASS, CAM, Critical-Care Pain Observation Tool (CPOT), 
and CAM-ICU Feature 1(cam_f1), and CAM-ICU Feature 2(cam_f2), and CAM-
ICU Feature 3(cam_f3), and CAM-ICU Feature 4(cam_f4)) 
 
All summary variables (e.g. delirium/coma-free days, delirium duration, and coma duration, 
VFD) are presented using imputed mental status. For VFD’s and ICU-Free days, patients who 
withdrew will have their last observation carried forward. 
Severity of Illness 
Missing values for SOFA components will be handled in the following ways: 
SOFA (Enrollment + daily throughout intervention period) 
• 
Substitutions for specific components: 
o Respiratory: If P/F ratio is not available, we will use the lowest S/F ratio8. 
o Central nervous system: Since GCS was not collected, we will use the lowest 
RASS available that day9. 
• 
Missing data at enrollment: For patients missing at least one SOFA component score, we 
will impute the next available value within the following two calendar days. If none are 
available, we will assume a normal value (0 points).  
Medications 
• 
Benzodiazepines include midazolam, lorazepam, and/or diazepam. Doses are expressed 
in midazolam equivalents. 
• 
Opioids include fentanyl, morphine, remifentanil and/or hydromorphone. Doses are 
expressed in fentanyl equivalents. 
• 
Antipsychotics include haloperidol, ziprasidone, quetiapine, olanzapine, and/or 
risperidone. Doses are expressed in haloperidol (iv) equivalents. 
 
Baseline IQCODE: If no questions (out of 16) are answered, then the patient’s IQCODE 
score is considered as missing. If data are partially available, then patient mean will be imputed 
for missing questions (i.e., mean of all non-missing questions). Final IQCODE score will be 
calculated by taking the mean of all the questions. 
Baseline KATZ ADL: If no questions (out of 6) are answered, then the patient’s KATZ 
ADL score is considered as missing. If data are partially available, then patient mean will be 
imputed for missing questions. (i.e., mean of all non-missing questions). Final ADL score will be 
calculated by adding up all the questions. 


 
 
 
 
 
 
 
 
 
25 
Baseline FAQ: If no questions (out of 10) are answered, then the patient’s FAQ score is 
considered as missing. If data are partially available, then patient mean will be imputed for 
missing questions (i.e., mean of all non-missing questions). Final FAQ score will be calculated 
by adding up all the questions. 
 
Unadjusted Analyses 
Continuous Outcomes 
We will analyze non-normally distributed continuous outcomes (delirium/coma-free days; 
ventilator-free days) using the Mann-Whitney test. These outcomes are typically not normally 
distributed; therefore, the assumptions for a test assuming normality would be violated. The 
nonparametric Mann-Whitney test does not assume that the outcome has a normal distribution 
and thus provides more power and reliability in the case of a non-normal distribution.  
 
The primary long-term outcome will be the TICS score. Depending on the distribution of this 
outcome, we will use either the independent two-sample t-test or the Mann-Whitney test. The 
distribution of the other long-term outcome measures (Digit Span, Logical Memory I, Logical 
Memory II, ADL, FAQ, Quality of Life EQ - 5D10, Similarities, Controlled Oral Word 
Association, Hayling Sentence Completion, Logical Memory I and Logical Memory II) will be 
described overall as well as by treatment group. We do not plan to compare these outcome 
measures between treatment groups using formal hypothesis testing in the primary manuscript.  
 
Time to Event Outcomes 
We will describe and test for differences in 90-day survival using Kaplan-Meier curves and the 
log-rank test, respectively. “Time 0” will be the time of randomization. For analysis of time-to-
event outcomes with competing risks, we will describe the cumulative incidences of both the 
outcome of interest and each competing risk, along with a modified chi-squared test for the 
difference between groups in the subdistribution of interest. We will detail how many and when 
patients were censored for each analysis. 
 
Timing of Final Analysis 
In-Hospital Database Cleaning & Lock Procedures 
MENDS2 uses the REDCap electronic data capture platform for data collection. Upon 
completion of the in-hospital portion of the MENDS2 study, the following procedures will be 
followed and documented within the Database Cleaning & Lock SOP: 


 
 
 
 
 
 
 
 
 
26 
1. The Vanderbilt Coordinating Center (VCC) will work with site coordinators to address 
all data issues revealed by ongoing data cleaning. This process will continue until all 
issues have been addressed. 
2. Upon completion of In-Hospital data cleaning, the REDCap database MENDS2 Study: 
Exclusion Log will be locked in the following way: 
a. Initially all users with current “view and edit” user privileges will be moved to 
“read only” user privileges.  
b. After the window closes for sites to export their data the database will be 
permanently moved to inactive status (meaning that no data can be changed). 
3. Upon completion of In-Hospital data cleaning, the REDCap database MENDS2 Study: 
In-Hospital Database will be locked in the following way: 
 . 
Initially all study site personnel will be restricted to “read-only” user access for the entire 
database. VCC Project Managers and the Follow-Up Team will be restricted to read-only access 
for all fields except those needed for patient contact, reconsenting, DNA permissions, notes to 
file and event reporting, and tracking dates of death and study withdrawal. All fields not needed 
by these teams will be restricted to read only by use of the @readonly action tags. The follow-up 
team will continue to be blinded (via restricted access) to all information about the hospital 
course, as has been the case throughout the study. 
  
  
VCC Project 
Managers
Follow-Up 
Team
Dates Tracking Form - all variables made read-only (using 
action tag @readonly) to all users except variables pertaining to 
consenting, death and study withdrawal
View and Edit
View and 
Edit 
Contact Form - all fields
Read Only
View and 
Edit
NTF - all fields
View and Edit
View and 
Edit
Adverse Events - all fields
View and Edit
View and 
Edit
DNA Log - all fields
View and Edit
No Access
All other forms/fields
Read Only
No Access
  
b. During the remaining Follow-Up period, the sites will be given a window for 
downloading their data for local storage.  
c. 
Once 6-month follow-up is completed, we will conduct final data cleans on the updated 
information and then permanently move the entire database to inactive status, meaning that no 
data can be changed unless serious errors are noted. 
 
A log of all steps in this process will be maintained in the Database Cleaning & Lock SOP. 


 
 
 
 
 
 
 
 
 
27 
 
REFERENCES: 
1. 
Gamble C, Krishan A, Stocken D, et al. Guidelines for the Content of Statistical Analysis 
Plans in Clinical Trials. Jama. Dec 19 2017;318(23):2337-2343. 
2. 
White H. A Heteroskedasticity-Consistent Covariance Matrix Estimator and a Direct Test 
for Heteroskedasticity. Econometrica. 1980;48(4):817-838. 
3. 
Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine--reporting 
of subgroup analyses in clinical trials. The New England journal of medicine. Nov 22 
2007;357(21):2189-2194. 
4. 
Liu Q, Shepherd BE, Li C, Harrell FE, Jr. Modeling continuous response variables using 
ordinal regression. Nov 30 2017;36(27):4316-4335. 
5. 
Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing 
Risk. Journal of the American Statistical Association. 1999/06/01 1999;94(446):496-509. 
6. 
Lachin JM. Worst-rank score analysis with informatively missing observations in clinical 
trials. Controlled clinical trials. Oct 1999;20(5):408-422. 
7. 
Harrell F. REGRESSION MODELING STRATEGIES: with applications to linear models, 
logistic and ordinal regression, and survival analysis. SPRINGER; 2016. 
8. 
Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of 
Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the 
Sequential Organ Failure Assessment score. Critical care medicine. Apr 
2009;37(4):1317-1321. 
9. 
Vasilevskis EE, Pandharipande PP, Graves AJ, et al. Validity of a Modified Sequential 
Organ Failure Assessment Score Using the Richmond Agitation-Sedation Scale. Critical 
care medicine. Jan 2016;44(1):138-146. 
10. 
Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development 
and testing of the D1 valuation model. Medical care. Mar 2005;43(3):203-220. 
 
 


 
Hypothesis:  Sedation of mechanically ventilated septic patients with an alpha2 agonist (dexmedetomidine) 
rather than a GABAergic agent (propofol) will improve short and long-term patient outcomes. 
Specific Aims:  
Aim 1: 
To determine whether dexmedetomidine for sedation of septic medical/surgical ICU patients will 
increase days alive without delirium or coma and increase days alive without mechanical ventilation 
compared with propofol 
Aim 2: 
To determine whether dexmedetomidine for sedation of septic medical/surgical ICU patients will 
increase survival at 90 days compared with propofol and decrease long-term cognitive impairment 
after critical illness  
Aim 3: 
To determine whether dexmedetomidine for sedation of septic medical/surgical ICU patients will 
decrease the pro-inflammatory cascade following sepsis compared with propofol 
 
Study Procedures by Research Coordinators 
• Study staff evaluate patients twice daily with RASS and CAM-ICU 
• Study staff collect blood samples on study day 1, 3, 5, 7, and 14 (if still in hospital)  
• Study staff will complete telephone follow-up interviews for cognitive function at 6 months 
Bedside Nurse Responsibilities: 
• Initiate and titrate study drug per weight-based table using clinical team’s RASS target 
• Document study drug infusion rates in HED/electronic medical record (Under “Other”- annotation 
should be “study drug.” Do not write PROPOFOL or DEXMEDETOMIDINE) 
• Document study drug titrations the “MENDS2 Study Drug Titration Form” 
• Cover infusion bag & infusion tubing with black sleeve as provided by pharmacy 
• Change study drug infusion bag & tubing a minimum of every 12 hours 
• Maintain study blinding by ensuring infusion remains covered with black sleeve, no study personnel 
are present for bag changes, & no verbal cues are given to the study/clinical teams about study drug 
• Utilize the rescue protocol for pain, undersedation with max study drug, chemical paralysis, or delirium  
• Screening and utilization of ABCDE protocol with patient including daily spontaneous awakening & 
breathing trials per unit protocol 
Research Coordinator(s):  
• (Coordinator Name), (Title), Pager (###-####) 
• (Coordinator Name), (Title), Pager (###-####) 
• (Coordinator Name), (Title), Pager (###-####) 
 
 
 
 
 
Version: 1 Date: 05-13-13 


 
Version: 2 Date: 11/03/16 
 
 
 
PAIN 
•First try to treat 
with 
intermittent 
boluses of 0.5-1 
mcg/kg of 
fentanyl or 
other opiates 
such as 
morphine or 
hydromorphone 
 
•If needed, 
continuous 
fentanyl 
infusions may be 
used  
RESCUE SEDATION 
•If on max study 
drug & still 
undersedated first 
try additional 
intermittent 
opiates (e.g. 
fentanyl, 
morphine,  
hydromorphone) 
or increase the 
continuous 
fentanyl  infusion 
 
•If on max study 
drug & cont 
fentanyl is ≥ 4-5 
mcg/kg/hr & pt is 
still undersedated 
use intermittent 
dose midazolam  
CHEMICAL PARALYSIS 
•Midazolam 
intermittent or via 
continuous infusion 
may be used 
 
•Reduce study drug to 
the lowest infusion 
rate on the weight 
based titation table 
& maintain at this 
level during chemical 
paralysis 
 
•Continuous 
midazolam infusions  
should be dc'd 1 
hour after the 
paralytic infusion is 
dc'd & study  drug 
titration should 
resume per protocol  
 
• When a bolus of 
chemical paralysis is 
required for 
procedures, 
intermittent 
midazolam or 
propofol will be 
permitted to provide 
amnesia  
HYPERACTIVE 
DELIRIUM 
Defined as CAM-ICU 
+ and RASS +1 to +4 
•May give 
haloperidol per 
tube or as 2-5mg IV 
intermittent doses 
 
•Quetiapine (oral or 
per tube) prn or 
scheduled with 
recommended 
starting doses of 
25-50 mg & 
titration per 
primary team  
 
•ABCDE Bundle 
Nonpharmalocigal 
interventions such 
as early mobility if 
passes safety 
screen 
Rescue Protocol 
Revised 
11/03/16 


Updated 5/11/13                                    
    
 
Protocol 1.02 
Study drug bag & tubing must be changed at least every 12 hours. 
 
Study Drug Administration 
 
Treatment Period – Trial Days 1 to 14 
Study drug can be administered for a maximum of 14 days. Patients have to be in the ICU, on invasive 
ventilation, and in need of sedation to get the study drug. 
 
Blinding 
 
It is essential to keep the clinical team and research team blinded to the patient’s treatment 
assignment. Only the patient’s primary nurse will know which drug the patient is receiving. 
 
The study drug bag and IV tubing should always remain covered. 
 
The bedside nurse should not disclose the treatment assignment to anyone at any time. Do not 
disclose the assignment to the research staff, the family, the patient, or the medical/nursing staff. 
 
Initiation  
 
No bolus dose of study medication will be allowed. 
 
Bedside nurse will initiate infusion based on patient weight in kg (see Titration Table). 
 
Study drug dose will be titrated by the bedside nurse in mL/hr according to the titration table to 
achieve the sedation (RASS) target set by the clinical (ICU) team. 
Titrating UP (Undersedation) 
 
Undersedation is defined as patient’s RASS is 1 or more levels higher than the clinical team’s sedation 
target RASS (e.g. patient RASS = +1 and target RASS = 0 or -1). 
 
If patient is undersedated, study drug rate will be increased according to the Titration Table every 10 
minutes until the max dose is reached or the patient reaches the target RASS. 
 
Titrating DOWN (Oversedation) 
 
Oversedation is defined as when the patient is more than 1 RASS level deeper than ICU team’s 
sedation target (e.g. patient RASS = -3 and target RASS = 0 or -1). 
 
If patient is oversedated, study drug rate will be decreased every 30 minutes per the Titration Table 
until the patient is within 1 RASS level of the target RASS.  
 
Study drug will only be held for oversedation if other sedatives (including fentanyl infusion if used for 
analgosedation) have been held, study drug has been titrated to lowest volume, and the patient 
remains oversedated for >30 minutes. 
Titrating Study Drug during a Spontaneous Awakening Trial (SAT) 
 
Patient will be evaluated daily for readiness for a SAT by first evaluating with a SAT safety screen.   
 
If patient passes the safety screen, study drug will be held until patient shows signs of failing the SAT. 
Intermittent pain meds are allowed to be delivered during this time, if needed. 
 
Study drug that is held for a SAT will be restarted, if needed, at ≤ 50% of the dose the patient 
required just prior to the SAT and then titrated to achieve target sedation score. 
 
Discontinuation 
 
Discontinue study drug if patient is liberated from invasive mechanical ventilation. 
 
Discontinue study drug if the managing clinical team determines the patient does not need ongoing 
sedation.  
 


Updated 5/11/13                                    
    
 
Protocol 1.02 
Study drug bag & tubing must be changed at least every 12 hours. 
 
Restarting Study Drug (with exception of restarting after SATs) 
 
If patient requires sedative therapy (and is still on mechanical ventilation) during the 14-day treatment 
period, the study drug will be restarted according to initiation rules (see Initiation section above), as 
long as study drug was not discontinued permanently for safety reasons (see Permanent 
Discontinuation section below).  
 
No study drug will be continued beyond Trial Day 14. After this point if patient requires sedation, it will 
be solely managed at the discretion of the clinical team. 
Temporary Holding 
 
Hypotension. If a patient’s systolic blood pressure is <80 mmHg and if deemed necessary by the 
managing clinical team, study drug will be held until fluid and/or vasopressor/inotrope therapy can be 
initiated and systolic blood pressure has increased to >80 mmHg.   
 
New onset symptomatic bradycardia (<50 beats/minute and systolic blood pressure <80 mm Hg).  
Study drug may be held by the managing clinical team until patient’s heart rate is >50 beats/min 
(either spontaneously or after administration of atropine or glycopyrrolate).   
 
Oversedation despite titration to lowest study drug rate. Study drug may be held until patient’s 
RASS level is at target if patient continues to be oversedated (i.e., more than 1 RASS level deeper than 
clinical team’s sedation target) despite other sedatives (including fentanyl infusions if used for 
analgosedation) being held and study drug being titrated to lowest volume for >30 minutes. 
Permanent Discontinuation 
If any of the following below occur, hold the study drug and contact the study team ASAP who 
will determine if a criteria for permanent discontinuation has been met.  
 
Second episode of symptomatic bradycardia (<50 beats/minute and systolic blood pressure <80 
mm Hg) while on study drug. Study drug may be continued, titrated down, or held during the first 
episode of symptomatic bradycardia, at the discretion of the clinical team. Clinical team would manage 
the bradycardia, and study drug should be restarted once it resolves. Symptomatic bradycardia that 
reoccurs while back on study drug will result in permanent discontinuation of study drug. 
 
New onset 2nd or 3rd degree heart block. Degree of heart block should be confirmed with clinical 
team or study PI before discontinuation. 
 
Serious allergic reaction to study drug as determined by the managing clinical team and principal 
investigator.  
 
New onset coma due to a known structural brain disease such as a stroke, intracranial 
hemorrhage, cranial trauma, malignancy, anoxic brain injury, or cerebral edema.  
 
Suspected Propofol Related Infusion Syndrome (commonly presents as cardiac failure, 
rhabdomyolysis, severe metabolic acidosis, and renal failure) or acidosis that cannot be explained by 
the medical condition of the patient. 
 
Any other study drug-related, life-threatening, serious adverse reaction. 
 
Withdrawal from study drug treatment at the discretion of the principal investigator, the 
patient/family, or the attending clinical physician. 


Version 1, Revised 5/13/13 
 
Please note that the bedside nurse is responsible to keep everyone blinded from identifying the study drug and to keep 
study drug concealed with IV coverings provided by the Investigational Pharmacy.  Never tell the study team what drug 
you think the patient is receiving or give description of the color of study drug.  Thank you for helping protect the 
integrity of this study and for helping us answer important questions regarding the efficacy of sedation and reducing 
neurological dysfunction and mortality! 
Patient’s weight in kg:____________________ 
 

Prot_000.pdf: 
MENDS II Protocol Version: 1.12 
Confidential 
1 of 52 
Protocol Date:  2018-10-01 
The MENDS II Study 
Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction 
and Mortality in Septic Patients with Acute Respiratory Failure  
 
 
NIH Grant Title: Altering Sedation Paradigms to Improve Brain Injury and  
Survival in Severe Sepsis 
 
FDA-IND #68658 
 
Pratik P. Pandharipande, MD, MSCI 
 
Department of Anesthesiology 
Division of Critical Care  
Vanderbilt University School of Medicine 
 
 
 
 
 
 
 
 
 
 
Contact Details 
 
Primary Investigator  
 
Pratik P. Pandharipande, MD, MSCI 
Phone  
(615) 300-2298 
Fax 
 
(615) 936-1269 
E-mail  
 
Pratik.pandharipande@vumc.org 
 
Co-Investigator 
 
 
E. Wesley Ely, MD, MPH 
 
 
 
 
 
Phone  
(615) 936-2795 
 
 
 
 
 
Fax 
 
(615) 936-1269 
 
 
 
 
 
E-mail  
wes.ely@vumc.org 
 
 
 


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Table of Contents: 
 
1.0 
Introduction and Specific Aims 
2.0 
Background 
3.0 
Preliminary Studies 
4.0 
Study Objectives and Endpoints 
5.0 
Inclusion/Exclusion Criteria 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Risks of Investigational Agents/Devices (side effects) 
9.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Privacy/Confidentiality Issues 
13.0 
Follow-up and Record Retention 
14.0 
References 
 
 


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1.0 
Introduction 
 
Severe sepsis is a life-threatening syndrome that affects more than 750,000 patients in 
the U.S. and is a leading cause of death worldwide, with a case fatality rate as high as 30%-50% 
in developed countries.1, 2 Acute respiratory failure (ARF) is a dominant determinant of 
outcomes for many with severe sepsis; over 70% of patients with severe sepsis, in fact, require 
mechanical ventilation (MV).3 One-third of these patients are formally diagnosed with acute 
respiratory distress syndrome (ARDS) or  acute lung injury (ALI), whereas all of them have 
severe hypoxemic/gas exchange abnormalities.4 Patients with acute respiratory failure due to 
sepsis are at high risk not only for death but for significant functional and cognitive decline, 
which can persist for years after recovery of lung function.1, 2, 5-9 These adverse long-term 
outcomes, which levy significant costs to patients and society,5-9  are usually preceded by acute 
brain injury (ABI), manifested as delirium and coma, which occurs in 50%-70% of MV septic 
patients.10-13  Despite advances in the management of acute respiratory failure and sepsis, there 
have been only marginal improvements in survival; the dearth of promising new therapeutics for 
the near future is marked by an absence of attention to the effects that supportive therapies may 
have on both short- and long-term outcomes.14-23  Sedatives, for example, are nearly universally 
given to septic mechanically ventilated patients. We now know that sedatives contribute to 
iatrogenic injury, prolonging ventilator time and inciting acute brain injury.12, 24-27  Compelling 
data now indicate that minimizing28-30 or altering patients’ exposure to specific sedative agents 
may be a new avenue for improving outcomes in severe sepsis with respiratory failure and acute 
brain injury.31-36  The GABAergic benzodiazepines, in particular, have been repeatedly shown to 
increase brain dysfunction, promote infection, and prolong MV, predisposing patients to higher 
mortality.12, 26, 27, 34-39  As a result of these data, the newer, shorter-acting GABAergic sedative 
agent, propofol, and the alpha2 agonist, dexmedetomidine, are becoming widely prescribed for 
the sedation of septic mechanically ventilated patients.13, 35, 36, 40-43 To date, there remain only a 
few randomized trials to guide clinicians regarding the beneficial effects and risks associated 
with these newer sedatives in patients with severe sepsis and respiratory failure, and yet there 
are data to indicate that GABAergic and alpha2 agonist sedative agents possess distinctly 
different effects on innate immunity, risk of infection,44-49 arousability,50, 51 duration of action,52, 
53 and suppression of respiratory drive.54  In small clinical studies55, 56 and preclinical work,45 
dexmedetomidine appears to offer superior anti-inflammatory effects compared with 
GABAergic agents, including propofol.  Dexmedetomidine improves bacterial clearance, 
whereas propofol reduces it;49 effects that may alter outcomes for septic ventilated patients, 
leading to preclinical work on GABAA antagonists as anti-infective agents.57, 58 Alpha2 agonists 
may also inhibit neuronal apoptosis, a deleterious effect of sepsis that is likely critical to the 
development of brain dysfunction in these vulnerable patients.34, 59, 60  Sedation with 
dexmedetomidine instead of benzodiazepines reduces delirium by 20%-30%35, 36 and improves 
arousability,50 facilitating “wake-up” strategies.29 Endogenous sleep pathways mediate the 
hypnotic response of both classes of drugs,61, 62 but GABAergic agents induce unconsciousness 
at the level of the hypothalamus, whereas the alpha2 agonists do so in the brainstem,61-63 an 
effect—more akin to natural sleep—which may improve autonomic function, immunity, and 
insulin resistance. These factors converge to suggest that sedation with an alpha2 agonist, rather 
than a GABAergic agent, may improve outcomes for septic mechanically ventilated patients, 
including brain function and survival.  We, therefore, propose to study the effects of 
sedatives—the alpha2 agonist dexmedetomidine and the GABAergic propofol—in severely 
septic patients with acute respiratory failure via a multicenter randomized, double-blind, 
trial.  In this study, we plan to consent approximately 580 adult medical or surgical intensive 


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care unit (ICU) patients with severe sepsis and on MV.  Although, the study participants will 
span the adult age spectrum, we anticipate the majority of them will be elderly based on our 
ongoing BRAIN-ICU cohort demographics and those of the participating sites as well as the 
fact that nearly two thirds of all ICU admissions are >65 years old.64, 65   
Specific Aims 
Aim 1: To determine whether sedation of mechanically ventilated severely septic patients with 
an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will 
(Aim 1A) increase days alive without delirium or coma (delirium/coma-free days) and 
(Aim 1B) increase ventilator-free days. 
Aim 2: To determine whether sedation of mechanically ventilated severely septic patients with 
an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will 
(Aim 2A) improve 90-day survival and (Aim 2B) decrease incidence and severity of 
long-term cognitive impairment. 
Aim 3: To determine whether sedation of mechanically ventilated severely septic patients with 
an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will 
reduce pro- and anti-inflammatory cytokines (CRP, interleukin-1 [IL-1], IL-6, IL-10, 
sTNFR1, HMGB1). 
 
To test the hypothesis, we plan to randomize mechanically ventilated, severely septic 
patients requiring sedation to targeted sedation with dexmedetomidine or propofol.  To reach 
this goal, we plan to enroll and randomize 440 patients in order to have at least 420 patients 
randomized who received study drug.  This will account for some disqualification after 
randomization. The study will be powered to detect a difference of 1.5 delirium/coma-free days 
between the two groups and an absolute difference in mortality of 10%. Patients will be assessed 
daily for delirium using the Confusion Assessment Method for the ICU (CAM-ICU);10, 11 other 
important clinical outcomes and safety parameters will be tracked daily in the ICU.  Survivors 
will be assessed 6-months post-randomization for cognitive impairment via a validated and 
reliable phone battery.  
 
2.0 
Background 
 “Septic shock is the rude unhinging of the machinery of life.” (Samuel Gross, 1862) 
 “For many aging people in good physical condition who succumb to an acute illness [e.g., 
sepsis, ARDS] cognitive decline [e.g., delirium followed by an acquired post-ICU long-
term cognitive impairment] is the main threat to their ability to recover and enjoy their 
favorite activities; for those whose physical activities were already limited, cognitive 
decline is a major additional threat to quality of life.”  National Research Council66 
 
2.1 
Severe sepsis, acute respiratory failure and acute brain dysfunction often occur 
concomitantly in mechanically ventilated patients.  There are an estimated 2 to 3 million 
patients on MV each year in high-income countries and the majority of these patients have 
sepsis with ALI, ARDS or ARF due to gas exchange abnormalities, and up to 50-80% of these 
MV patients have acute brain dysfunction, manifesting as delirium and/or coma).10-13, 60, 67, 68  
Although separate entities, sepsis and delirium are closely linked in terms of pathophysiology 
and share many of the same inflammatory pathways and cellular interactions resulting in 
widespread effects on other organs and tissues.60, 68-73 In the United States, severe sepsis alone 
accounts for an estimated 250,000 deaths,2 and exceeds the number of annual deaths from 


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myocardial infarctions, HIV/AIDS, breast cancer and asthma. Indeed, while mortality from 
severe sepsis is upwards of 30-40% in developed countries,2, 74, 75 with only slight temporal 
improvements,74, 75 that of ST-elevation myocardial infarction is much less at 7% and on the 
decline.67 Furthermore, with the aging population, the number of cases of severe sepsis is 
expected to increase by 50% by 2030 unless new therapeutic options are discovered.2 While the 
incidence and mortality associated with severe sepsis is staggering, and sepsis results in 
longer times on MV and in ICUs, a major but often missed cause of increased morbidity in 
ventilated septic patients is delirium, and its complications.69-71, 76  
2.2 
Delirium in ventilated septic patients is associated with mortality and poor 
cognitive function and functional status.  Delirium occurs in 50-80% of MV patients10-13 and 
carries enormous financial77 and societal burdens due to its association with increased 
mortality,37, 38, 78 prolonged hospital stays,79 and its relationship to long-term 
neuropsychological deficits.80-82  Each additional day of delirium independently increases risk 
of death by 10%,37, 38 strongly supporting Aim 1 of this MENDS II study, aimed at reducing 
duration of delirium in patients with ARF and sepsis. It is estimated that ICU delirium is 
associated with $4-$16 billion annually in the U.S.,77 not including cost of lost workdays, 
caregiver burden, or cognitive rehabilitation for the 50-66% of patients with dementia-like 
deficits years later8, 9, 80, 82-84 (supporting Aim 2 of MENDS II aimed at reducing incidence 
of long-term brain dysfunction). Sepsis, too, has been shown to independently and 
significantly alter the trajectory of cognitive impairment with almost a 3-fold increase in the risk 
of developing cognitive impairment in survivors of sepsis.7 While it is unclear as to whether it is 
sepsis that contributes to worse cognitive impairment, or if this is a consequence of the closely 
associated brain dysfunction, it is extremely concerning that the two episodes of ICU care, on 
average, that each American will experience in their lifetime will result in millions of survivors 
suffering mild to severe ICU-acquired cognitive impairment that impairs quality of life.  
2.3 
Sedation used to keep ventilated septic patients comfortable can lead to delirium 
and iatrogenic harm. The mainstay of therapy in severe sepsis is aggressive source control, 
appropriate choice of antibiotics and the consideration of activated protein-C in select cases.14, 15   
Apart from these, key elements in the management of severe sepsis remain supportive (e.g., 
goal-directed resuscitation, ventilation management, glucose control, etc.).85-92  Sedative and 
analgesic medications are part of these supportive treatments, and are almost universally used to 
provide patient comfort, treat pain and anxiety, and prevent agitation.93  Yet, they have shown 
to prolong time on MV and in ICU.24 Deep sedation has also been shown to be associated with 
burst suppression, or an obliteration of brain wave activity on an encephalogram, associated 
with a higher mortality in a important minority of critically ill patients.94  While psychoactive 
medications have traditionally been compared using surrogate markers such as time on the 
ventilator and ICU and hospital length of stay, our team has found that commonly prescribed 
benzodiazepine GABAergic agents, such as lorazepam and midazolam,  are independent (and 
iatrogenic) risk factors for daily development of delirium (see section 3.0) in three separate 
cohorts.27 12, 95 These data showed, for the first time, that benzodiazepines are associated with 
more acute brain dysfunction prompting clinicians and researchers to study alternative sedation 
paradigms to either decrease the exposure to sedatives or to move away from the practice of 
using benzodiazepines in order to improve patient outcomes.13, 28, 29, 35, 36, 40-42  With the  
pathogenesis of delirium still unclear,96 a leading hypothesis is perturbations in 
inflammation69-71 that may have common elements with pathways involved in sepsis.60, 68  


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2.4 
Sedative medications can dysregulate the body’s natural control of inflammation.  
To understand how sedation may play a role in dysregulating the body’s natural response to 
inflammation, we need to first succinctly review the inflammatory response to infection. Sepsis 
is the systemic inflammatory response to infection and is characterized by dysregulated 
production of cytokines, a pathological state that causes tissue injury and consequently organ 
dysfunction and death.60, 68 It is characterized by an early unrestrained production of pro-
inflammatory cytokines such as tumor necrosis factor (TNF) and interleukins (IL) such as IL-1, 
IL-6 etc., and late mediators such as high-mobility group protein B1 (HMGB1), which 
perpetuate inflammatory response and lead to organ dysfunctions. 60   Anti-inflammatory 
cytokines such as soluble TNF receptor-1 (sTNFR-1), IL-1ra, IL-10 are released in an attempt 
to attenuate the pro-inflammatory response and reduce organ damage; failure or dysregulation 
of this compensatory anti-inflammatory response syndrome (CARS) further worsens 
outcomes.60  The brain, too, responds to systemic infections and injury with an inflammatory 
response of its own that includes the production of cytokines, cell infiltration, and tissue 
damage.97, 98  This local inflammatory response is thought to alter patterns of neuronal activity 
resulting in delirium. In addition to the inflammatory responses described above, the 
parasympathetic (cholinergic) anti-inflammatory pathway plays an important role in attenuation 
of pro-inflammatory cytokines from macrophages, without any effects on anti-inflammatory 
cytokines such as IL-10.99, 100   The body generally regulates this balance between the pro 
and anti-inflammatory cytokines; unfortunately, commonly prescribed GABAergic 
sedative agents have immunomodulatory properties that may alter this balance and 
contribute to worse outcomes.  
2.5 
GABAergic sedatives, like benzodiazepines, impact the immune response.  
GABAergic agents, such as midazolam, impair nuclear factor kappa B (NFkB) and mitogen 
activated protein kinase (MAPK) signaling, leading to reduced responsiveness to inflammatory 
stimuli, including pathogens.46 This effect typically manifests itself as reduced cytokine 
production that may have utility in septic shock, however this mechanism also blunts bacterial 
killing.46  In vivo animal studies have demonstrated that the GABAergic agents increase 
mortality in live bacterial infection with intranasal Streptococcus pneumonia,  intraperitoneal 
Klebsiella pneumonia,101  Mycobacterium bovis,102 and Salmonella typhimurium infection that 
may be caused by impairment of neutrophil48 and macrophage46 function. Review of the 
available evidence suggests that this impaired immune response to pathogens is common to the 
whole class of GABA agonists studied so far.34 In contrast, GABAA antagonists improve 
outcomes in infective models.57, 58 Bicuculline57 improves acute mortality in severely septic rats 
and securinine,58 a GABAA antagonist, enhances killing of Coxiella burnetii in vitro and in vivo 
by alveolar macrophages. Consistent with the hypothesis that GABAergic agents may impair 
immune responses to infection, critically ill patients sedated with midazolam appear more 
susceptible to secondary bacterial infections than those sedated with dexmedetomidine,35 and 
septic patients on lorazepam have a greater likelihood of death than patients sedated with 
dexmedetomidine.36 
2.6 
Propofol and dexmedetomidine may differentially affect inflammation and improve 
clinical outcomes in sepsis and delirium.  Compelling data now indicate that a new avenue for 
improving outcomes in severe sepsis and delirium may be via newer sedative agents that lack 
the deleterious effects of benzodiazepine GABAA mediated immunomodulation.31-36 These 
agents include the shorter acting GABAergic agent propofol and the alpha2 agonist 
dexmedetomidine, which are rapidly becoming the pillars of sedation in critically ill patients, 13, 


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35, 36, 40, 42, 43  and yet are different from each other in terms of receptor specificity, 
immunomodulation including bacterial clearance, apoptosis, maintenance of sleep architecture, 
delirium risk, mortality and side effect profile. A comparison of these specific properties is 
provided below. 
[1] 
Propofol is a 2-6 di-iso-propyl phenol intravenous GABAergic sedative agent that 
has been studied and found superior to benzodiazepines for sedation in the ICU with 
respect to time on MV, faster rousability,  greater times at target sedation and faster 
extubations.40, 41, 103 Dexmedetomidine is a highly selective alpha2 receptor agonist 
that inhibits the release of norepinephrine (NE),50 resulting in sedation and analgesia 
and blunting of the stress response, without respiratory depression.54, 55, 104, 105 
Dexmedetomidine has been studied against lorazepam in the MENDS13 double-blind 
randomized controlled trial and was found to be superior in reducing the duration 
and prevalence of brain dysfunction,13 and further time on MV and mortality in the 
septic subgroup, without any differences in hemodynamic profiles or adverse 
events.36 The SEDCOM study,35 compared dexmedetomidine with midazolam, and 
found that dexmedetomidine patients spent fewer days on MV,  experienced less 
delirium, and developed less tachycardia and hypertension. 
[2] 
As mentioned earlier, the dysregulated production of pro-inflammatory cytokines60, 
68 is associated with worse outcomes in sepsis. The body itself attempts to reign this 
pro-inflammatory cytokine cascade by two mechanisms—(2.a) the production of 
anti-inflammatory cytokines,60 and (2.b) the parasympathetic (cholinergic) reflex 
that attenuates inflammation.99, 100  Propofol shows favorable properties of reducing 
the pro-inflammatory cytokines in animal models;106, 107 however, human studies55, 
108 have been contradictory with an increase in the pro-inflammatory cytokine 
production. Additionally propofol has not been shown to influence the 
parasympathetic reflex. Dexmedetomidine, on the other hand, has consistently 
attenuated pro-inflammatory cytokines in animal and human studies, with 
corresponding improvements in outcomes including survival. Its vagomimetic action 
may also play a role in potentiating the parasympathetic reflex. 50 
[3] 
Propofol, similar to the data on the other GABAergics (benzodiazepines) presented 
in section 2.5, impairs bacterial clearance from the lung and spleen in rabbits 
injected with Escherichia (E.) coli in vivo, and E. coli and Staphylococcus aureus in 
vitro,49, 109 through inhibition both of myeloid (in particular neutrophil) and 
lymphoid cell function.49, 110, 111 Dexmedetomidine, on the other hand, does not 
suppress neutrophil function and helps bacterial clearance (see section 3.5)112 
[4] 
Propofol has not been associated with beneficial effects on apoptosis, while 
dexmedetomidine inhibits neuronal apoptosis and apoptosis in other vital organs.34, 
59, 60 
[5] 
Both propofol and dexmedetomidine have been associated with improving 
restorative sleep.  Endogenous sleep pathways mediate the hypnotic response of both 
classes of drugs,61, 62 but GABAergic agents induce unconsciousness at the level of 
the hypothalamus, whereas the alpha2 agonists do so in the brainstem,61-63 an effect—
more akin to natural sleep—which may improve autonomic function and immunity. 


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This image cannot currently be displayed.
Lorazepam Dose (mg) 
p=0.02 
Lorazepam Dose (mg) 
p=0.003 
Probability of delirium
Figure 1. GABA-ergic agents and delirium 
[6] 
As eluded in point [1], benzodiazepines have been associated with delirium, but data 
on propofol are inconclusive. Dexmedetomidine, however, has been shown to reduce 
duration and prevalence of brain dysfunction in two randomized controlled trials 
compared to benzodiazepines.13;35, 36 A comparative trial (the PRODEX study, Orion 
Pharma press release) in low severity illness patients, with approximately 25% septic 
patients, has shown equipoise between the two agents in delirium outcomes. 
Dexmedetomidine, however, has been shown to be superior to propofol with regards 
to its effect on maintenance of cognition,51 and improvement of attention as 
compared to benzodiazepines.33 
[7] 
GABAergic agents may promote infection,49, 110 and the intralipid formulation of 
propofol may play a role in this. Dexmedetomidine, on the other hand, has been 
associated with lower secondary infections and mortality in septic patients when 
compared with a benzodiazepine.35, 36   
[8] 
Side effects associated with propofol include hypertriglyceridemia, pancreatitis, 
acidemia and propofol infusion syndrome.113 Propofol infusion syndrome is rare.  
About 20 adult cases have been described, mostly in patients with acute neurological 
illness, acute inflammatory disease complicated by severe infections or even sepsis, 
and receiving catecholamines and/or steroids in addition to propofol.113 Common 
side effects seen with dexmedetomidine include bradycardia (including a reported 
cardiac arrest in which dexmedetomidine was part of the multifactorial causes for the 
event) and hypotension, though in studies in critically ill patients, including septic 
patients, there has not been a reported increase in vasopressor use.35, 36   
Additionally, one trial reported hyperglycemia with dexmedetomidine.35, 36   
 
Thus there are data supporting beneficial effects of both propofol and dexmedetomidine.  
While propofol offers significant benefits over benzodiazepines, data indicate that 
dexmedetomidine is superior to propofol with regard to its effects on innate immunity and 
inflammation,44-49 cognition,51 apoptosis,34, 59  and delirium.35, 36 All these factors converge to 
suggest that sedation with an alpha2 agonist rather than a GABAergic agent may improve 
outcomes, including brain function and survival, for septic MV patients. Physicians are now 
challenged, due to the absence of head to head comparisons of these two agents in high 
severity of illness, severely septic patients, to understand the benefit to risk profile. This 
presents an unmet scientific gap in knowledge, which has to be addressed to ensure that 
our most vulnerable patients are treated in the most effective and safe manner.  The 
MENDS II trial will address this need. 
 
3.0 
Preliminary Studies 
 
3.1 
Benzodiazepines and delirium. Of the three 
components of patient comfort (pain, anxiety, and 
delirium) included in current guidelines for use of 
sedatives and analgesics in ICU patients,93 only 
delirium has been found to be an independent 
predictor of death. Pharmacological data was 
analyzed from 198 medical ICU patients,37 using 
time-dependent multivariable analysis, to test the 


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Fig 3.  Probability of transitioning to delirium 
hypothesis that sedative and analgesic medications are independent risk factors for the 
development of delirium after adjusting for relevant covariates. Every unit dose of lorazepam in 
the previous 24 hours was associated with increased probability of development of delirium 
[O.R. 1.2 (95% C.I. 1.1 to 1.4), p =0.003] (Fig 1), whereas propofol were associated with higher 
but not statistically significant odds ratios.27 Using a similar methodology midazolam was also 
shown as a risk factor for delirium in surgical, trauma and burn ICU patients.12, 95 These data 
support Aim1A of MENDS II (reducing delirium by use of alpha2 agonists instead of 
GABAergic agents). Data on opiates is inconsistent, with opiates being risk factors for delirium 
in surgical patients, but not in trauma and burn patients where pain is significant and adequate 
treatment may offer benefit.27  
3.2 
Delirium and Long-term Cognitive Impairment. This cohort study82 enrolled 126 
adult ventilated medical ICU survivors and followed them for 12 months. Multiple linear 
regression was used to analyze the association between delirium duration and 12-month 
cognitive performance, adjusting for covariates. Follow-up 
data were obtained for 80% of survivors. Duration of 
delirium (Fig 2) independently predicted worse cognition at 
3 months (P=0.02) and 12 months (P=0.03).82 These data 
demonstrate our coordinating center’s success in 
achieving high long-term follow-up rates and add 
support for the idea that an intervention to reduce 
delirium duration might produce improvements in long-
term cognitive function, justifying Aim 2B (cognitive 
function) in MENDS II. 
 
3.3 
Changing sedation paradigms reduces duration and prevalence of brain 
dysfunction. The MENDS study,13 which enrolled both medical and surgical ICU patients, was 
the first to evaluate the benefit of sedation targeting alpha2 receptors compared to the standard 
of care GABAergic agents to 
reduce brain dysfunction.  This 
trial showed that compared to 
lorazepam, patients sedated with 
dexmedetomidine achieved 
sedation targets more often and 
had more days alive without 
delirium or coma, with important 
trends toward a reduction in death 
at 28-days (27% in lorazepam 
versus 17% dexmedetomidine). 
Patients on dexmedetomidine had 
a 60% lower risk of developing 
delirium (Fig 3) versus 
lorazepam, further supporting 
Aim 1A of MENDS II.  
 
3.4 
Alpha2 agonists improve survival in patients with sepsis compared to GABAergic 
agents. In this a priori-determined subgroup analysis36 of septic vs non-septic patients from the 


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Fig 4.  Dexmedetomidine improves 28-day survival in 
septic patients 
-
0
7
14
21
28 
0 
20
40
60
80
100 
Days
Patients alive (%) 
Dexmedetomidine 
Lorazepam
HR 0.3 (0.1 - 0.9). P=0.04
Effect of Diazepam or Clonidine treatment on
Survival from Co-infection
0
50
100
150
0
50
100
150
Diazepam 2 mg kg -1
Clonidine 5 mcg kg-1
Time (h)
Percent survival
Effect of Propofol or Dexmedetomidine treatment on
Survival from Streptococcus pneumoniae Pneumonia
0
50
100
150
0
50
100
150
Dexmedetomidine 5 mcg kg-1
Propofol 10 mg kg-1
Time (h)
Percent survival
MENDS double-blind randomized controlled trial, 63 (31 dexmedetomidine; 32 lorazepam) 
were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. 
Compared with septic patients who received lorazepam, the septic patients receiving 
dexmedetomidine had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for 
difference, 1.1 to 4.9), and 6 (0.3, 11.1) 
more ventilator-free days (VFD). The 
beneficial effects of dexmedetomidine were 
more pronounced in septic patients than in 
non-septic patients for both DCFDs and 
VFDs (supporting Aim 1B) (P-value for 
interaction = 0.09 and 0.02 respectively). 
Additionally, sedation with 
dexmedetomidine, compared with 
lorazepam, reduced the daily risk of 
delirium [OR, CI 0.3 (0.1, 0.7)] in both 
septic and non-septic patients. Risk of 
dying at 28 days was reduced by 70% 
[hazard ratio 0.3 (0.1, 0.9)] in 
dexmedetomidine patients with sepsis (Fig 
4) as compared to the lorazepam patients; this reduction in death was not seen in non-septic 
patients (supporting Aim 2A of MENDS II). 
 
3.5 
Alpha2 agonists improve survival in animal models with infections compared to 
GABAergic agents. In order to confirm a survival benefit conferred by alpha2 adrenoceptor 
agonists over GABAergic agents, diazepam 
versus clonidine and propofol versus 
dexmedetomidine (drugs with similar half-lives) 
were compared in two infection paradigms. In the 
prolonged infection model, adult C57BL/6 mice 
infected with 50HA of X31 influenza (intranasal) 
were administered diazepam, clonidine or 
placebo, 4 hours after influenza infection. Seven 
days later, both groups of animals were super 
infected with D39 (serotype 2) Streptococcus 
pneumoniae infection (1 x 106 colony forming 
units ml-1 intranasal). Median survival time in the 
placebo group was 72 hours from the time of 
bacterial superinfection.  Clonidine increased 
median survival time compared to diazepam (84 
versus 42 hours) and reduced the hazard ratio of 
death (HR 0.06 [0.01 – 0.32]; p = 0.0008) (Fig 5).  
In the acute infection model, adult C57BL/6 mice 
infected with 5 x 104 colony forming units ml-1 Streptococcus pneumoniae intranasal had a 19% 
survival (3 out of 16 mice). In this model comparison of dexmedetomidine (n = 15) with 
propofol (n = 16) treatment started four hours after infection revealed that dexmedetomidine 
increased survival compared to propofol (33% versus 0%; p = 0.02). Thus our clinical (3.4) 
Fig. 5 


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and preclinical work (3.5) are supportive of Aim 2B of MENDS II where we hypothesize 
that survival may be better with alpha2 agonists over GABAergic agents. 
 
4.0 
Study Objectives and Endpoints 
 
4.1 
Study Objectives. The primary objective of the MENDS II study is to determine the 
efficacy and safety of dexmedetomidine vs. propofol in mechanically ventilated medical and 
surgical patients with severe sepsis. 
 
4.2 
Efficacy Endpoints 
 
4.2.1 Primary Endpoint.  The trial’s primary endpoint (Aim 1A) will be delirium/coma-
free days (DCFDs), defined as number of days alive and free of delirium and coma during the 
14-day Treatment Period (from randomization, which will be Study Day 1, until Study Day 14). 
Patients will be evaluated for delirium by trained research nurses with the CAM-ICU,10, 11a 
validated instrument for diagnosing delirium, even in non-verbal ventilated patients, that takes 
on an average 2 minutes and can be administered by non-psychiatrist personnel (Fig 6). 
Delirium assessments will be performed twice daily while in the ICU and then once daily until 
conclusion of the combined Treatment/Post Study Drug Period (see section 7.2), hospital 
discharge or death (whichever is first). Patients who are unresponsive to voice are categorized 
as comatose; those responsive to voice and CAM-ICU positive are categorized as delirious; 
those who are CAM-ICU negative are called normal. The DCFD continuous variable represents 
duration of time a patient is alive and free of brain dysfunction (delirium and coma) and has 
been used in other high-impact studies.13, 28 For example, if during a 14 day period a patient is 
comatose the first 3 days, then has delirium (or CAM-ICU positive) the next 4 days, and then 
normal or CAM-ICU negative the remaining 7 days, he will have 7 =[14-(3+4)] delirium/coma-
free days. On the other hand, suppose a patient is comatose the first 3 days, then has delirium 
(or CAM-ICU positive) the next 4 days and then dies, he will have 0 delirium/coma-free days, 
since there were no days that the patient was alive and free of delirium or coma. 
The MENDS II study will have tremendous implications for practice, based on the 
outcome of DCFD results, even if the secondary outcome of mortality is neutral, given ours and 
others’ recent data that every additional day of brain dysfunction is independently associated 
with higher mortality and cognitive impairment in survivors.37-39, 82  We will also assess 
delirium days in survivors and daily prevalence of delirium after randomization as additional 
brain injury outcomes. Delirium days was not chosen as a primary end point because delirium 
Feature 1: Acute change or fluctuating course 
of mental status 
And 
       Feature 2: Inattention 
And 
Feature 3: Altered level of consciousness 
Feature 4: Disorganized Thinking 
Or 
Fig. 6  CAM-ICU 


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days can be curtailed by death; similarly delirium-free days was not used because delirium-free 
days fails to account for coma; thus patients could artificially be considered to have more 
delirium-free days (thus a good outcome) when in fact the reason they were delirium-free was 
because of coma (an untoward outcome). The analysis of DCFDs and other secondary outcomes 
will be conducted using Intention-to-Treat (ITT) population, defined as all patients who were 
randomized to study drug. We chose a 14 day evaluation period for delirium, because it 
represents the best balance of gaining valuable clinical information, while maximizing resource 
utilization, given the average study drug infusion to be 7 days and maximum duration to be 14 
days. Thus our follow-up period will cover 7 additional days of delirium monitoring after the 
study drug is stopped in the majority of our patients. 
 
4.2.2 Secondary Endpoints 
[1] 
Ventilator-free days (VFDs) (Aim 1B), i.e., days alive and free of MV at 28 days. 
This endpoint has been used by the NHLBI’s ARDSNet in numerous critical care 
trials examining ICU populations.88, 89, 114, 115 
[2] 
90-day survival (Aim 2A) 
[3] 
Neuropsychological function, Activities of Daily Living (ADL)116 and 
Instrumental ADLs117 will be assessed 6 months after randomization (Aim 2B) 
using a validated and reliable telephone battery118 for post-ICU patients, to measure 
incidence, duration, and severity of dysfunction in memory, attention, reasoning, and 
executive function domains as well as assess independence and quality of life (see 
section 8.1).    
[4] 
Markers of inflammation (Aim 3) will be assessed on Days 1, 3, 5, 7 and 14 (see 
details in 7.2.3) 
 
[5] 
Organ dysfunctions will be tracked until conclusion of the combined 
Treatment/Post Study Drug Period, hospital discharge or death (whichever happens 
first) using daily SOFA scores and continuous as well as established predefined cut 
offs for each organ failure: Kidney, Cr > 2 mg/dL or urine < 400 cc/day; Lung, 
PaO2/FiO2 <300 or SaO2/FiO2 <315;119  Liver, total bilirubin > 2 mg/dL; 
Coagulation, Platelet count < 100,000/mm3; and Hemodynamic, need for 
vasopressor,120, 121 consistent with definitions utilized in published studies of organ 
dysfunction in critically ill patients.122 
[6] 
Acute Respiratory Distress Syndrome. We will monitor a patient’s oxygenation 
status by tracking daily SaO2/FiO2 ratios.119 A SaO2/FiO2 ratio <235 correlates to a 
PaO2/FiO2 ratio of <200, which is the oxygenation threshold for ARDS.119 Chest X-
rays that are ordered as part of routine clinical care will be followed daily in patients 
who meet ARDS oxygenation threshold and patients with bilateral infiltrates 
confirmed by the medical team, will be considered to have ARDS. Time to onset of 
ARDS and duration of ARDS will be tracked until conclusion of the combined 
Treatment/Post Study Drug Period, hospital discharge, or death (whichever happens 
first). 
 
4.3 
Safety Endpoints.  Safety endpoints tracked until conclusion of the combined 
Treatment/Post Study Drug Period, hospital discharge or death (whichever happens first) 
include daily monitoring for hypotension (defined as systolic blood pressure <80 mmHg, 
duration and dose of vasopressors/inotropes using SOFA scores), arrhythmias (tachy and/or 


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brady), acidosis, and weekly for triglyceridemia and adrenal insufficiency. Patients will be 
monitored for withdrawal for 48-hours after study drug termination, assessing for hypertension, 
tachycardia and diaphoresis. Vital signs will be monitored per established standards in the ICUs 
and wards. Select laboratory values from standard laboratory measures of blood counts and 
chemistries will be collected daily, when ordered as part of usual clinical care.  
 
5.0 
Inclusion/Exclusion Criteria 
 
5.1 
Inclusion Criteria. Consecutive patients will be eligible for inclusion in the MENDS II 
study if they are: [1] adult patients (≥18 years old) [2] in a medical or surgical ICU and [3] on 
MV, requiring sedation and [4] have a suspected or known infection. 
 
5.2 
Exclusion Criteria. Patients will be excluded (i.e., not consented) for any of the 
following reasons: 
[1] 
Rapidly resolving organ failure, indicated by planned immediate discontinuation of 
MV, at time of screening for study enrollment 
[2] 
Pregnant or breastfeeding 
[3] 
Severe dementia or neurodegenerative disease, defined as either cognitive 
impairment that makes the patient incapable of living independently at baseline or 
IQCODE >4.5,123 measured using a patient’s qualified surrogate. This exclusion also 
pertains to mental illnesses requiring long-term institutionalization, acquired or 
congenital mental retardation, severe neuromuscular disorders, Parkinson’s disease, 
Huntington’s disease, Alzheimer’s and debilitating cerebrovascular disease. It also 
excludes patients in coma or with severe cognitive deficits due to structural brain 
diseases such as stroke, intracranial hemorrhage, cranial trauma, malignancy, anoxic 
brain injury, or cerebral edema. 
[4] 
Present history of 2nd or 3rd degree heart block, or persistent bradycardia < 50 
beats/minute that requires intervention (e.g., atropine, glycopyrrolate). If patient has 
a pacemaker for bradyarrythmias, then patient does not meet this exclusion criterion 
and may be enrolled.  
[5] 
Benzodiazepine dependency or history of alcohol dependency based on the medical 
team’s decision to institute a specific treatment plan involving benzodiazepines 
(either as continuous infusions or intermittent intravenous boluses) for this 
dependency.  
[6] 
Active seizures during this ICU admission being treated with intravenous 
benzodiazepines. 
[7] 
Expected death within 24 hours of enrollment or lack of commitment to aggressive 
treatment by family or the medical team (e.g., likely to withdraw life support 
measures within 24 hrs of screening). 
[8] 
Inability to understand English or deafness that will preclude delirium evaluation. 
The inability to understand English (for example in Spanish-only or Mandarin-only 
speaking patients) will not result in exclusion at centers where the research staff is 
proficient and/or translation services are actively available in that particular 
language; these patients will not be followed in the long-term follow-up phase of the 
trial since the testing materials are primarily available only in English. Patients with 
laryngectomies and those with hearing deficits are eligible for enrollment if their 
medical condition permits them to communicate with research staff.    


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[9] 
Inability to obtain informed consent from the patient or an authorized representative 
within 48 hours of meeting all inclusion criteria for the following reasons: 
(a)  Patient and/or surrogate refusal 
(b)  Patient unable to consent and no surrogate available in the 48 hour window 
(c)  48-hour period of eligibility was exceeded prior to screen  
[10] 
Prisoners. 
[11] 
Medical team following patient unwilling to use the sedation regimens. 
[12] 
Documented allergy to propofol or dexmedetomidine. 
[13] 
Current enrollment in a study that does not allow co-enrollment or that uses delirium 
as a primary outcome. 
[14]  
Patients who are on muscle relaxant infusions at time of screening with plans to 
maintain paralysis >48 hours 
[15] 
Greater than 96 hours on mechanical ventilation prior to meeting all inclusion 
criteria.  
 
6.0 
Enrollment/Randomization  
 
 
6.1. 
Screening and Obtaining Informed Consent.  Study personnel at each site will screen 
the ICU census.  When an eligible patient is identified (i.e., inclusion criteria are met and no 
exclusion criteria are present), informed consent will be pursued. Surrogate consent will be 
required for most patients because during the initial phase of their illness they will often be 
comatose, sedated, on MV, or delirious. A consent/re-consent process will be used (surrogate 
consent at enrollment and re-consenting patients when competent), in keeping with recent 
literature on consenting delirious and/or ICU patients.124, 125  All patients consented via 
surrogate will be re-consented for participation in the trial once competent. 
Once informed consent is obtained, if not already confirmed, patients will be assessed for 
advanced heart block, pregnancy (female patients of childbearing potential only), and dementia 
via the IQCODE. When a patient’s telemetry strip is negative for advanced heart block, 
IQCODE <4.5 and female patients of childbearing potential have a negative pregnancy test, 
they will be randomized and advanced to the Interventional Trial Phase of the study (see section 
7.2 & 7.3).  At this time the patient is assigned via randomization to one of the two treatment 
groups: dexmedetomidine or propofol.   
Randomization will be conducted using computer-generated, randomly chosen permuted 
block sizes of 6 and 8, stratified by study center and age (<65 vs > 65 years).  We will 
randomize patients in a 1:1 ratio to sedation with dexmedetomidine or propofol. The 
randomization scheme will be created by the study’s primary biostatistician and distributed 
directly to each site’s investigational pharmacy as a set of randomization lists stratified by study 
center and age (<65 vs > 65 years).  Once a consented patient has entered the Interventional 
Trial Phase, an order for blinded study drug is placed, and the investigational pharmacist will 
refer to the appropriate randomization list (determined by patient’s age) to establish that 
patient’s treatment assignment. The lists will only be accessible to investigational pharmacists 
so that treatment assignment will be known only by the investigational pharmacists.  
 
6.2 
Blinding.  The challenge of blinding propofol, a milky fat emulsion, and 
dexmedetomidine, a clear aqueous solution, is evident.  Nevertheless, apart from investigational 
pharmacists, all study personnel, patients, and physicians will attempt to remain blinded to each 
patient’s treatment assignment throughout enrollment, follow-up, and data analysis. Study drug 


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will, therefore, be administered via intravenous infusion covered by an opaque bag along with 
sleeves to cover the intravenous tubing. Study personnel are prohibited from entering a patient’s 
room during infusion bag or tubing changes to further reduce risk of unblinding of study 
personnel by visualization of study drug.  End-points such as ventilator-free days, mortality, and 
long-term cognitive impairment are unlikely to be influenced, should unblinding be suspected. 
Instances of unblinding are anticipated and when known will be recorded in the study database. 
If an adverse event is considered study-drug related, unexpected and serious, the study drug will 
be immediately discontinued and the event will be reviewed via the usual process, which may 
involve unblinded evaluation by the Data Safety Monitoring Board (DSMB) Chair, as outlined 
in the Data Safety Monitoring Plan (see sections 9.2 &9.3). 
 
7.0 
Study Procedures 
 
7.1 
Enrollment.  After informed consent is obtained, on the day of enrollment baseline data 
will be collected and the following procedures conducted: 
 [1] 
As part of a Pre-Hospital Function Assessment a dementia assessment via surrogate 
interview will ascertain the patient’s physical and cognitive abilities prior to the 
current hospitalization.  Rather than relying on a “label” of dementia in the medical 
record, we will use the surrogate-completed IQCODE.126-128  Any patient with severe 
dementia, based on an IQCODE >4.5,123 will be excluded from further participation 
in the study, as described in the exclusion criteria (see section 5.2).  The Pre-
Hospital Function Assessment form will ascertain additional important information 
about the patient’s pre-hospital functional status, including history of depression and 
chronic pain as well as provide information regarding tobacco, alcohol and illicit 
substance use 
[2] 
A pregnancy test (beta-hCG) will be done in all females of childbearing potential 
unless a pregnancy test (urine or serum hCG) has been performed during the current 
hospitalization that ruled out pregnancy. 
[3] 
All patients will be assessed for advanced heart block using a bedside telemetry 
strip.  Advanced heart block will be defined as second or third degree block on 
telemetry per the MENDS II study. 
 
7.2 
In-Hospital Phase.  The In-Hospital Phase will comprise of the Treatment Period 
(Study Days 1-14), during which time study drug will be infused per the study drug 
administration rules (see section 7.2.1) and the Post-Study Drug period (2 calendar days after 
discontinuation of study drug). In most instances (when study drug is administered for < 12 
days), the Post-Study Drug Period will fall within the treatment period. When study drug  is 
required for >12 days, the Post-Study Drug period will extend beyond the treatment period such 
that for e.g., patients who receive study drug for the entire 14-day treatment period will have the 
Post-Study Drug Period last until Study Day 16.  
 Once it has been confirmed that the patient qualifies for randomization [e.g. patient’s 
telemetry strip is negative for advanced heart block, female patients of childbearing potential 
have a negative pregnancy test (either serum or urine), and IQCODE is less than 4.5] they will 
advance to the Interventional Trial and enter the In-Hospital Phase of the trial.   Upon entering 
the Interventional Trial Phase, each patient will be assigned, via randomization, to one of the 
two treatment groups, and study drug will be delivered in a double-blind manner per titration 
rules as outlined in section 7.2.1 when in the ICU on mechanical ventilation, and needing 


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sedation per the managing clinical team, until study drug withdrawal, death, or for a maximum 
of 14 days—the Treatment Period— (whichever occurs first).  
  
 
The following data will be collected during the In-Hospital Phase: 
[1] 
On enrollment the patient’s medical records will be used to collect demographics, 
preexisting conditions, admission severity of illness and organ failure.  If obtained as 
part of routine medical care, results of additional test results will also be collected 
and may include hematologic laboratory values and blood chemistries, [e.g. WBC, 
HCT, potassium, sodium, BUN, creatinine, albumin, bilirubin, SGOT (AST), SGPT 
(ALT), lactate, ammonia, troponin, and glucose]. 
 [2] 
Throughout the study, data reflecting current severity of illness, recent and ongoing 
treatments (including medications and mechanical ventilator status), vital signs 
(including daily worst SaO2/FiO2 ratios), routine lab results, tracking of sepsis and 
ventilator management, and complications (e.g., infections and device removals), 
will be collected from the patient’s medical records. These data will be generated 
as part of routine clinical care and will not require study-related tests.  
[3] 
A direct patient assessment will occur twice daily while in the ICU and once a day 
when on the wards to determine level of sedation using the RASS129, 130, assess for 
pain using the Critical-Care Pain Observation Tool (CPOT), assess for delirium 
using the CAM-ICU, and assess for diaphoresis.10, 11, 131 
[4] 
A bedside checklist will be used to collect data regarding adherence to the 
nonpharmacologic ABCDE protocol (see section 7.2.2), which includes standardized 
components of ventilator weaning, sedation, and delirium management. Components 
of the ABCDE protocol will be documented as complete or incomplete on a daily 
basis by ICU staff and/or study personnel after they are implemented. 
[5] 
Co-administered psychoactive medications, including sedatives, analgesics, and 
antipsychotics, will be tracked daily in the study. 
[6] 
Blood specimens will be collected as outlined in section 7.2.3 on all consented 
patients. 
[7] 
Assessment for Catatonia: At select participating sites and in a convenience 
sample, patients will be screened up to twice daily while in the ICU and up to once 
daily when on the wards with the Bush Francis Catatonia Rating Scale (BFCRS), a 
bedside clinical tool used widely in psychiatric consultations to diagnose catatonia, 
and for motor symptoms with the Delirium Motor Subtype Scale (DMSS).  Together 
these assessments will take 5 minutes on average to perform.  These evaluations will 
for the first time evaluate the prevalence of catatonia in critically ill patients, and 
prospectively explore the extent to which an overlap syndrome exists between 
delirium and catatonia. For those patients who receive a catatonia assessment - a 
telephone assessment identical to the 6 month neuropsychological battery will also 
be conducted 12 months after randomization.  These patients will also receive a 
depression inventory (BDI-II) and a PTSD screening tool (PCL-5) at both 6 and 12 
months. 
[8] 
At select participating sites, and in a convenience sample of patients, we will 
connect patients to the noninvasive Root® patient monitoring and connectivity 
platform by Massimo for up to 7 days. This enables the monitoring of several 
physiologic parameters, including electroencephalography (EEG), cerebral oximetry, 


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and capnography with one portable monitoring platform. We will monitor the raw 
(EEG) and spectral analysis patterns of patients randomized to dexmedetomidine and 
propofol, using the portable SedLine Sedation Monitor through the Root® platform.  
The SedLine Sedation Monitor is a patient-connected, 4-channel processed EEG 
monitor. It displays electrode status, EEG waveforms, Density Spectral Array 
(DSA), and Patient State Index (PSI). It is intended to monitor the state of the brain 
by real-time data acquisition and processing of EEG.  We will use the Masimo 
Rainbow SET® through the Root® platform to continuously measure additional 
blood constituents and physiologic parameter like the Oxygen Saturation (SpO2) and 
the non invasive hemoglobin (Sphb). We will use the O3regional oximetry that uses 
near-infrared spectroscopy (NIRS) to continuously measure cerebral tissue oxygen 
saturation(rSO2) on the Root® platform. Finally, the Root® platform will allow the 
ISATM   CO2 module for capnography monitoring, end-tidal carbon dioxide (EtCO2) 
waveform  and measurements and trend of EtCO2, fractional concentration of 
inspiration of CO2 (FiCO2), and respiratory rate (RR). The research team and 
medical team will be blinded to the raw EEG and spectral analysis cerebral 
oximetry, and all other monitoring parameters which will be downloaded directly 
from the monitor to a USB port and then stored in the database. These evaluations 
will for the first time evaluate the EEG patterns and spectral analysis of critically ill 
septic patients on dexmedetomidine and propofol and provide insights into its 
relationship with sleep, delirium, coma, and long-term cognitive outcomes.  
 
7.2.1 Study Drug Administration.  Upon entry into the Interventional Trial, randomization 
will be carried out by the investigational pharmacist at each study center according to the 
randomization scheme provided by the study biostatistician. The pharmacist at each site will 
prepare and deliver study drug to the bedside nurse according to orders placed by study 
personnel at each site.  Study drug will be titrated by the bedside nurse in accordance with the 
weight-based titration table (Table 2). 
[1]       Route and Concentration.  All study drug will be administered intravenously 
(IV) by continuous infusion at concentrations of 10 mg/mL propofol or 5 mcg/mL 
dexmedetomidine.  Patients will only receive study drug while in the ICU and on mechanical 
ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice. 
[2] 
Dosing Range.  Study drug dose will be titrated in a double-blind manner 
according to clinical effect to achieve a “goal” or “target” Richmond Agitation-Sedation Score 
(Table 3) set by the managing clinical team (see Titration section below).  For sites that do not 
utilize the RASS scale, the VCC will provide titration instructions using their local sedation-
agitation scale.  For patients in the propofol group, dose will range from 5-50 mcg/kg/min.  For 
patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.  For example, 
a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide either 25 
mcg/kg/min of propofol or 0.75 mcg/kg/hr of dexmedetomidine. These dose ranges have been 
selected after literature review and discussions with critical care practitioners, investigational 
pharmacists, and the MENDS II study steering committee. 13, 35, 40, 132 Patient doses will be 
calculated based on each patient's enrollment weight, with no cap to the maximum 
weight.  Table 2 includes the infusion rates for patients weighing 40-140kg; an additional 
titration table for patients >140 kg is available to sites from the VCC. 


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Table 2. Study drug concentration and weight-based titration table for 40-140kgs 
 
 
 
 
 
[3] 
Initiation.  No bolus dose of study medication will be allowed.  Since most patients are 
already receiving sedation prior to enrollment this is often not required. The bedside nurse will 
initiate this infusion based on patient weight in kg starting at 5-15 mcg/kg/min propofol and 
0.15-0.45 mcg/kg/hr dexmedetomidine.  (see Table 2) starting at 5-15 mcg/kg/min propofol and 
0.15-0.45 mcg/kg/hr dexmedetomidine. 
[4] 
Titration.  Study drug dose will be titrated every 10 minutes by the bedside nurse in 
mL/hr according the weight-based titration table (see Table 2) to achieve the RASS target 
(Table 3) set by the managing clinical team. 
 
Table 3. Richmond Agitation-Sedation Scale (RASS)129, 130 
 
+4 
Combative 
Combative, violent, immediate danger to staff 
+3 
Very agitated 
Pulls or removes tube(s) or catheter(s); aggressive  
+2 
Agitated 
Frequent nonpurposeful movement, fights ventilator 
+1 
Restless 
  Anxious, apprehensive but movements are not aggressive or vigorous 
0 
Alert and calm 
 
-1 
Drowsy 
Not fully alert, but sustained awakening to voice (eye opening & contact > 10 sec) 
-2 
Light sedation   
Briefly awakens to voice (eye opening & contact < 10 sec)  
-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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(a) 
Titrating Up (undersedation: Patient RASS > Target RASS). If a patient’s 
RASS is 1 or more levels higher than the Target RASS (e.g. patient RASS +1 
& target RASS 0 or -1), study drug volume will be increased according to 
weight-based titration table (see Table 2) every 10 minutes in increments of 5 
mcg/kg/min for propofol or 0.15 mcg/kg/hr for dexmedetomidine, until the 
maximum dose is reached (1.5 mcg/kg/hr dexmedetomidine or 50 
mcg/kg/min propofol) or the patient reaches the target RASS. 
(b) 
Titrating Down (oversedation: Patient RASS < Target RASS).  If 
oversedated (i.e., more than 1 RASS level deeper than ICU team’s sedation 
target), study drug volume will be decreased every 30 minutes per the 
weight-based titration table (see Table 2) in decrements of 5 mcg/kg/min for 
propofol or 0.15 mcg/kg/hr for dexmedetomidine until the patient is within 1 
RASS level of the target RASS. Study drug will be held if other sedatives 
have been held, study drug has been titrated to lowest volume (5 mcg/kg/min 
for propofol or 0.15 mcg/kg/), and the patient remains oversedated (i.e., more 
than 1 RASS level deeper than ICU team’s sedation target) for >30 minutes. 
(c) 
Titrating Study Drug during a Spontaneous Awakening Trial (SAT) (see 
section 7.2.2). Patients will be evaluated daily for readiness for a SAT by 
first evaluating patients with a SAT safety screen.  In patients passing the 
safety screen, study drug will be held until patients show signs of failing the 
SAT indicating a need for sedation. Study drug that is held for the 
spontaneous awakening trial will be restarted, if needed, to the lowest 
possible infusion rate that is needed to achieve target RASS (see section 
7.2.2).  
(d) 
Restarting Study Drug (with exception of restarting after SAT as outlined in 
section 7.2.1[4]c above).  Study drug will be discontinued if a patient is 
liberated from mechanical ventilation, or if the managing clinical team 
determines the patient does not need ongoing sedation. If, however, at any 
time during the 14-day Treatment Period (starting from enrollment day, 
which is Trial Day 1, through Trial Day 14) a patient again requires sedative 
therapy and is still on mechanical ventilation, the study drug will be restarted 
according to initiation rules (see Initiation section 7.2.1[3] above), as long as 
study drug was not discontinued permanently for safety reasons (see 
Permanent Discontinuation section 7.2.1[6] below). No study drug will be 
continued beyond Trial Day 14, irrespective of the duration of therapy within 
the 14-day Treatment Period.  
[5] 
Holding.  Throughout the treatment period, study drug may be temporarily held for 
the following reasons: 
(a)  Hypotension. If a patient’s systolic blood pressure is <80 mmHg and if 
deemed necessary by the managing clinical team, study drug will be held 
until fluid and/or vasopressor/inotrope therapy can be initiated and systolic 
blood pressure has increased to >80 mmHg.  Since this is a study in severely 
septic patients, hypotension may occur frequently and will be monitored as a 
safety outcome.  
(b)     New onset symptomatic bradycardia (<50 beats/minute and systolic blood 
pressure <80 mm Hg). Study drug may be held if deemed necessary by the 


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managing clinical team until atropine is administered and patients heart rate 
is >50 beats/min.  
(c).    Oversedation despite titration to lowest study drug rate. Study drug may be 
held if patient continues to be oversedated (i.e., more than 1 RASS level 
deeper than ICU team’s sedation target), all other sedatives have been held 
and study has been titrated to lowest volume (5 mcg/kg/min for propofol or 
0.15 mcg/kg/) for >30 minutes, until patients RASS level is at target.  
(d) 
General anesthesia. Study drug may be held if patient is receiving general 
anesthesia for a surgical operation.  Study drug may be held until the patient 
returns to the ICU setting and resumes sedation per ICU target sedation scale 
orders.   
[6] 
Permanent Discontinuation.  Study drug will be permanently discontinued at any 
time during the trial for any of the following safety reasons.  Management of these 
conditions is left to the discretion of the medical team. 
(a) 
Second episode of symptomatic bradycardia (<50 beats/minute and systolic 
blood pressure <80 mm Hg) while on study drug.  As described above in 
7.2.1[5]b, study drug may be continued, titrated down or held during the first 
episode of symptomatic bradycardia, at the discretion of the medical team. 
Medical team would manage the bradycardia and once it resolves, study drug 
should be restarted, if it had been stopped. Symptomatic bradycardia that 
reoccurs while back on study drug will result in permanent discontinuation.  
(b) 
New onset 2nd or 3rd degree heart block. Degree of heart block should be 
confirmed with medical team or PI before discontinuation.  
(c) 
Serious allergic reactions to study drug as determined by the managing 
clinical team and principal investigator.  
(d) 
New onset coma due to a known structural brain disease such as stroke, 
intracranial hemorrhage, cranial trauma, malignancy, anoxic brain injury, or 
cerebral edema.  
(e) 
Suspected Propofol Infusion Syndrome (commonly presents as cardiac 
failure, rhabdomyolysis, severe metabolic acidosis and renal failure) or 
acidosis that cannot be explained by the medical condition of the patient. 
These are considered severe clinical outcomes and tracked. 
(e) 
Any other study drug-related, life-threatening, serious adverse reactions. 
(f) 
Withdrawal from study drug treatment at the discretion of the principal 
investigator, the patient/family, or the attending physician. 
In the event that study drug is permanently discontinued, the managing clinical team 
will be notified by study personnel, and may then order sedative/analgesia 
management per standard ICU sedation protocol.  
7.2.2 Management Components.   
[1] 
Management of pain, rescue sedation, and the chemically paralyzed patient.  
Patients will be monitored for pain using the Critical-Care Pain Observation Tool 
(CPOT), and intermittent boluses of 0.5-1 mcg/kg of fentanyl (or other standard of 
care opiates such as morphine or hydromorphone) or continuous fentanyl infusions 
will be permitted for analgesia as determined necessary by the managing clinical 
team. In circumstances where sedation target is not met with maximum study drug 
infusion, additional intermittent opiates (IV opiates such as fentanyl, morphine or 


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hydromorphone or po opiates) or continuous fentanyl may be used to help attain 
sedation target. Occasionally, despite maximum study drug and use of significant (4-
5 mcg/kg/hr) continuous fentanyl, patients may still be undersedated; in these rare 
circumstances intermittent dose midazolam will be permitted and tracked. In the rare 
instance, when sedation is required beyond the 14 day Treatment Period, sedation 
will be administered per existing ICU protocol and tracked until hospital discharge, 
death or the end of the Post-Study Drug Period (whichever is earlier). Chemical 
paralysis is used in < 5% of patients in ICUs, and when needed, intermittent 
midazolam or continuous midazolam will be permitted and tracked, since 
dexmedetomidine may not provide adequate amnesia. Study drug will be reduced to 
the lowest infusion rate for the patient’s weight according to the weight based 
titration table being used for the patient and maintained at this level during the time 
chemical paralysis is ongoing. Midazolam infusions that are started to provide 
amnesia during sustained chemical paralysis will be discontinued approximately one 
hour after discontinuation of chemical paralysis, while study drug will continue and 
management will be per titration rules. We expect our rescue protocol to minimize, 
and the randomization to balance the effects of these medications. Similarly 
intermittent midazolam or propofol will be permitted to provide amnesia when short-
term muscle relaxation is employed during procedures e.g. bronchoscopies, 
tracheostomies, etc. 
[2] 
Delirium Protocol (ABCDE Protocol).28, 133-136  During the Treatment Period, we 
will standardize and/or track components of ICU care that may influence delirium 
risk via an evidence-based non-pharmacologic protocol referred to as the ABCDE 
protocol. Study personnel will be well-trained with this protocol during the MENDS 
II startup meeting and compliance will be emphasized and tracked throughout the 
study. Local ICU nursing staff at each study center will receive a standardized 
educational packet that focuses on delirium recognition, risk factors, and prevention. 
When knowledge gaps are identified or compliance drops below 80%, as measured 
by daily compliance checks, additional education will be provided. The ABCDE 
protocol has 3 components: 
(a)  ABCDE (Awakening and Breathing Coordination). Based on our “Wake 
Up and Breathe” protocol proven to improve outcomes, including one-year 
survival,28, 136 the ABC component includes standardized SATs (i.e., daily 
interruption of sedation) paired with spontaneous breathing trials (SBTs),137 
both administered only when specific safety criteria are met. Study drug that is 
held for the spontaneous awakening trial will be restarted, if needed, at the 
lowest possible infusion rate that is needed to achieve target RASS. All study 
centers use validated sedation scales to facilitate goal-directed sedation, a 
practice that will continue throughout the MENDS II study. Ventilator 
management will be standardized according to each institution’s approved 
protocols, including the use of low tidal volume ventilation for acute lung 
injury.88 
(b)  ABCDE (Delirium monitoring and management). The Delirium component 
of ABCDE will include nonpharmacologic strategies, given that the majority of 
delirium in ICUs is the hypoactive subtype.138, 139  The protocol includes 
nonpharmacologic strategies that have been shown to reduce delirium in non-


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ICU settings140-150  Study personnel will encourage members of the ICU team 
to perform the following tasks: 
• Reorient and cognitively stimulate patients by conveying the day, date, 
place, and reason for hospitalization, updating whiteboards with caregiver 
names, requesting placement of a clock and calendar in the room, and 
discussing current events.140-143, 145, 146, 148, 151-153 
• Determine need for hearing aids and/or eye glasses from the surrogate 
and request that the surrogate provide these to the patient when 
appropriate.141-143, 145, 146, 148, 151, 152 
• Monitor and manage pain level in all patients daily with the CPOT or 
other assessments, in accordance with practice guidelines and local ICU 
policies.93, 152, 154-157 
• Maintain sleep preservation using techniques including noise reduction 
strategies (e.g., minimize noise outside the room, offer white noise or 
earplugs), normalizing day-night variation in illumination, minimizing 
interruptions during normal sleeping hours via “time out” strategy, 
maintaining ventilator synchrony, and promoting comfort and relaxation 
(e.g., back care, massage, oral care, washing face/hands, and daytime 
bath).141, 143, 145, 146, 151, 158-163 
• Patients with hyperactive (agitated) delirium (i.e. RASS +1 to +4 and 
CAM-ICU positive) will be permitted either per tube or intravenously 
haloperidol  starting between 0.5-5 mg. Patients with either an allergy to 
haloperidol or in patients where the treating clinical team desires to use 
an oral atypical antipsychotic, quetiapine will be permitted as needed 
(prn) or scheduled with recommended starting doses of 25-50 mg and 
titration per primary team.  All antipsychotic medication will be tracked 
in the database until the end of the combined Treatment/Post Study Drug 
Period, hospital discharge or death (whichever is earlier). 
(c)  ABCDE (Early mobility and Exercise). The Exercise component of the 
ABCDE protocol will include strategies to promote mobility and exercise in 
the earliest phases of critical illness.  Early physical/occupational therapy 
significantly reduced delirium duration for mechanically ventilated ICU 
patients in a recent randomized controlled trial.133  Study personnel will 
encourage members of the ICU team, including the bedside nurses and  
physical/occupational therapists, to evaluate each patient’s readiness for 
mobility and exercise and coordinate the following activities: removal of 
restraints, active range of motion, sitting on the side of the bed, sitting in a 
chair, standing in place, and ambulation. 133, 141, 145, 151-153, 164, 165 
(d) Barriers and Facilitators to the ABCDE bundle.  At sites that would like to 
participate, critical care providers (i.e., nurses, respiratory therapists, 
pharmacists, physicians, occupational therapists [OT], and/or physical 
therapists [PT]) will be asked to complete a voluntary electronic survey (i.e., 
the ABCDE Bundle Provider Survey) designed to identify barriers and 
facilitators to the use of the ABCDE bundle.  In addition, managers (e.g., 
nurse manager, respiratory therapy manager, and/or PT/OT manager) will be 
asked to provide details about key organizational structures and processes that 


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may influence a provider’s ability to use the ABCDE bundle.  Lastly, units 
will be observed for accessibility of equipment useful for applying the 
ABCDE bundle and unit layout.  Both the manager evaluation and the unit 
observation will be accomplished utilizing the ABCDE Unit Observation and 
Manager Questionnaire. When barriers and facilitators are identified, this 
information will be provided to study personnel and/or managers at each site. 
 
[3] 
Sepsis and Mechanical Ventilation. Management of sepsis and MV will be 
directed by standard ICU protocols based on the surviving sepsis guidelines.15  The 
managing clinical team will dictate use of these guidelines according to patient need.  
Study personnel will track important determinants of care including: choice of 
antibiotic, vasopressor and inotrope use, and blood glucose levels.15 Patients will be 
evaluated daily by the medical team as part of standard ICU protocols for readiness 
for SATs, SBTs, and subsequently extubation.  
 
7.2.3 Monitoring.  The risks of propofol and dexmedetomidine include oversedation, 
bradycardia, hypotension, acidosis, hypertriglyceridemia, hyperglycemia, adrenal insufficiency, 
and propofol infusion syndrome. Throughout the Interventional Trial Period, study personnel 
will carefully monitor all patients daily for evidence of these potential adverse effects, 
determine study drug efficacy and safety, and monitor other factors that may influence outcome.  
Should adverse effects occur, the above section (7.2.1) describes how study drug will be 
titrated, held, or permanently discontinued.  Additionally, patients will be monitored for two full 
days following discontinuation of the study drug. This will be the Post-Study Drug Period and 
will be contained within the treatment period if study drug is discontinued prior to or on study 
day 12. For those patients that receive study drug for more than 12 days during the treatment 
period of 14 days, the Post-Study Drug Period will extend beyond the Treatment period.  
[1] 
Efficacy.  In addition to delirium, coma, and ventilator-free days, time-to-event 
outcomes including ICU length of stay and survival, will be assessed until the 
outcome in question or a censoring event occurs. Twice daily, while in ICU and once 
thereafter until end of Post-Study Drug Period, hospital discharge or death 
(whichever is first), study personnel will determine level of sedation using the 
RASS129, 130 and assess for delirium using the CAM-ICU.10, 11, 131  
[2] 
Safety.  Patients will be monitored as part of routine ICU care for adverse clinical 
outcomes including but not limited to oversedation, bradycardia, hypotension, 
acidosis, hypertriglyceridemia, hyperglycemia, adrenal insufficiency, and propofol 
infusion syndrome.  Additionally, study personnel will specifically assess patients 
for the following safety outcomes: 
(a) 
Triglycerides according to plasma level drawn on Trial Days 7 (or earlier if 
planned hospital discharge is before Day 7) and 14 (or earlier if planned 
hospital discharge is before Day 14). 
(b) 
Cortisol according to plasma level drawn on Trial Days 7(or earlier if 
planned hospital discharge is before Day 7) and 14 (or earlier if planned 
hospital discharge is before Day 14).  
(c) 
Arrhythmia and/or Heart Block according to telemetry or a12-Lead 
electrocardiogram while in the ICU until the end of the combined 
Treatment/Post-Study Drug Period.  


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(d) 
Hyperactivity or agitation according to daily RASS139 until the end of the 
combined Treatment/Post-Study Drug Period (see section 7.2.2 for rescue 
protocol). 
(e) 
Development of new cases of ARDS based on criteria described in 4.2.2 until 
the end of the combined Treatment/Post-Study Drug Period. All aspects of 
management of patient’s ARDS will be determined by the medical team, 
including if deemed necessary, stopping of the study drug. 
(f) 
Organ dysfunctions will be tracked until conclusion of the combined 
Treatment/Post-Study Drug Period using daily SOFA scores and continuous 
as well as established predefined cut offs for each organ failure: Kidney, Cr > 
2 mg/dL or urine < 400 cc/day; Lung, PaO2/FiO2 <300 or SaO2/FiO2 <315;119  
Liver, total bilirubin > 2 mg/dL; Coagulation, Platelet count < 100,000/mm3; 
and Hemodynamic, need for vasopressor,120, 121 consistent with definitions 
utilized in published studies of organ dysfunction in critically ill patients.122 
[3] 
Biological specimens.  Plasma will be obtained on approximately Trial Days 1, 3, 5, 
7 and 14.  A maximum of 30 mL of blood will be collected at each time point (150 
mL max during the study), processed, and stored at -80º C prior to being shipped to 
the Vanderbilt Coordinating Center biorepository for storage and batched analyses of 
the following: 
(a) 
Genetic predictors of delirium duration, including, but not limited to, the 
apolipoprotein E4 polymorphism.166-168 
(b) 
Inflammatory/coagulopathic biomarkers, (e.g., IL-1, IL-6, IL-10, CRP, 
sTNFR1, and HMGB1) based on their importance in sepsis and kinetic 
responses.169-171, 171, 172, 172, 173, 173, 174, 174-177  Furthermore, combination of 
pro- and anti-inflammatory cytokine markers improves the predictive quality 
of these biomarkers for mortality.178 
(c) 
Other biomarkers to be determined by ongoing and future studies. 
(d)  At select participating sites, the Cholinesterase Activity and DeliriUm during 
Critical illness Study (CADUCeuS) – a substudy within the MENDS II study 
will examine whole blood acetylcholinesterase (AChE) and 
butyrylcholinesterase (BuChE) activities as biomarkers for delirium during 
critical illness and for long-term cognitive impairment in survivors of critical 
illness. During the blood collection on study days 1, 3, 5, 7, & 14 AChE and 
BuChE activities in the collected blood will additionally be measured using 
ChE Check (LISA-CHE, Dr. F. Köhler Chemie [DFKC] Bensheim, 
Germany), a point-of-care device that reliably measures AChE and BuChE 
activities in whole blood within 4 minutes of specimen collection194,195,196. 
 
 
[4] 
Delirium Experience and Baseline Chronic Pain Evaluation. After resolution of 
delirium and prior to hospital discharge, patients will be asked to recall their memory 
and delirium experience using a modified Delirium Experience Questionnaire (DEQ) 
193. Additionally, patients will be asked about the presence of chronic pain prior to 
this hospital admission and any medications that were taken to manage that pain. 
 
[5] 
Other data.  The patient’s medical records will be used during the In-Hospital Phase   
to collect vital signs and other data reflecting current severity of illness, recent and 


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ongoing treatments (including medications and mechanical ventilator status), routine 
lab results, and complications (e.g., infections and device removals).  These data will 
be generated as part of routine care and will not require study-related tests. 
 
7.3 
Long-term Follow-up Phase.  We will evaluate long-term outcomes among survivors 
(Aim 2B), including neuropsychological function and ADL/IADLs 6 months after 
randomization.  Under the direction of the Vanderbilt Coordinating Center’s lead 
neuropsychologist, trained study personnel will assess patients using the following validated 
telephone assessments: 
[1] 
Delirium will be evaluated via the “phone” Confusion Assessment Method179 
algorithm.  Patients diagnosed with delirium will not be assessed further at that time, 
but contacted at weekly intervals and tested if/when delirium resolves. 
[2] 
A neuropsychological phone battery118 derived from standard cognitive tests and 
proven feasible and valid for phone use in a study of ICU survivors (with similar 
characteristics to those targeted for enrollment in the MENDS II study) will be used 
to assess memory, attention, reasoning, and executive functioning.  
[3] 
Activities of Daily Living (ADL)116 and Instrumental ADLs (IADLs)117 
[4] 
Quality of Life will be assessed using the EQ-5D, a short, easy to administer, well-
validated, and widely used instrument.180-182 
[5] 
Brief Pain Inventory Short Form (BPI) 183 will be used to assess patients for the 
presence of chronic pain. The BPI is one of the most widely used measurement tools 
for assessing clinical pain and consists of 9 questions, taking only a few minutes to 
complete. In addition to examining prevalence of chronic pain and chronic pain 
interference in ICU survivors, we will utilize the BPI to identify potential risk factors 
(e.g., sedative and analgesic exposure in the hospital) for chronic pain after critical 
illness. 
 
In addition to the battery described, data will be collected regarding intervening events that 
happened since hospital discharge including, but not limited to, death and re-hospitalizations. 
Vital status at 6 months after randomization and date of death (if applicable) will be determined 
via medical records or the Social Security Death Index if not already known at hospital 
discharge. 
7.3.1 Long-term Follow-Up Patient Retention Plan.  In order to maximize full 6-month 
participation of the randomized patients, the Long-Term Follow-Up Committee will rely on 
strategies refined over the past 10 years to produce a Follow-Up assessment rate of >85%. 
Study personnel will be instructed to obtain as much contact information as possible at time of 
enrollment (e.g. multiple phone numbers, mailing addresses, discharge destination, etc.). The 
Neuropsychology Coordinator will perform the following interventions to maintain >85% 
Follow-Up assessment rates: 
[1] 
Following hospital discharge a letter will be sent to patients reminding them about 
the Follow-Up Period and introducing them to the Follow-Up staff. 
[2] 
A periodic phone call, letter, postcard, or email will serve as an additional reminder 
of study participation. 


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[3] 
Weekly meetings will be conducted with study staff to evaluate the status of follow-
up evaluations, with a particular focus on devising and implementing effective 
strategies to reach patients who may be difficult to contact.  
7.4 
Data Collection/Case Report Form Details.  During all study phases, all data will be 
directly entered into electronic case report forms (eCRFs) in a secured password-protected 
database with the exception of the Pre-Hospital Function Assessment and the assessments in the 
Long-Term Follow-Up Assessment, which will be collected on paper CRFs (due to copyright 
restrictions) and later entered into the eCRFs for storage in the secured password-protected 
database.  Additionally, all signed Informed Consent Documents will be uploaded to the study 
database.  This will allow the VCC ready access to review the consent forms for appropriate 
version use and completeness.  This study will utilize Research Electronic Data Capture 
(REDCap) for data collection, transmission and storage.  REDCap is a secure, web-based 
application for building and managing online databases.  Vanderbilt University, with 
collaboration from a consortium of institutional partners, including the Vanderbilt Institute for 
Clinical and Translation Research (VICTR) Informatics Core, developed and manages a 
software toolset and workflow methodology for electronic collection and management of 
research and clinical trial data.  All study data will be entered via a password protected, study 
unique REDCap database website.  REDCap servers are housed in a local data center at 
Vanderbilt and all web-based information transmission is encrypted.  REDCap was developed 
specifically around HIPAA-Security guidelines and is recommended by both the Vanderbilt 
University Privacy Office and Institutional Review Board. REDCap has been disseminated for 
use locally at other institutions and currently supports > 140 academic/non-profit consortium 
partners and 11,000 research end-users (www.project-redcap.org). 
7.5 
Schedule of Events  
*Variable  
Enrollment 
 
Treatment Period & 
Post-Study Drug 
Period 
6 Month 
Follow-up 
12 Month 
Follow-up 
Pre-Hospital Function Assessment (ADL,116 IADL/FAQ,117 IQCODE,123, 
126-128, AUDIT) 
X 
 
 
 
Demographics, Comorbidities184,APACHE II185 
X 
 
 
 
SOFA120, 186 
X 
Daily 
 
 
Rhythm strip assessment for advanced heart block 
X 
Daily 
 
 
Pregnancy test (either urine or serum Beta hCG) 
X 
 
 
 
Blood draw: IL-1, IL-6, IL-10, CRP, sTNFR1, HMGB1 
 
Approximately 
Days 1,3,5,7,14 
 
 
Blood draw: whole blood AChE and BuChE at participating sites194,195,196 
(Blood draw above will be used when possible) 
 
Approximately 
Days 1,3,5,7,14 
 
 
Hematology/Chemistry, Neuroimaging 
X 
Daily 
 
 
Co-administered sedative/analgesic/antipsychotic medications 
 
Daily 
 
 
RASS (target/actual),129, 130 CAM-ICU10, 11 
 
1-2x daily 
 
 
Bush Francis Catatonia Rating Scale (BFCRS), and Delirium Motor 
Subtype Scale (DMSS) at participating sites   
 
1-2x daily 
 
 
Hospital-acquired infections (blood, urine, sputum) 
 
Daily 
 
 
ABCDE Protocol Compliance & Sepsis/Ventilator tracking   
 
Daily 
 
 
Safety assessments. As part of routine ICU care 
 
Daily 
 
 
Plasma triglycerides & cortisol 
 
Approximately 
Days 7,14 
 
 
SaO2/FiO2, PaO2/FiO2 ratio, Chest X-ray to evaluate ARDS 
 
Daily 
 
 
EEG via portable SedLine Sedation Monitor at participating sites   
 
Up to 7 days 
 
 


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Delirium Experience Questionnaire193 and Chronic Pain Questions 
 
X 
 
 
Long-term telephone follow-up: CAM,179 neuropsychological battery,118 
ADL,116 IADL/FAQ,117  EuroQOL quality of life (EQ-5D)180-182, BPI183 
 
 
X 
 
Catatonia Patients ONLY: At both the 6 and 12 month follow-up dates, 
patients will be assessed with the long-term telephone battery along with 
the BDI-II and PCL-5. 
 
 
X 
X 
*Abbreviations (alphabetical):  AChE- acetylcholinesterase ADL- activities of daily living, APACHE II- Acute Physiologic 
Chronic Health Evaluation II, AUDIT- Alcohol Use Disorders Identification Test, BDI-II – Beck Depression Inventory II, 
BPI- Brief Pain Inventory, BuChE- butyrylcholinesterase, CAM- Confusion Assessment Method, CAM-ICU- Confusion 
Assessment Method for ICU, CRP- C-reactive protein, EEG- Electroencephalograph, FAQ- Functional Activities 
Questionnaire for IADLs, HMGB1- High-mobility group protein 1, IADL- instrumental activities of daily living, IL- 
interleukin, IQCODE- Informant Questionnaire of Cognitive Decline in Elderly, MV-mechanical ventilation, PCL-5 - PTSD 
Checklist, RASS- Richmond Agitation Sedation Scale, SOFA- Sequential Organ Failure Assessment, sTNFr1- soluble TNF 
receptor 1  
 
7.6 
The Vanderbilt Coordinating Center (VCC).  The VCC has extensive experience in 
the conduct of large, phase III clinical trials over the past decade.  The VCC will perform 
(among other functions) the following: communicate with the FDA using a schedule of 
reporting in accordance with IND policies, design the database and data collection tool, conduct 
startup meetings and site-training regarding protocol implementation and delirium monitoring to 
standardize all research activities during the trial, monitor enrollment pace and quality to ensure 
patients meet the inclusion/exclusion criteria, maintain blinding, track adverse events and 
ensure safety reporting, ensure protocol compliance, store plasma, serum, and genetic samples 
for planned and future analyses, conduct follow-up phone testing of neuropsychological 
function and quality of life via neuropsychology technicians, and work with the study centers 
and local study personnel using multiple proven patient retention techniques that have 
consistently achieved over 80% follow-up during previous studies. 
 
 
8.0 
 Risks of Investigational Agents/Devices (side effects) 
 
8.1 
Side Effects of Study Drug (Propofol and Dexmedetomidine). The risks of the 
sedative medications include oversedation, hypotension, bradycardia, acidosis, triglyceridemia, 
propofol infusion syndrome, and adrenal insufficiency. Study personnel will carefully monitor 
all patients for evidence of potential adverse effects from the study drugs until conclusion of the 
combined Treatment/Post-Study Drug Period. These assessments are described in section 7.2.3. 
Should any of these occur, adverse events will be reported to the coordinating center, with 
Adverse Events reported within 24 hours (see section 9.0). From an immediate clinical 
management perspective, section 7.2.2 describes how study drug will be titrated, held, or 
permanently discontinued, depending on the adverse effect.  
 
8.2 
Risks from Blood Draws. All patients will have blood drawn for research purposes. 
The risks of drawing blood are uncommon and may include bleeding and bruising. Commonly, 
having blood drawn is painful and rarely can lead to infection at the site of the blood draw. For 
this reason, it will be our standard approach whenever possible to obtain the majority of blood 
for research purposes through existing intravenous peripheral, central or arterial catheters since 
these patients routinely have such catheters while in the ICU. Rarely the AChE and BuChe 
testing194,195,196 will require a finger stick to be performed. The amount of blood drawn for 


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biological specimens is minimal, represents a small percentage of the amount of blood taken 
during the course of a standard ICU stay, and will not represent a significant risk to the patient.  
 
8.3 
Risks from ECG and SedLine Sedation Monitoring. As mentioned above an ECG 
may be done to evaluate heart rhythms and heart block.  The ECG electrode pads may cause 
skin irritation.  While it is rare, there may also be local allergic reactions and/or skin tears from 
the SedLine Sedation Monitor sensors. This study staff will monitor the skin condition daily 
when using the sensors.  
 
8.4 
Steps Taken to Reduce Risks and Increase Impact of Study. The following are a 
highlighted “top ten” list of actions we have explicitly taken to minimize risk for the study 
population and to maximize the ultimate impact of this investigation on the field of medicine.187  
[1] 
Interventions included in the MENDS II study are supported by a well-grounded and 
clearly described rationale suggesting potential, though unproven, benefit for eligible 
patients. 
[2] 
All interventions are common and with established equipoise within the context of 
usual care and considered good or competent care in light of an absence of clear 
proof in favor of one over the other. 
[3] 
Experts in the fields of critical care, neuropsychology, nursing, pharmacology, and 
clinical trial design have developed the interventions being studied. 
[4] 
The management of patients in both treatment groups will be guided by explicit 
MENDS II protocols so that the results of the trial can be clearly interpreted and 
imitated, where appropriate, in clinical practice. This will also allow for the use of 
the “superior group” as a control in future trials. 
[5] 
The MENDS II protocol will adjust study drug dose to meet individual patient needs 
in the attempt to deliver safe and effective care to critically ill old and younger 
patients. This protocol is explicitly designed and drafted from landmark trials to 
meet patients’ needs over time and provide individualized care. 
[6] 
The titration protocol for study drug and the management components for pain, 
rescue sedation, and hyperactive delirium are designed to minimize risks in 
comparison to anticipated benefits. 
[7] 
Because most previous comparator trials of either dexmedetomidine or propofol 
versus benzodiazepines have shown superior outcomes with dexmedetomidine and 
propofol, no benzodiazepine control arm was included, to safeguard patients from 
receiving sedative agents whose use is on the decline.  
[8] 
An independent and qualified Data Safety Monitoring Board (DSMB) will be 
established (see section 9.5.1, 9.5.2 and 9.5.3.) to review the research protocol prior 
to the start of the study and conduct interim analyses for safety and review data on 
serious adverse events as close to real-time as possible.  
[9] 
We will work very closely with the regulatory authorities including our IRB and the 
FDA to make certain that this proposal is safe and that they agree with our planned 
oversight and approach to due diligence in monitoring and reviewing all adverse 
events during the conduct of the trial. The FDA-IND for this study is #68658. 
[10] 
Rigorous monitoring and reporting of prospectively defined Adverse Events (AEs)  
including Suspected Unexpected Serious Adverse Reactions (SUSARs) and 
unexpected problems (UPs) will be conducted as outlined in section 9.2 and 9.3, to 
comprehensively monitor safety during the trial.  


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9.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
A system has been established to report and track clinical outcomes, (AEs) including SUSARs 
and UPs that increased risk.  Study personnel will monitor the safety of subjects and follow 
them until the event resolves or is explained. 
 
9.1 
Clinical Outcomes (not considered Adverse Events).  In this study of critically ill 
patients who are at high risk for death or other adverse outcomes due to their underlying critical 
illness, clinical outcomes including death and organ dysfunction, will be systematically tracked 
(collected in the CRF) and will be included as part of the safety and efficacy analyses for this 
study. For the purposes of reporting, death and organ dysfunction will not be recorded as 
adverse events unless the investigator believes the event may have been caused by study drug 
and is more severe or prolonged than expected given the underlying critical illness 
(investigator’s discretion). This approach (considering death and organ dysfunction as outcomes 
rather than adverse events) is common in ICU trials because these outcomes occur commonly in 
the ICU and because it mandates that data regarding death, organ dysfunction, and expected 
safety outcomes be tracked systematically for all patients and analyzed appropriately. All 
clinical outcomes (with the exception of death and duration of MV- see 9.1.1 and 9.1.2 below) will 
be systemically tracked until conclusion of the combined Treatment/Post-Study Drug Period, i.e., 
they will be tracked from randomization until Study Day 16 at a maximum, hospital discharge, or 
death, whichever comes earlier. Listed below are events that will be tracked as clinical outcomes 
and will not therefore be required to be reported as adverse events during this study (unless believed 
to be study-drug related and more severe or prolonged than expected given the underlying critical 
illness):  
[1] 
Death. All deaths occurring within the Interventional Trial will be reported on the 
CRF in the death summary section. For deaths thought to be caused by study drug, 
an AE/SUSAR will be reported along with the death summary 
[2] 
Respiratory failure, including need for MV (invasive or noninvasive) or episodes of 
hypoxemia. Duration of MV will be tracked for up to 28 days to evaluate VFDs 
[3] 
Circulatory failure, including shock (whether requiring vasopressors or not) and 
cardiac arrhythmias, and hypo/hypertension 
[4] 
Hepatic failure or injury leading to increased bilirubin, AST, or ALT 
[5] 
Renal failure or injury leading to an increased creatinine or acute hemodialysis 
[6] 
Coagulation derangements (e.g., thrombocytopenia) 
[7] 
Neuropsychological dysfunction that is believed to be newly acquired 
[8] 
Alterations in vital signs (e.g., temperature, heart rate, blood pressure, oxygen 
saturation) 
[9] 
ICU readmissions 
[10] 
Infections 
[11] 
Alterations in routine safety labs (e.g.,  liver function tests, creatine kinase, 
creatinine, cortisol, triglyceride, and lactate).  
[12]  
The following known adverse reactions to propofol and/or dexmedetomidine: 
 
(a) bradycardia 
 
(b) tachycardia 
 
(c) hypotension 


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(d) hypertension 
 
(e) triglyceridemia 
 
(f) sedation 
 
(g) respiratory depression 
 
(h) lactic acidosis 
 
(i) cardiac rhythm disturbances 
 
(j) propofol infusion syndrome 
 
9.2 
Adverse Events (AEs), Suspected Unexpected Serious Adverse Reactions 
(SUSARs), and Unanticipated Problems (UPs)  
[1] 
Adverse Event (AE) is defined as any untoward medical occurrence for a patient 
enrolled in the trial that is not tracked as a clinical outcome (see section 9.1), 
regardless of whether the event is considered study drug-related or not. If a subject 
experiences an AE after informed consent is signed but before receiving study drug, 
the event will be reported as an “AE not study drug related.” Prior to enrollment, 
study site personnel will note the occurrence and nature of each subject’s medical 
condition(s). During the study, site personnel will note changes in these condition(s) 
and/or the occurrence and nature of any AEs. All AEs occurring after consent and 
until the end of combined Treatment/Post-Study Drug Period, hospital discharge, or 
death (whichever comes first) will be recorded in the database. This period is the 
window of time during which study drug-related adverse reactions are expected 
based on the duration of the Treatment Period and the Post-Study Drug Period.  An 
AE that later meets criteria for an UP or SUSAR between the start of study drug and 
hospital discharge will be reported as an UP or SUSAR. If study drug is 
discontinued as a result of an AE, study personnel will document the circumstances 
leading to discontinuation of study drug. In cases where the investigator notes an 
unanticipated benefit to the subject, study site personnel will enter “unanticipated 
benefit” with the actual event description (e.g., “unanticipated benefit - sleeping 
longer”).  
 
 
All AEs will be evaluated for the following three criteria: relatedness to study 
drug, expectedness, and seriousness.  An AE will be considered serious if it results 
in any of the criteria below (regardless of whether it is deemed study drug related): 
(a) 
Life-threatening condition with immediate risk of death within the context of 
a patient’s event (i.e., a well-tolerated bradyarrhythmia is not an SAE, 
whereas the same rhythm resulting in cardiac arrest and CPR is an SAE) 
(b) 
Inpatient hospitalization or prolongation of existing hospitalization 
(c) 
Persistent or significant incapacitation or substantial disruption of the ability 
to conduct normal life functions 
(d) 
Significant hazard, contraindication, or side effect according to the PI 
(e) 
Any breech in the confidentiality of patient’s data 
(f) 
Investigators will determine whether an AE is related to study drug based on 
a temporal relationship to administration, as well as whether the event is 
unanticipated and unexplained given clinical course, previous conditions, and 
concomitant medications. 
[2] 
All AEs that are (1) suspected to be study drug related, (2) unexpected, and (3) meet 
any of the following seriousness criteria must be reported as Suspected Unexpected 
Serious Adverse Reactions (SUSAR): 


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(a) 
Death 
(b) 
A life-threatening episode requiring immediate intervention 
(c) 
An event resulting in hospitalization or that prolongs existing hospitalization 
(d) 
Events resulting in persistent or significant incapacitation or disability 
(e) 
An episode that requires intervention to prevent the above and/or permanent 
impairment or damage 
[3] 
Unanticipated problems (UPs) are defined as any incident, experience, or outcome 
that meets all of the following criteria:  unexpected, related or possibly related to 
participation in the research; and suggest that the research places subjects or others 
at a greater risk of harm than was previously known or recognized. UPs may result 
in adverse events and they may not. Protocol noncompliance that results in harm to a 
patient would be both a UP and AE whereas protocol noncompliance that increased 
risk to a patient but did not result in harm would only be classified as a UP that 
increased risk.   
 
9.3 
Communication and Reporting of Adverse Events and Unexpected Problems with 
Coordinating Center and Regulatory Bodies. In order to ensure proper and timely reporting 
of all AEs and UPs, there will be a clear communication plan for all sites to follow. Sites will be 
responsible for reporting all AEs and UPs that increased risk to patients to the VCC; they will 
also follow their local IRB policies to determine when AEs and UPs should be reported to the 
local IRB. The VCC will be responsible for reporting the events to the proper regulatory bodies 
(i.e., FDA, NIH, DSMB, and Coordinating Center IRB) in a timely manner and in 
communicating any responses from those bodies back to the sites. The procedures for reporting 
the various events will be as follows: 
[1] 
SUSARs. In the event that a SUSAR occurs the study drug should be permanently 
discontinued immediately.  The event will be recorded in the patient’s study chart in 
the electronic database. All SUSARs will be reported to the VCC within 24 hours of 
occurrence by telephone call. As required, VCC will report the event within 48 hours 
to the DSMB Chair. The DSMB report will be due and sent to the Vanderbilt IRB 
and NIH within 7 days. When the DSMB Chair/DSMB suspects an event is study-
drug related, they will have the opportunity to access unblinded data in order to 
conduct appropriate safety monitoring. There should be no need for the site 
investigators to be unblinded since the study drug should have been stopped at the 
time of event occurrence per titrating rules of the study protocol. The DSMB Chair 
will work in concert with the rest of the DSMB to determine if any necessary actions 
need to occur as result of the event in order to increase the safety of the protocol. If 
the Data Safety Monitor or the DSMB suspect an imbalance between the SUSARs in 
the study groups, they will have the right to convene a full DSMB meeting and have 
access to other supporting data to determine safety and ongoing conduct of the study, 
without having to wait for the set meetings annually and N=236 as discussed in 
9.5.3. 
[2] 
UPs. All suspected UPs that possibly increase the risk to patients will be recorded in 
the patient’s study chart in the electronic database, reported to the site IRB within 5 
days of occurrence, and reported to the VCC within 5 days of occurrence.  Any of 
these reports that the site IRB determines to meet the OHRP definition of UP and 
thus the requirement for reporting to the OHRP, will subsequently be reported by  


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the VCC to the DSMB within 15 days of receipt of the site IRB notification and to 
the NIH within 30 days of receipt of the site IRB notification.  
[3] 
All remaining AEs (i.e., AEs that are not SUSARS or UPs) will be recorded in the 
patient’s study chart in the electronic database and reported to the VCC within 5 
days of occurrence. As required, the VCC will provide a batched report of all study 
wide AEs annually to each regulatory body as part of the annual review process. 
9.4 
Data Monitoring Plan. To ensure data is accurately and completely collected during 
the MENDS II study, the VCC will follow a specific Data Monitoring Plan modeled after the 
FDA’s guidelines for the monitoring of clinical investigations. Once each year, a VCC member 
will visit each study site to assure that the facilities continue to be acceptable for the purpose of 
the study, the study protocol is being followed, changes to the protocol have been approved by 
the local IRB, and the site investigator is carrying out the agreed-upon activities and has not 
delegated them to other unspecified staff. Also, the monitor will review subject records to 
determine whether data collected is accurate, complete, and current. Per the FDA guidelines, the 
monitor will compare a representative number of subject records and other supporting 
documents with the investigator’s reports. Specifically, site visits will include the following: 
[1] 
A Technical Review will occur annually and will consist of a VCC research nurse 
examining the quality and accuracy of data, regulatory documents and drug 
accountability. Data quality and accuracy will be reviewed through a CRF data and 
source document review. The monitor will randomly select three subjects (or 10% of 
the subjects enrolled since the last site visit, if more than 30 were enrolled in that 
time) to serve as a representative sample. Regulatory Document Review will consist 
of a review of IRB approvals, informed consents, critical documents, and 
protocols/amendments.  
[2] 
A Scientific Review will occur at the discretion of the VCC as needed and could 
consist of presentations by the site staff on their organizational structure, patient 
recruitment, and staff training, and quality control procedures. The site monitoring 
team will include a VCC research nurse as well as the MENDS II Principal or Co-
Investigator (alternating).  
The site monitoring reports from these reviews will be submitted to the DSMB and other 
regulatory bodies (IRB, FDA and NIH) as requested and/or required. Data accuracy reports 
(including site comparisons) as well as site monitoring updates will be presented to the VCC. 
This Monitoring Plan will serve as a method for identifying systematic problems and provide a 
means in which to institute resolution and follow-up and therefore increase data quality. 
 
9.5 
Data Safety Monitoring Board (DSMB) 
 
9.5.1 Membership. The DSMB will include 5 independent members (3 members will 
constitute a quorum) who are not study investigators and have no financial, scientific, or other 
conflict of interest with the trial; written documentation attesting to absence of conflict of 
interest will be required. Potential members will be chosen by the MENDS II steering 
committee and study PI in discussion with the NHLBI Program Official. The PI will 
recommend experts/representatives from the following fields as potential members of the 
DSMB: critical care medicine, ethics, clinical trial methodology, and biostatistics. A 
chairperson will be selected and will be responsible for overseeing meetings, developing 
agendas in consultation with the PI, and being the contact person for the DSMB. 
 


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9.5.2 Initial Meeting. Prior to the initiation of the trial, the DSMB will meet and review the 
entire IRB-approved study protocol with regard to subject safety, recruitment, randomization, 
intervention, data management, quality control and analysis. If the protocol is deemed 
satisfactory by the DSMB, they will recommend to the VCC that subject recruitment begin. If, 
alternatively, modifications to the protocol or other study documents are needed, the DSMB 
will recommend such modifications and postpone its recommendation to begin recruitment. 
This initial meeting may occur via conference call or in person and will begin with an 
introduction by the PI and VCC Co-Investigator, then continue as a closed session, including 
only DSMB members and (if available) NHLBI program staff. 
 
9.5.3 Additional Meetings. The DSMB is responsible for identifying problems related to 
safety (including all AEs/SUSARs), requesting additional data relevant to safety (including all 
AEs/SUSARs), proposing analyses of safety endpoints as needed, and considering the rationale 
for continuation of the study in light of safety data, progress of randomization, retention, 
protocol adherence, and data management. After the initial meeting, the DSMB will meet at the 
end of each calendar year for annual safety reviews and also at the specified interim analyses (at 
N=236, see section 11.4, for detailed description). Reports of AEs and SUSARs for the interim 
look at the data will initially be provided to the DSMB in a blinded fashion (i.e., treatment 
group assignment will not be revealed), but the DSMB will retain the right to request an 
unblinded report. Only DSMB members will have access to unblinded data in order to preserve 
the integrity of data and minimize potential for bias while maintaining appropriate safety 
monitoring. After each DSMB meeting, the chairperson will provide a written report to the 
VCC and the NHLBI program official. In addition, the VCC, in turn, will provide the reports to 
the Vanderbilt University IRB and to all sites for submission to their local IRBs. 
 
10.0 
Study Withdrawal / Discontinuation.  Subjects may be withdrawn from study 
participation at the discretion of the investigator or if the patient/family or attending physician 
requests that the subject be withdrawn.  The reason and date of every withdrawal will be 
recorded.  The Informed Consent Document will notify participants that their participation is 
voluntary, and they can tell the study staff at any time if they decide to stop participating. In 
addition, if they choose to withdraw their authorization for study staff to access protected health 
information (PHI) in the medical record, they may do so by notifying study staff in writing (the 
address is provided). If a participant chooses to no longer participate but does not notify study staff 
that they withdraw authorization for access to PHI, their medical record may be accessed to obtain 
outcomes and safety data. Follow-up will be performed for all discontinuations due to an SAE or 
other safety concern until resolution, until deemed chronic and stable, or as long as clinically 
appropriate. Data and specimen destruction will be over seen by the Vanderbilt Coordinating 
Center for patients that withdraw from the study and want to have their data and specimens 
destroyed.   
 
11.0 
Statistical Considerations  
 
11.1 
Power analyses and sample size calculations for Aim 1A (DCFDs). Based on the 
demographic data from our NIH-sponsored BRAIN-ICU cohort, we anticipate patients in the 
MENDS II control group will have a mean±SD of 6.8±5.2 DCFDs during the 14-day study 
period. The study has been repowered/resized due to concerns about the feasibility of 
completing study enrollment. With approval from the DSMB, we will randomize at least 210 


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patients in each group to receive study drug, and with a 2-sided alpha of 0.05, we will have 85% 
power to demonstrate a difference of 1.5 DCFDs between dexmedetomidine and propofol 
(primary outcome), which we believe has face validity as a clinically meaningful difference in 
the duration of acute brain injury. Importantly, this sample size will also provide 80% power 
to detect a 12% absolute improvement in 90-day survival with dexmedetomidine, assuming 
the 90-day mortality in patients receiving propofol to be 30% (which is conservative given the 
25% mortality at 28 days in the both the recent PROWESS-Shock control group and MENDS 
lorazepam group). The ability to detect a 12% improvement in 90-days mortality is also realistic 
given the 25% absolute reduction in mortality at 28 days in the MENDS septic subgroup with 
dexmedetomidine. In order to achieve this sample size of at least 420 patients enrolled, 
randomized and receiving study drug, we will randomize approximately 440 in order to account 
for disqualifications post randomization. 
 
 
11.2 
Power Analyses for Long-Term Cognitive Impairment (Aim 2B). We expect to 
follow >80% of survivors for evaluation of LTCI. Based on the expected mortality rates (see 
above), we expect an overall 25% mortality across the two groups and plan to test 252 
(=420x0.75x0.80) patients for LTCI at 6 months. With 252 patients, we will have up to 17 
degrees of freedom in our multivariable linear regression to account for potential confounders. 
The proposed study will have adequate—indeed abundant—ability to assess the independent 
effect of the intervention on cognitive impairment while controlling for confounders. 
 
11.3 
Data Analysis Plan. To determine the effect of the two sedative regimens on DCFDs 
and other continuous outcomes, we will use the Mann-Whitney test (Wilcoxon rank-sum tests). 
For ICU LOS, and 90-day mortality, Kaplan-Meier curves and log-rank test will be used, while 
censoring patients at time of death. We will perform sensitivity analyses using multivariable 
regression to adjust for imbalances in baseline factors; linear regression will be used for DCFDs 
and Cox regression for time-to-event outcomes (ICU LOS, mortality). Proportionality 
assumptions for Cox regression will be assessed using partial residual plots. No adjustments 
will be made for multiple comparisons when examining secondary outcomes in keeping with 
authoritative recommendations188-190 and standard practice in analyzing multiple, prospectively 
defined outcomes in a trial. 
 
11.4 
Interim Examination of Results by DSMB. In addition to the final analysis of 420 
randomized patients who received study drug, we plan yearly safety reviews and then one 
interim analysis at 300 patients by the DSMB. The yearly safety reviews will only review 
protocol compliance, collated adverse event reporting, selected outcomes (excluding the 
primary outcome) and quality control. At N=236 patients (~118 patients per group), we will 
conduct data analysis for early stopping due to safety and efficacy based on DCFDs and 
mortality outcomes. Using the O’Brien-Fleming method191, 192 (adjusting for two planned 
analyses at N=236 and 420) with a 2-sided significance level at 5 %, the study will be stopped 
early if test statistics reach a critical value (standardized Z score) of ± 2.76 (corresponding to p-
value of 0.006) at the interim analysis of 236 patients. Statistical significance at the final 
analysis will be referred by a critical level of 1.976 or 2-sided significance level of 0.044. 
 
11.5 
Intention-to-Treat (ITT) Principle and Missing Data. For all primary analyses, we 
will employ intention-to-treat (ITT) (see section 4.2.1).  When data cannot be collected, we will 


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impute missing variables via multiple imputation methods. For Aim 2B, missing data are 
common due to deaths and loss to follow-up.  While our team has a proven track record of 
achieving high follow-up we will carefully analyze whether particular baseline demographics 
are associated with missing evaluations of long-term testing among ICU survivors.  Loss due to 
deaths is not random and may be associated with more severe cognitive or functional deficits 
among those not tested, which will likely bias towards the null. 
 
11.6 
Statistical Meetings.  The VCC will work regularly with our statisticians at the ongoing 
weekly biostatistics meetings. Final analyses will occur during the last 6 months of the study 
period, when monitoring, quality checks, data lock, archiving and manuscript preparation will 
take place. 
 
12.0 
Privacy/Confidentiality Issues 
 
 
At no time will we reveal subject identities in any manner, whether in presentation, 
description or publication of the research for scientific purposes.  All data obtained with subject 
or provider identifiers will be kept in locked file cabinets to ensure confidentiality, and all paper 
file contents will be shredded before disposal.  All subjects will be assigned a unique study 
number for use in the computer database, and all electronic data will be kept in password-
protected computer files to ensure confidentiality.  All biological specimens (serum, plasma, 
and DNA samples), maintain for batched assay after trial completion, will be stored in a locked 
–80 °C freezer and labeled with date and study ID# only, without any patient identifiers.  These 
samples will be accessible only to designated co-investigators.  Results of the specified 
laboratory tests will be maintained in a password-protected database to be accessed only by 
designated co-investigators. 
 
Most data will be collected from medical records or direct assessments and entered 
directly into the study database via electronic case report forms (eCRFs). Paper CRFs will be 
used for baseline dementia, quality of life, and follow-up neuropsychological battery (some 
require copyrighted forms). Once collected on paper, data will be directly entered into the 
database. The study will utilize a centralized database located on Vanderbilt’s secure REDCap 
database system. 
 
Access to the database will be secured by two layers of passwords: First the staff must 
access the trial based website and only then will they be able to access the link to the database 
via another password. Each study site will only have access to their local study patients’ data. 
Only the Coordinating Center will have access to all the patient data.   
 
13.0 
Follow-up and Record Retention 
 
13.1 
Duration of Record Retention.  Information stored in the database will be stored for an 
indefinite period of time for future reference, including for use in subsequent data analyses.  
Throughout the study, all collected data will be entered directly in to the secure password-
protected web-based database. 
 
13.2 
Method for Indefinite Archival of Information.  Biological specimens will be stored 
for an indefinite period of time for use in future studies (as described in the informed consent 
document).  Because genetic markers of risk for delirium and other study outcomes are not 
currently known, storage of specimens for later research use is required to advance this 


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knowledge of ICU delirium.  It is our hope that polymorphisms will eventually be identified that 
will help us better understand the pathogenesis of delirium and patients’ response (or lack 
thereof) to therapy.  When such information is available, it would be invaluable to have a bank 
of genetic samples available for testing that can be coupled with a comprehensive set of clinical 
data such as the database being collected in this investigation. 
 
13.3     Timeline and Duration of Study. As shown in Figure 7, the study is planned to last 7 
years and recruit and randomize approximately 440 patients into the Interventional Trial (i.e., 
clinical trial). We will begin with a 6-month start-up, during which the VCC will continue to 
work diligently with each site through weekly calls, start-up meetings, and the ongoing 
processes with regulatory authorities (e.g., NIH, FDA, DSMB, and IRBs) to solidify 
infrastructure and begin enrollment. Recruitment will be completed over 60-66 months with an 
additional 6 months of follow-up; each site is expected to consent and randomize approximately 
25 patients per year.  During recruitment and testing, VCC will diligently monitor data 
collection (see section 9.4), conduct data cleaning, conference calls, in-person meetings with 
study personnel at all sites to ensure compliance, and overall efficiency of study 
implementation. We will also work regularly with our statisticians to execute the planned analyses. 
The final analyses will occur during the last 6 months of the study period, when monitoring, quality 
checks, archiving and manuscript preparation will take place.  
 


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Anesthesiology 2009 September 25. 
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