This document summarizes the background, objectives, and methods of the MENDS2 trial, a triple-blind randomized controlled trial comparing dexmedetomidine to propofol for sedation in mechanically ventilated adults with sepsis. The trial aims to test if dexmedetomidine results in better short-term outcomes like fewer days of delirium or coma and longer-term outcomes like mortality at 90 days compared to propofol. Over 400 patients will be randomly assigned to receive either dexmedetomidine or propofol infusion titrated to light sedation levels. The primary outcome is the number of days alive without delirium or coma during the 14-day intervention period. Secondary outcomes include ventil

1. Anna Sandler, PharmD Candidate ‘2023
8/12/2022
BACKGROUND
Title Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with
Sepsis
The MENDS2 trial
Background  More than 750,000 cases of sepsis occur each year in the US, and over 20% of
sepsis patients receive mechanical ventilation.1
 Sedatives are typically administered to patients receiving mechanical ventilation
to promote comfort and maintain ethical care.
 Deep sedation can lead to delirium, an acute state of confusion that can lead to
short-term memory loss, sleep disturbances and delusions, ultimately
complicating the intensive care unit (ICU) stay.2,3
 Delirium has been linked to more anxiety and depressive episodes, higher
mortality rates, and longer time on mechanical ventilation .4,5
 The Society of Critical Care Medicine (SCCM) 2018 guidelines6
recommend
targeting light sedation, or a Richmond-Agitation-Sedation (RASS) score of -1 to
0 in patients receiving mechanical ventilation.
 Dexmedetomidine and propofol are equally preferred as first-line sedatives over
benzodiazepines for continuous sedation due to improved length of stay,
decreased delirium, and less adverse effects7,8 (conditional recommendation,
low quality of evidence).
 Recommended sedatives in patients receiving mechanical ventilation:
 Dexmedetomidine (PrecedexTM
)9
 Mechanism of action (MOA): Selective alpha2 adrenergic receptor
agonist; works on the receptors in the brainstem to inhibit
norepinephrine release and induce sedation.
 Pharmacokinetics (PK): IV load seldom used,10
continuous infusion peak
effect: 60 minutes; duration post continuous infusion: 60-240 minutes;
adult distribution: ~118 L, rapid, 94% protein bound; metabolism: N-
glucuronidation, N-methylation, CYP2A6, adult terminal half-life
(t1/2): up to 3 hours; IV excretion: urine (95%), feces (4%).
 Dosing for sedation: Continuous infusion: 0.2-1.5 mcg/kg/hour, titrated
by 0.2 mcg/kg/hour every 30 minutes.
Dose adjustments: Consider reducing doses in hepatic impairment but no
specific guidance by manufacturer for IV formulation.
Adverse effects (AEs): Bradycardia, hypotension, constipation, nausea,
drowsiness.
Potential benefits: Immunomodulatory effects, including when tested in
septic rats.11–13
 Propofol (Diprivan®)14
 MOA: GABAA receptor agonist and NMDA receptor blocker, producing
global CNS depression.
PK: Duration: 3-10 minutes following a bolus; Distribution:2-10 L/kg in
adults after 10-day infusion, highly lipophilic, 97-99% protein bound;
metabolism: hepatic sulfation and glucuronidation; terminal t1/2: 4-7
hours after 10-day infusion but may be up to 1-3 days; excretion: mainly
urine feces <2%.
Dosing in mechanical ventilation: Initial 5 mcg/kg/min, increased by 5-10
mcg/kg/minute every 5-10 minutes, maintenance dose: 5-50

2. 2
mcg/kg/minute.
Dose adjustments: Consider decreased doses in older adults due to higher
peak plasma concentrations10, no adjustments needed in kidney or hepatic
impairment.
AEs: Respiratory depression, propofol-related infusion syndrome
(PRIS):bradycardia or tachycardia, hypotension, metabolic acidosis
and/or rhabdomyolysis.
Previous trials 2007: Effect of Sedation With Dexmedetomidine versus (vs.) Lorazepam on Acute
Brain Dysfunction in Mechanically Ventilated Patients (The MENDS trial)8
 Lower risk of developing and more days alive without delirium or coma with
dexmedetomidine compared to lorazepam.
2010: Effect of dexmedetomidine versus lorazepam on outcome in patients with
sepsis: an a priori-designed analysis of the MENDS randomized controlled trial15
 Subgroup analysis revealed septic patients receiving dexmedetomidine had
more delirium/coma-free days and ventilator-free days on average compared
with septic patients receiving lorazepam.
 Limitations: Subgroup analysis and risk of type I error, potential small
clinical effect sizes.
2012: Dexmedetomidine vs. Midazolam or Propofol for Sedation During Prolonged
Mechanical Ventilation. Two Randomized Controlled Trials (The MIDEX and
PRODEX trials)16
 Two phase 3 multicenter randomized double-blind trials (RCTs)
comparing midazolam with dexmedetomidine and propofol with
dexmedetomidine with respect to time at target sedation levels and duration
of mechanical ventilation.
 Estimated ratio of dexmedetomidine vs. propofol time at target sedation was
1.00 (95% confidence interval (CI), 0.92-1.08; P= 0.97), and median
duration of mechanical ventilation for dexmedetomidine was 97 hours
compared with 118 hours for propofol (P= .24). Dexmedetomidine-
treated patients were more interactive than with propofol (P < 0.001).
 Limitations: Lack of delirium and mortality assessment, outcomes not
studied solely in sepsis patients.
2017: Early Sedation with Dexmedetomidine in Critically Ill Patients (The SPICE
III trial)17
 Open-label RCT comparing rate of death from any cause at 90 days in
ventilated ICU patients receiving dexmedetomidine or usual care (mainly
propofol).
 No differences between dexmedetomidine and usual-care group with respect
to death from any cause at 90 days (dexmedetomidine-29.1%, usual care-
29.1%; adjusted risk difference, 0.0; 95% CI, -2.9-2.8; P=0.98).
 Limitations: Permission of rescue dexmedetomidine in comparator groups
and use of non-trial sedatives to achieve target sedation levels,
dexmedetomidine group required supplemental propofol to achieve sedation
levels, 40-45% of participants had RASS scores of -5 to -3, not studied
solely in sepsis patients
2020: The effect of dexmedetomidine on vasopressor requirements in patients with
septic shock: a subgroup analysis of the SPICE III Trial18
 Post-hoc subgroup analysis that evaluated early vasopressor requirements in
the septic shock cohort.
 No differences in median norepinephrine (NEq) dose between
dexmedetomidine and usual-care group (p=0.17), lower NEq/mean arterial
pressure (MAP) in dexmedetomidine group (p=0.04).
 Limitations: Post-hoc analysis and risk of type I error.

3. Anna Sandler, PharmD Candidate ‘2023
8/12/2022
Why this study? Whether dexmedetomidine leads to better outcomes in mechanically ventilated
patients with sepsis when compared with propofol is yet to be elucidated.
GENERAL STUDY OVERVIEW
Objectives Test whether dexmedetomidine results in better short-term and long-term outcomes
than propofol in mechanically ventilated adults with sepsis.
Trial design Triple-blind RCT (Participant, Investigator, and Outcomes Assessor all blinded)
Null Hypothesis Dexmedetomidine does not lead to better outcomes than propofol in mechanically
ventilated adults with sepsis.
Funding Source National Institutes of Health
METHODS
Inclusion criteria  ≥18 years old
 Admitted to the medical or surgical ICU
 Suspected or known infection being treated with antibiotics
 Treated with continuous sedation for invasive mechanical ventilation
Exclusion criteria  Baseline severe cognitive impairment (e.g., dementia or neurodegenerative
disease)
 Pregnant or breast-feeding patients
 Second-degree or third-degree heart block or persistent bradycardia
requiring intervention
 Indication for benzodiazepines
 Immediate discontinuation of mechanical ventilation expected
 Expected neuromuscular blockade for > 48 hours
 > 96 hours receipt of mechanical ventilation before
Interventions + Control  Screening/enrollment: May 2013-December 2018
 Patients randomized to dexmedetomidine or propofol in a 1:1 ratio with
stratification by enrollment site and age (< 65 years vs. ≥65)
 Medication titration every 10 minutes by bedside nurses to light sedation
(RASS -2 to 0)
 Dexmedetomidine: 0.15-1.5 mcg/kg actual body weight (TBW)/hour
 Propofol: 5-50 mcg/kg TBW/minute
 Holding guidelines in the event of hypotension, bradycardia or deeper
sedation levels; persistent symptomatic bradycardia, new onset heart block,
or PRIS warranted permanent discontinuation
 Duration: 14-day intervention period, extubation, or ICU discharge,
whichever came first
 Other therapies: opioid boluses or fentanyl infusions for pain, fluids,
vasopressors and antibiotics based on international guideline
recommendations
 Practice sites to adhere to the ABCDE bundle*
 Rescue protocol: 1) Treat with bolus opioids, and if needed continuous
fentanyl, 2) rescue sedation with intermittent midazolam after maxing-
out opioids
 Trial drugs reduced to lowest infusion rates if procedural sedation
(propofol or midazolam) or deep sedation (midazolam) for paralysis
was required
 Delirium treated with haloperidol (2-5 mg IV) or quetiapine (25-50 mg PO
or per tube)
 Care assessments: ABCDE bundle adherence recordings, RASS scores,
Confusion Assessment Method for the ICU (CAM-ICU) for delirium, and

4. 4
Critical Care Pain Observation Tool (COPT) for pain
 Frequency assessments: twice daily in the ICU, once daily after transfer from
ICU
Primary + Secondary Endpoints Primary Endpoint: Number of days alive without delirium or coma during
intervention period
Statistical Test:  Proportional-odds logistic regression (Odds ratios,
OR), adjusted analyses as the primary analyses**
Secondary
Endpoint(s):
 Ventilator-free days at 28-days
 Death at 90 days
 Total score of the age-adjusted 6-month global
cognition using Telephone Interview for Cognitive
Status (TICS-T) questionnaire
o Minimally clinically important
difference (MCID): 5 points
Statistical Test:  Proportional-odds logistic regression
 Cox proportional-hazards regression to analyze
death at 90 days (Hazard ratios, HR)
Safety Endpoint(s) Endpoint:  Bradycardia (HR < 60 BPM), acute respiratory
distress syndrome (ARDS), hypotension (SBP <
90 mmHg), organ dysfunction
Statistical Test: Descriptive statistics
Additional Statistical Analyses  Approximately 420 total patients needed to provide 85% power to detect a 1.5-
day difference in the primary outcome between groups
 80% power to detect a 12 percentage-point absolute difference in mortality at 90
days
 80% power to detect 3.9-point difference in TICS-T
 Level of significance for endpoints: P< alpha of 0.05
 Data analyzed in the modified intention-to-treat population (mITT):
randomization+ receipt of a trial drug
RESULTS
Total enrollment  A total of 432 patients underwent randomization, 422 (mITT) began receiving
dexmedetomidine (n=214) or propofol (n=208)
 Sites: Various US ICUs
Baseline characteristics  Comparable groups (dexmedetomidine (n= 214), propofol (n=208))
 Median age (interquartile range (IQR))-year: 59 (48-68)
 White (%.): 88, 85
 Black (%): 7,11
 Latinx (%): 6, 9
 Median days of mechanical ventilation before trial enrollment (IQR): 0.98
(0.58-1.36), 0.97 (0.61-1.54)
 Median hours from meeting inclusion criteria to drug initiation: 22.4, 22.1
 Median APACHE II score19***
at ICU admission (IQR): 27 (21-32), 27 (22-32)
 Median total SOFA score****
at trial enrollment (IQR): 10 (8-13), 10 (8-12)
 Shock, receiving vasopressor, at enrollment (%): 56, 49
 Confirmed infection by culture (%): 68, 63
 Suspected infection, not confirmed by culture (%): 27, 33
 Commonly known or suspected sources of infection (%): Lung (54,64); Urinary
Tract (21,26); Blood (43, 38)
 Delirium at enrollment (%): 35, 44
 Dexmedetomidine before enrollment (%) (16,12)
 Propofol before enrollment (%) (61, 62)

5. Anna Sandler, PharmD Candidate ‘2023
8/12/2022
 Benzodiazepine before enrollment (%) (29, 35)
Efficacy-Adherence and
Sedation Regimen
 Median days of receipt od drug (IQR): 3.0 (2.0-5.0), 4.0 (2.0-6.0)
 Median RASS score (IQR): dexmedetomidine: -2 (-3.00 to -1.00); propofol:
-1.95 (-3.03 to -0.98)
 Percent time at target sedation level while receiving drug:
dexmedetomidine 57%: propofol 60%
 Comparable ABCDE bundle adherence between the two treatment arms (~85-
98% adherence)
 Midazolam exposure (%): 53, 43
 Part of chemical paralysis: 17% of patients
 Open-label propofol exposure (%): 13,8
 Higher median daily dose (mcg/kg/min) in dexmedetomidine group:
10.8 vs. 4.8 in propofol group
 Open-label dexmedetomidine exposure (%): 4, 3
 Antipsychotic exposure (%): 42, 42
 Pain well controlled between the two groups: median CPOT: 0.33, 0.31
 Withdrawal from trial during hospitalization (%): 5,4
 Drug permanently discontinued (%): 12,11
Efficacy-Primary Outcome  Met modified power criterion (> 420 patients)
 No significant differences between adjusted median number of days without
delirium or coma over 14-day intervention period between dexmedetomidine
and propofol (10.7 days vs. 10.8 days; OR, 0.96; 95% CI 0.74 to 1.26)
Efficacy-Secondary Outcomes  No significant differences between dexmedetomidine and propofol with respect to
number of ventilator-free days at day 28 (23.7 versus 24.0; OR 0.98; 95% CI
0.63-1.51) or death at 90 days (38% vs. 39%; HR 1.06: 95% CI 0.74-1.52)
 No significant differences between dexmedetomidine and propofol in TICS-T
scores at 6 months (adjusted median score, 40.9 vs. 41.4; OR 0.94; 95% CI
0.66-1.33)
Safety/Adverse Events  Endpoints during 14-day study period (dexmedetomidine, n= 214, propofol, n= 208)
 Mostly Comparable safety profiles and incidences of organ dysfunction
 Hypotension (%) (56, 55)
 ARDS (%) 52, 65
 Bradycardia 30%, 19%
 Symptomatic bradycardia leading to discontinuation: dexmedetomidine: 4 (2%);
propofol 3 (1%)
AUTHORS’ CONCLUSIONS
The researchers did not find evidence that sedation with dexmedetomidine led to more days alive without acute brain
dysfunction than propofol. No difference was found between the two treatment groups with respect to ventilator-free days at 28
days, death at 90 days, or global cognition using the TICS-T score at 6 months. Safety endpoints were similar in the two groups.
CRITIQUE/DISCUSSION
Patient Population Strengths:  Groups well matched
 Multi-center study
 Good representation of different infectious causes of sepsis and
inclusion of critically ill patients
Limitations:  Mainly white group
 Relatively young cohort limits extrapolation to older patients
 Exclusion of those with heart block or symptomatic bradycardia
 Exclusion of those on a mechanical ventilator > 96 hours

6. 6
Intervention Strengths:  Randomization with stratification to ensure equal balance of
enrollment site and age cohorts between the two treatment arms
and account for site-practice differences
 Independent Data Safety Monitoring Board (DSMB) reviewed
protocol and data for serious adverse events
 Use of triple-blinding and masking medication bags
 Pain treated and adherence to the ABCDE bundle
 Lower open-label sedative doses
Limitations:  Lack of explanation for open-label propofol or dexmedetomidine
use
 Use of antipsychotics before and during intervention period to
treat delirium
 Lack of washout period to account for prior dexmedetomidine or
propofol use, unknown duration of prior sedative use
Endpoints Strengths:  Clinically meaningful outcomes assessed
 Assessed outcomes at 90 days and at 6 months
Limitations:  Outcomes related to ventilator-free days and mortality only
evaluated as secondary endpoints
 Safety endpoints only included in the supplement
 Did not assess sepsis-related outcomes such as vasopressor
requirements as the primary endpoint
Statistics Strengths:  Correction for potential confounding baseline characteristics with
regression models and adjusted analyses clustered by study site
Limitations:  Power would only allow detection of a TICS-T score difference
that is not clinically important
 Use of a mITT protocol vs. ITT?
CONCLUSION AND RECOMMENDATIONS
Presenter’s Discussion and
Conclusion
In the MENDS2 trial, sedation with dexmedetomidine was not superior to propofol with
respect to number of days alive without delirium or coma in mechanically ventilated adults
with sepsis. Similar trends were observed in ventilator-free days at day 28, death at 90 days
and global cognition. This study had a number of strengths to increase internal validity
compared with prior trials, including lower cross-over rates and doses, triple-blinding, and
adherence to pain and ABCDE protocols. Moreover, the primary outcome was unique in that
it assessed incidence of delirium and coma; improvements in quality of life and independent
function have been shown to be important in the assessment of patient-centered outcomes in
clinical research studies. 6,20
This trial had a number of limitations that need to be addressed.
Due to slow enrollment and reduced sample size, the trial may have been underpowered to
detect a difference between the two agents studied. Patients were only at goal sedation about
60% of the time; although the researchers state 17% of patients received midazolam for
chemical paralysis, it was unclear the exact reasons patients were not at the target levels.
Moreover, despite the measures undertaken to preserve blinding, unmasking to a clinician or
research member occurred in 14% of the patients. The researchers also excluded patients on
mechanical ventilation > 96 hours, potentially biasing the sample as longer ventilation has
been associated with increased mortality and length of stay.21,22
Application to Patient Care Overall, the results of the MENDS2 trial reinforce the SCCM guidelines in the context of
mechanically ventilated sepsis patients. The decision to use dexmedetomidine or propofol
for early, light sedation in these patients should be based on patient-specific factors and
sedative PK/PD profiles. 6,23
The results may be different in patients who are older than the
cohort studied, those who have been on mechanical ventilation > 96 hours, and in a more
prolonged sedative exposure course > 14 days.

7. Anna Sandler, PharmD Candidate ‘2023
8/12/2022
Foot notes:
* awakening and breathing coordination, choice of sedation, delirium monitoring and management, and early mobility
**some of the covariates used for the regression models included: age, education, baseline cognitive function, preexisting
comorbidities, sedative doses prior to enrollment and infection type.
***Acute Physiology and Chronic Health Disease Classification System II, used to classify severity of disease within 24 hours of
admission of a patient to an ICU. Higher scores correspond to more severe disease and higher risk of death. This classification takes
into account, heart rate, MAP, arterial pH, respiratory rate, WBC count, serum creatinine, age, serum K and Na, Glasgow coma
scale, PaO2 hematocrit and chronic health problems to generate a score that approximates mortality: 0-4 points (4%), 5-9 points
(8%), 10-14 points (24%), 20-24 (40%), 25-29 (55%), 30-34 (~73%), 35-100 (85%)
*** Although there is no direct conversion of the SOFA score to mortality, a rough estimate can be made based on the maximum
SOFA score during a patient’s ICU stay. Score (risk %) estimates: 7-9 (15-20%); 10-12 (40-50%); 13-14 (50-60%)

8. 8
References:
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doi:10.1002/jhm.1949
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11.Venn RM, Bryant A, Hall GM, Grounds RM. Effects of dexmedetomidine on adrenocortical function, and the
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13.Hughes CG, Mailloux PT, Devlin JW, et al. Dexmedetomidine or Propofol for Sedation in Mechanically
Ventilated Adults with Sepsis. N Engl J Med. 2021;384(15):1424-1436. doi:10.1056/NEJMoa2024922
14.Propofol: Drug Information. Lexicomp. Accessed 8/5/2022.
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patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care Lond
Engl. 2010;14(2):R38. doi:10.1186/cc8916
16.Jakob SM. Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation:
Two Randomized Controlled Trials. JAMA. 2012;307(11):1151. doi:10.1001/jama.2012.304
17.Shehabi Y, Howe BD, Bellomo R, et al. Early Sedation with Dexmedetomidine in Critically Ill Patients. N Engl J
Med. 2019;380(26):2506-2517. doi:10.1056/NEJMoa1904710

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8/12/2022
18.Cioccari L, Luethi N, Bailey M, et al. The effect of dexmedetomidine on vasopressor requirements in patients
with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial.
Crit Care. 2020;24(1):441. doi:10.1186/s13054-020-03115-x
19.Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system.
Crit Care Med. 1985;13(10):818-829.
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Clinical Research in Acute Respiratory Failure Survivors: An International Modified Delphi Consensus Study.
Crit Care Med. 2017;45(6):1001-1010. doi:10.1097/CCM.0000000000002435
21.Loss SH, Oliveira RP de, Maccari JG, et al. The reality of patients requiring prolonged mechanical ventilation: a
multicenter study. Rev Bras Ter Intensiva. 2015;27(1). doi:10.5935/0103-507X.20150006
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Utilization after Prolonged Mechanical Ventilation. Ann Am Thorac Soc. 2017;14(3):355-362.
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2008;14(4):403-407. doi:10.1097/MCC.0b013e32830280b3

10. 10
Appendix:
A. Rescue protocol
B. Calculator for SOFA-related mortality risk
https://clincalc.com/IcuMortality/SOFA.aspx#1