What does the evidence say about dexmedetomidine versus propofol for sedation in mechanically ventilated adults with sepsis? Is there a significant difference between days alive without delirium or coma for the two medicines?

Comment by InpharmD Researcher

Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. No significant difference between days alive without delirium or coma was noted.

Background

As per the Society of Critical Care Medicine, The Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the intensive care unit (ICU) suggest using either propofol or dexmedetomidine over benzodiazepines for sedation in critically ill, mechanically ventilated adults. The panelist recognized that dexmedetomidine should not be used when deep sedation (with or without neuromuscular blockade) is required, and stated that desirable and undesirable consequences of using propofol (vs dexmedetomidine) were balanced; therefore, a conditional recommendation to use either agents for sedation of critically ill adults was issued. Implementation is dependent on the availability of the drug and its associated cost at individual institutions. [1]

Relevant Prescribing Information

PRECEDEX (TM) (dexmedetomidine hydrochloride) is an alpha2-adrenergic agonist indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting, and for sedation of non-intubated patients prior to and/or during surgical and other procedures. Precedex injection 200 mcg/2 mL (100 mcg/mL) is clear and colorless, and available in 2 mL clear glass vials For ICU patients, dexmedetomidine should be initiated at one mcg/kg over 10 minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hour. Patients on dexmedetomidine should be constantly monitored. Warnings and precautions include hypotension, bradycardia, use with vasodilators and negative chronotropic agents, transient hypertension, arousability, tolerance, and tachyphylaxis. The most common adverse reactions (incidence >2%) are hypotension, bradycardia, and dry mouth. The medicine should be stored at USP controlled room temperature, 20 to 25 °C (68 to 77 °F) with excursions allowed from 15 to 30°C (59 to 86°F). [1]

DIPRIVAN® (propofol) Injectable Emulsion, USP is a sterile, nonpyrogenic emulsion containing 10 mg/mL of propofol suitable for intravenous administration, and indicated for anesthesia, and sedation for mechanically ventilated patients in the ICU. Propofol dosing begins with 5 mcg/kg/minute; increasing by 5 to 10 mcg/kg/minute every 5 to 10 minutes until goal sedation level is achieved. The usual maintenance dose is 5 to 50 mcg/kg/minute. Maximum dose (not well defined; may vary by institution) is 60 to 80 mcg/kg/minute. Contraindications to propofol include hypersensitivity to propofol or any component of the formulation; hypersensitivity to eggs, egg products, soybeans, or soy products; when general anesthesia or sedation is contraindicated. Warnings and precautions include anaphylaxis and hypersensitivity, ECG (QT-interval) changes, hypertriglyceridemia, hypotension, injection site reactions, myoclonus, and propofol-related infusion syndrome. Common adverse reactions (>10%) include hypotension, involuntary body movements, injection site reactions, and apnea. The medication should be stored between 4°C to 25°C (40°F to 77°F); refrigeration is not required. Do not freeze. Shake well before use. Withdraw from vial into a syringe immediately after sterile vented spike inserted. Administration should begin immediately and completed within 12 hours after the vial has been opened. Do not use if there is evidence of separation of phases of emulsion.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Please see Table 1 for your response.

Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis

Design

Multicentered, double-blind, randomized, controlled trial

N= 432

Objective

To test whether dexmedetomidine leads to better short-term and long-term outcomes than propofol in mechanically ventilated adults with sepsis.

Study Groups

Dexmedetomidine: n= 214

Propofol: n= 208

Inclusion Criteria

Sequentially admitted to a medical or surgical ICU, had suspected or known infection, and were treated with continuous sedation for invasive mechanical ventilation

Exclusion Criteria

Had baseline severe cognitive impairment; were pregnant or breast-feeding; were blind, deaf, or unable to understand approved languages; had second-degree or third-degree heart block or persistent bradycardia requiring intervention; had an allergy to dexmedetomidine or propofol; had an indication for benzodiazepines; were anticipated to have immediate discontinuation of mechanical ventilation; were expected to have neuromuscular blockade for more than 48 hours; were in a moribund state; or had received mechanical ventilation for more than 96 hours before meeting all inclusion criteria

Methods

This trial was conducted at 13 medical centers across the United States.

A weight-based dosing guideline (0.15 to 1.5 μg per kilogram of actual body weight per hour for dexmedetomidine and 5 to 50 μg per kilogram of actual body weight per minute for propofol) was used with the trial drug being adjusted every 10 minutes to meet the sedation goals. The Richmond Agitation–Sedation Scale (RASS was used to set the sedation goal, which was primarily light sedation (RASS score 0 to −2).

Dexmedetomidine was administered at a median dose of 0.27 μg per kilogram per hour, while propofol was administered at a median dose of 10.21 μg per kilogram per minute.

Administration of the trial drug was temporarily held in the event of hypotension, bradycardia, sedation deeper than the target level, spontaneous awakening trials, or surgery. The trial drug was permanently discontinued if the patient had persistent symptomatic bradycardia, new onset second- or third-degree heart block, serious allergic reactions, suspected propofol-related infusion syndrome, or any serious adverse event related to the intervention.

The trial drug was discontinued after the 14-day intervention period, extubation, or discharge from the ICU, whichever came first.

If the patient had pain, it was treated with intermittent opioid boluses or fentanyl infusion, depending on the decision of the clinical team.

The Confusion Assessment Method for the ICU (CAM-ICU) for delirium, and the Critical Care Pain Observation Tool for pain were used assessment markers. Assessments were made twice daily in the ICU and then once daily after transfer from the ICU for up to 14 days or until discharge from the hospital or death.

Duration

Median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0)

Intervention period: 14 days

Outcome Measures

The primary efficacy end point was the number of calendar days alive without delirium or coma during the 14-day intervention period.

Secondary efficacy end points included ventilator-free days at 28 days, death at 90 days, and global cognition at 6 months using the age-adjusted TICS total score (TICS-T score).

Baseline characteristics

Characteristic	Dexmedetomidine	Propofol
Median age (IQR) — yr	59 (48-68)	60 (50-68)
Female sex — no. (%)	93 (43)	88 *42)
Median body-mass index (IQR)	30 (25-38)	29 (25-37)
Race or ethnic group — no. (%)
White	188 (88)	177 (85)
Black	15 (7)	23 (11)
Latinx	12 (6)	18 (9)
Multiple or other	11 (5)	8 (4)
Median IQCODE-SF score (IQR)	3.06 (3.00-3.23)	3.00 (3.00-3.25)
Median Charlson Comorbidities Index score (IQR)	2 (1-4)	2 (1-4)
Admitted to surgical ICU — no. (%)	76 (36)	72 (35)
Median APACHE II score at ICU admission (IQR)	27 (21-32)	27 (22-32)
Median days from ICU admission to trial enrollment (IQR)	1.21 (0.67-1.95)	1.17 (0.68-1.94)
Median days of mechanical ventilation before trial enrollment (IQR)	0.98 (0.58-1.36)	0.97 (0.61-1.54)
Median total SOFA score at trial enrollment (IQR)	10 (8-13)	10 (8-12)
Shock, receiving vasopressor, at enrollment — no. (%)	119 (56)	102 (49)
Infection status — no. (%)
Infection confirmed by culture	146 (68)	132 (63)
Infection suspected but not confirmed by culture	58 (27)	68 (33)
Infection ruled out	10 (5)	8 (4)
Dexmedetomidine before enrollment — no. (%)	35 (16)	25 (12)
Propofol before enrollment — no. (%)	131 (61)	129 (62)
Benzodiazepine before enrollment — no. (%)	62 (29)	73 (35)
Opioid before enrollment — no. (%)	144 (67)	147 (71)
Antipsychotic agent before enrollment — no. (%)	24 (11)	27 (13)
Delirium at enrollment — no. (%)	75 (35)	91 (44)
Level of arousal closest to the time of randomization — no. (%)
Coma: RASS −5 or −4	81 (38)	74 (36)
Deep sedation: RASS −3	29 (14)	38 (18)
Light sedation: RASS −2 or −1	85 (40)	75 (36)
Awake and calm: RASS 0	13 (6)	14 (7)
Agitated: RASS +1 to +4	6 (3)	7 (3)

Results

Primary and Secondary Efficacy End Points
End Point	Dexmedetomidine (n= 214)	Propofol (n= 208)
Days alive without delirium or coma at 14 days:
Unadjusted no. of days — median (IQR)	8.0 (1.0-12.8)	7.5 (1.8-11.2)
Adjusted no. of days — median (95% CI)	10.7 (8.5-12.5)	10.8 (8.7-12.6)
Adjusted odds ratio (95% CI)	0.96 (0.74-1.26)	Reference
Ventilator-free days at 28 days:
Unadjusted no. of days — median (IQR)	20.9 (0.0-26.1)	19.9 (4.2-24.9)
Adjusted no. days — median (95% CI)	23.7 (20.5-25.4)	24.0 (20.9-25.4)
Adjusted odds ratio (95% CI)	0.98 (0.63-1.51)	Reference
Death at 90 days:
Unadjusted no. of patients (%)	81 (38)	82 (39)
Adjusted hazard ratio (95% CI)	1.06 (0.74-1.52)	Reference
TICS-T score at 6 months:
Unadjusted score — median (IQR)	39 (28-48)	38 (30-46)
Adjusted score — median (95% CI)	40.9 (33.6-47.1)	41.4 (34.0-47.3)
Adjusted odds ratio (95% CI)	0.94 (0.66-1.33)	Reference

Safety

Organ dysfunction during 14-day treatment period
Organ system–no.(%)	Dexmedetomidine (n= 214)	Propofol (n= 208)
Cardiovascular	143 (67%)	134 (64%)
Coagulation	83 (39%)	88 (42%)
Hepatic	48 (22%)	44 (21%)
Renal	105 (49%)	87 (42%)
Respiratory	211 (99%)	207 (100%)

Safety end points during 14-day study period by treatment group
End point	Dexmedetomidine (n=214)	Propofol (n= 208)
Hypotension (SBP<80 mm Hg)—no. (%)	119 (56%)	115 (55%)
Median CV SOFA score [IQR]	0.91[0.43-1.98]	1.00[0.50-1.44]
Bradycardia (HR<60 bpm)—no. (%)	65 (30%)	39 (19%)
Tachycardia (HR>100 bpm)—no. (%)	163 (76%)	165 (79%)
Severe lactic acidosis (>5 mmol/L)—no. (%)	31 (14%)	30 (14%)
ARDS—no. (%)	111 (52%)	135 (65%)

Study Author Conclusions

Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol.

InpharmD^TM Researcher

Critique

The MENDS2 trial is a well-designed, randomized study evaluating multiple outcomes that could help find sedation paradigms to improve brain injury and survival in sepsis. However, limitations are present in the unmasking of the group assignenments to physicians and/or the research team. Episodes of unmasking occurred in 14% of patients and cross-contamination amongst the sedatives could have been possible.

References:
[1] Hughes CG, Mailloux PT, Devlin JW, Swan JT, Sanders RD, Anzueto A, Jackson JC, Hoskins AS, Pun BT, Orun OM, Raman R, Stollings JL, Kiehl AL, Duprey MS, Bui LN, O'Neal HR Jr, Snyder A, Gropper MA, Guntupalli KK, Stashenko GJ, Patel MB, Brummel NE, Girard TD, Dittus RS, Bernard GR, Ely EW, Pandharipande PP; MENDS2 Study Investigators. Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. N Engl J Med. 2021 Apr 15;384(15):1424-1436. doi:10.1056/NEJMoa2024922. Epub 2021 Feb 2. PMID: 33528922.