Clonidine vs. Dexmedetomidine in Agitated Delirium in Intensive Care Patients (Clodex)

February 13, 2021 updated by: Olivier Lheureux, Erasme University Hospital

Effect of Clonidine vs. Dexmedetomidine in Addition to Standard Treatment in Agitated Delirium in Intensive Care Patients: Pilot Study.

Delirium is one of the most common manifestations of cerebral dysfunction in severely ill patients.

The international guidelines for the prevention of delirium in intensive care recommend the daily application of environmental, behavioral and pharmacological strategies. In the case of the agitated form of delirium, experts recommend the use of low-dose neuroleptics and α-2 agonists to control psychotic manifestations rather than traditional sedatives (mainly benzodiazepines) that can clearly aggravate delirium.

Currently, two pharmacological α-2 agonists, clonidine (Catapressan®, Boehringer Ingelheim) and dexmedetomidine (Dexdor®, Orion Corporation), are marketed and commonly used in intensive care for their sedative, anxiolytic and analgesic properties.

To our knowledge, no studies have compared the effects of clonidine and dexmedetomidine in agitated delirium in intensive care patients. Therefore, our goal is to compare the safety of clonidine and dexmedetomidine (in terms of bradycardia and / or hypotension) in addition to standard treatment in the context of agitated delirium in intensive care patients.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Delirium is one of the most common manifestations of cerebral dysfunction in severely ill patients (60 to 80% of ventilated patients), leading not only to short-term complications (prolonged duration of ventilation, prolonged hospital stay, and increased mortality) but also long-term repercussions in the form of impaired cognitive functions, post-traumatic stress syndromes, and decreased quality of life. Different forms of delirium coexist: some patients are very agitated while others are, on the contrary, in an apathetic state. In intensive care patients, the agitated form of delirium is particularly problematic because of the risk of self-extubation and removal of other critical medical devices.

Pain, stress, anxiety and deregulation of wake / sleep cycles are important risk factors for delirium occurrence and are unfortunately frequently encountered in varying degrees in intensive care.

The international guidelines for the prevention of delirium in intensive care recommend the daily application of environmental, behavioral and pharmacological strategies. Thus, the early mobilization of the patient, the respect of the waking / sleep cycles, the adequate control of the pain represent effective measures of prevention. These guidelines also emphasize the importance of minimal use of sedative treatments while ensuring the comfort and safety of patients.

Finally, in the case of the agitated form of delirium, experts recommend the use of low-dose neuroleptics and α-2 agonists to control psychotic manifestations rather than traditional sedatives (mainly benzodiazepines) that can clearly aggravate delirium.

The α-2 receptors constitute a family of receptors coupled to transmembrane G proteins with 3 pharmacological subtypes, α-2A, α-2B and α-2C. The α-2A and α-2C subtypes are mainly found in the central nervous system. Stimulation of these receptor subtypes may be responsible for sedation, analgesia and sympatholytic effects. Α-2B receptors are more common on vascular smooth muscle and have been shown to have vasopressor effects. By their inhibitory action on adenylyl cyclase, the 3 subtypes have several effects: 1) they reduce the levels of cyclic adenosine monophosphate, 2) they cause a hyperpolarization of noradrenergic neurons in the brain stem, in particular in the locus ceruleus, 3) they suppress the neural discharge. This suppression inhibits the release of norepinephrine into the synapse resulting in a modulatory effect on the anxiety, wakefulness and sleep of patients. Activation of this negative feedback loop may also result in reduced heart rate and blood pressure by sympatholytic action.

Currently, two pharmacological α-2 agonists, clonidine (Catapressan®, Boehringer Ingelheim) and dexmedetomidine (Dexdor®, Orion Corporation), are marketed and commonly used in intensive care for their sedative, anxiolytic and analgesic properties. Unlike traditional sedatives (benzodiazepines and propofol) that leave the patient unresponsive to stimuli or stupor, sedation achieved by administering these α-2 agonists has several advantages. The α-2 agonists lower the general level of alertness (NREM, indifference to the environment and pain), but leave the waking ability intact. Therefore, under α-2 agonists, patients are more easily awake until a return to full consciousness, able to respond to simple orders, participate in their sessions of physiotherapy and communicate, within the limits of the presence of an intubation probe or non-invasive ventilation mask. In addition, these agents do not cause respiratory depression.

Clonidine is an α-2 agonist that has an affinity of 200/1 for α-2 receptors versus α-1 receptors. Initially marketed for its antihypertensive properties, clonidine is used in intensive care for its sedative and analgesic effects, especially in the treatment of delirium or alcohol withdrawal syndromes (alcohol, opioids, or benzodiazepines). The pharmacodynamics of this α-2 agonist is characterized by hepatic metabolism and renal elimination. The half-life elimination time is about 24 hours. The doses administered ranged from 0.01 μg / kg / min to 0.03 μg / kg / min and the main reported side effects were: bradycardia, low blood pressure and dry mouth. Pharmacodynamically, clonidine has the advantage to be very affordable (about 90 euros per patient for a week of treatment).

Dexmedetomidine is the newest of the α-2 agonists. Its affinity and specificity for α-2 receptors is much greater than that of clonidine (1600/1 α-2 / α-1 receptors)25. The pharmacodynamics of this α-2 agonist is characterized by hepatic metabolism and elimination almost completely renal. The half-life elimination time is about 2 hours. The recommended doses vary between 0.4 μg / kg / h and can be titrated up to 1.4 μg / kg / h. The main reported side effects are: bradycardia and low blood pressure. Its cost, on the other hand, is much higher (800 euros per patient for a one week treatment). The efficacy of dexmedetomidine has been demonstrated in terms of reduced mechanical ventilation time and ICU length of hospitalization when compared to placebo, traditional sedatives (propofol or benzodiazepines), neuroletics in the context of critical care delirium.

To date, only one study has compared the effects of clonidine and dexmedetomidine in a prospective, randomized manner (n = 70) in order to achieve short-term deep sedation in post-operative mechanical ventilation patients. Study confirms sedative efficacy of α-2 agonists and suggests greater hemodynamic stability under dexmedetomidine.

To our knowledge, no studies have compared the effects of clonidine and dexmedetomidine in agitated delirium in intensive care patients. Therefore, our goal is to compare the safety of clonidine and dexmedetomidine (in terms of bradycardia and / or hypotension) in addition to standard treatment in the context of agitated delirium in intensive care patients. Bradycardia is defined by a heart rate <60 / min (or a decrease of 20% of the initial heart rate) and arterial hypotension by one of the following criteria:

  • systolic blood pressure less than 90mmHg o(r a decrease of 20% of the initial systolic arterial pressure)
  • initiation of a vasopressor treatment
  • 10% increase in the dose of vasopressor treatment, if already started

Study Type

Interventional

Enrollment (Anticipated)

50

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • present agitated delirium, confirmed by the CAM-ICU diagnostic scale
  • require mechanical restraint or psychotropic / sedative

Exclusion Criteria:

  • Acute neurological central or medullary problems (vascular, traumatic, infectious, tumoral causes)
  • Severe hepatic insufficiency (Child C cirrhosis)
  • Severe renal insufficiency (creatinine clearance <30ml / min) or renal replacement therapy
  • Bradycardia <60 / min
  • 2nd or 3rd degree atrioventricular block (unless placed pacemaker)
  • Hemodynamic instability (MAP <60mmHg despite adequate vascular filling and vasopressor treatment).
  • Pregnant woman or breastfeeding
  • Use of α-2 agonist or antagonist agents within 24 hours of randomization
  • Allergy known to one of the α-2 agonists used in the study
  • Moribund patient (survival prognosis at limited 24h or therapeutic de-escalation envisaged)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Clonidine
Given that agitated delirium requires rapid medical intervention, α-2 agonist therapy (clonidine) will be administered as soon as possible, The sedative and analgesic treatments will be administered and titrated according to the scales on the usual protocol of the service (evaluation of sedation (NICS) and analgesia (VAS, BPS, BPS-NI). In case of excessive sedation assessed by the scores and administration of combined treatments (α-2 agonist and other sedatives), the reduction of the doses of other sedatives will be preferred over the α-2 agonist treatment. In case of insufficient sedation despite maximal doses of α-2 agonist, other sedatives (choosen by the attending physician) will administered and titrated according to the scales for pain and sedation evaluation.
Drug: Clonidine
The doses administered (clonidine 1500mg diluted in NaCl0.9% solution of 50 ml) ranged from 0.01μg/kg/min to 0.03μg/kg/min.
Other Names:
  • Dexmedetomidine
Experimental: Dexmedetomidine
Given that agitated delirium requires rapid medical intervention, α-2 agonist therapy (dexmedetomidine) will be administered as soon as possible. The α-2 agonist treatment that will be started will depend on the allocation of the previously randomized unit. The sedative and analgesic treatments will be administered and titrated according to the scales on the usual protocol of the service (evaluation of sedation (NICS) and analgesia (VAS, BPS, BPS-NI). In case of excessive sedation assessed by the scores and administration of combined treatments (α-2 agonist and other sedatives), the reduction of the doses of other sedatives will be preferred over the α-2 agonist treatment. In case of insufficient sedation despite maximal doses of α-2 agonist, other sedatives (choosen by the attending physician) will administered and titrated according to the scales for pain and sedation evaluation.
Drug: Dexmedetomidine
The doses administered (dexmedetomidine 200mg diluted in NaCl0.9% 50ml) ranged from 0.4μg/kg/h and can be titrated up to 1.4μg/kg/h.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
hemodynamic tolerance
Time Frame: Up to 7 days

Bradycardia is defined by a heart rate <60 / min (or a decrease of 20% of the initial heart rate) and arterial hypotension by one of the following criteria:

  • systolic blood pressure less than 90mmHg o(r a decrease of 20% of the initial systolic arterial pressure)
  • initiation of a vasopressor treatment
  • 10% increase in the dose of vasopressor treatment, if already started
Up to 7 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
number of living days without ventilation over 28 days
Time Frame: Up to 28 days
Up to 28 days
time to obtain a sedative sedation score (NICS -1 to 1)
Time Frame: up to 7 days
NICS = Nursing instrument confusion score. From -3 to + 3. Positive means agitation. Negative means sedation.
up to 7 days
time to obtain a first CAM-ICU test indicating the absence of delirium
Time Frame: Up to 7 days
Confusion assessment method in ICU). CAM ICU positive means delirium.
Up to 7 days
duration of delirium by evaluation CAM-ICU
Time Frame: Up to 7 days
Confusion assessment method in ICU). CAM ICU positive means delirium.
Up to 7 days
use of other sedative and psychotropic medications (number and total doses)
Time Frame: Up to 7 days
Up to 7 days
number of catheters / agitation extubation
Time Frame: Up to 7 days
Up to 7 days
Number of patients with tracheostomy
Time Frame: Up to 28 days
Up to 28 days
daily assessment of organ dysfunction by SOFA score
Time Frame: Up to 7 days
Sequential Organ Failure assessment score. From 0 to 24. 24 means worse outcome.
Up to 7 days
28 day survival or exit from the ICU
Time Frame: Up to 28 days
Up to 28 days
length of stay USI
Time Frame: through study completion, an average of 2 years
through study completion, an average of 2 years
length of hospital stay
Time Frame: through study completion, an average of 2 years
through study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Erasme University Hospital

Investigators

  • Study Director: Creteur Jacques, MD PhD, CUB Erasme Hospital ULB

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2021

Primary Completion (Anticipated)

February 28, 2022

Study Completion (Anticipated)

February 28, 2023

Study Registration Dates

First Submitted

February 10, 2021

First Submitted That Met QC Criteria

February 13, 2021

First Posted (Actual)

February 17, 2021

Study Record Updates

Last Update Posted (Actual)

February 17, 2021

Last Update Submitted That Met QC Criteria

February 13, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P2020/421

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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