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

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.

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

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.

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.

The doses administered (clonidine 1500mg diluted in NaCl0.9% solution of 50 ml) ranged from 0.01μg/kg/min to 0.03μg/kg/min.

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.

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

NICS = Nursing instrument confusion score. From -3 to + 3. Positive means agitation. Negative means sedation.

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)

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