Dexmedetomidine in icu hashemian

Dexmedetomidine in ICU

Seyed Mohammadreza Hashemian MD.FCCMSepehr Roozdar MD

Dexmedetomidine( Precedex® )

Dexmedetomidine Pharmacology

Dexmedetomidine Chemical Structure

Active dextro enantiomer of Medetomidine

Dexmedetomidine Pharmacology Mechanism of Action:

Selective central Alpha-2 adrenergic receptor agonist (esp. 2a subtype) / 8 times more specific than Clonidine

Binds to pre- and post-synaptic adrenergic neurons in the central nervous system (CNS) Its effects are dose-dependently reversed by

administration of a selective α-2 antagonist, such as Atipamezole

Alpha 2 Agonists Pathways

Alpha 2 Agonists Effects

Dexmedetomidine Pharmacology Pharmacokinetics

Distribution: Rapid (steady-state volume of distribution: 118 L)

Onset of action (IV route): 15-30 minutes Tmax (time needed to reach peak concentrations): 1 hour

(after continuous IV infusion) Protein binding: 94% (serum Albumin & α1-glycoprotein) Follows linear or zero-order kinetics (a constant amount

of the drug is eliminated per hour) Elimination half-life (t ½ β): between 2.0 and 2.5 hours Metabolism: Liver through glucuronide conjugation and

biotransformation (by cytochrome P450 enzyme system) Excretion: 95% urinary & 4% fecal

Adverse Effects of Dexmedetomidine Hypotension (24-54%) Bradycardia (5-14%) Atrial fibrillation (4-5%) Hypovolemia (3%) ↓ urine output Pleural effusion Hypocalcaemia (1%) Nausea (3-9%) Xerostomia (3-4%) Hyperglycemia

Dexmedetomidine & Sedation Mechanism of sedation:

Acting on high density of alpha-2 receptors in locus coeruleus (Predominant noradrenergic nucleus in brain / Modulator of alertness) Produces “Cooperative sedation” (Allows for easy awakening / Facilitates routine patient assessment as it allows the patient to interact with healthcare professionals)

Dexmedetomidine

Dexmedetomidine & Sedation(Literature Review)

Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial (Richard R. Riker, MD et. al ; JAMA, February 4, 2009—Vol 301, No. 5)

At comparable sedation levels, Dexmedetomidine-treated patients spent time on the ventilator, experienced

delirium, and developed tachycardia and hypertension.

The most notable adverse effect of Dexmedetomidine was bradycardia

Dexmedetomidine & Sedation(Literature Review)

Dexmedetomidine as a Sedative Agent in Critically Ill Patients: A Meta-Analysis of Randomized Controlled Trials (Laura Pasin et. al ; PLOS ONE, December 2013, Volume 8, Issue 12, e82913)

Dexmedetomidine could help to ICU stay and time to extubation, in critically ill patients.

Dexmedetomidine & Sedation(Literature Review)

Dexmedetomidine: a unique clinical profile in ICU sedation (Steve Chaplin; FUTURE PRESCRIBER Vol 13(3) )

Dexmedetomidine the median duration of mechanical ventilation compared with midazolam, but not

propofol.

Dexmedetomidine also the median time to extubation compared with both agents

Dexmedetomidine & Sedation(Literature Review)

Sedation with dexmedetomidine in the intensive care setting (Anthony T et. al; GerlachOpen Access Emergency Medicine 2011:3 77–85)

Dexmedetomidine is an α-agonist that does not produce respiratory depression and is an option for sedation in ICU patients.

However, it is associated with hemodynamic

side effects, including clinically significant bradycardia.

Dexmedetomidine & Sedation(Literature Review)

Comparison between dexmedetomidine and propofol for sedation in the intaensive care unit: patient and clinician perceptions (R. M. Venn et. al; British Journal of Anesthesia)

An equivalent depth of sedation between dex and propofol in the ICU was achieved and dexmedetomidine could

opioid requirement by 50%

Opioid Sparing Role of Dexmedetomidine that reduced the need for opioids without compromising patient comfort in the

ICU(Randomized open label multicentral controlled trials of 295 adults

undergoing CABG)

Dexmedetomidine & Delirium

As compared with lorazepam and midazolam, Dexmedetomidine resulted in delirium and a duration of mechanical ventilation but not reduced stays in the ICU or hospital

Dexmedetomidine administration spent time undergoing mechanical ventilation

Dexmedetomidine & Delirium

Dexmedetomidine has been described to be effective in treating four patients with agitation and hyperadrenergic states refractory to haloperidol.

Dexmedetomidine may be of great benefit in treating and preventing agitation and delirium in perioperative and ICU patient care

Dexmedetomidine may be of great benefit in treating and preventing agitation and delirium in perioperative and ICU patient care

Delirium Percentage Comparison

Dexmedetomidine & Sedation(Literature Review) Management of ICU –related agitation

and delirium with Dexmedotimidine(Hashemian, topics in thoracic

surgery 2012, ISBN: 978-953-51-0010-2)

Dexmedetomidine & Sedation(Literature Review)

Sedation and Delirium in the Intensive Care Unit (Michael C. Reade et. al; N Eng J 2013,370;5)

Dexmedetomidine may have advantages over benzodiazepines, since it produces analgesia, causes respiratory depression, and seemingly provides a qualitatively different type of sedation(Cooperative Sedation)

Agitated patient

Pain Anxiety

Delirium

In a studies it was found once a analgesic was given more than 60% patients do not require sedation.We suggest that analgesia-first sedation be used in adult ICU patients A1

PAD

PAD Guideline 2013 & Dexmedetomidine

PAD 2013 Says:

We suggest that in adult ICU patients with delirium unrelated to alcohol or benzodiazepine withdrawal, continuous i.v. infusions of Dexmedetomidine rather than benzodiazepine infusions be administered for sedation to reduce the duration of delirium in these patients. (+2B)

PAD

Dexmedetomidine & AWS Concerns in AWS:

1. Agitation and autonomic hyperactivity control is essential in severe AWS

2. Benzodiazepine monotherapy may be insufficient for control of AWS

Dexmedetomidine & AWS

Potential Benefits of Dexmedetomidine:

1. Provides sedation and autonomic activity 2. No effect on respiratory function

Review of Dexmedetomidine for severe AWS

Clinical outcomes and efficacy Case series comparing pre- and post-

Dexmedetomidine show rapid response : 1. Improved CIWA-Ar score 2. in blood pressure and heart rate 3. in benzodiazepines and haloperidol usage Proposed benefits: Avoid mechanical ventilation

and facilitate extubation

Safety Hypotension and bradycardia most common

adverse effects

Dexmedetomidine & SeizureAnticonvulsant Data:

An animal study(Rats) has shown that Dexmedetomidine decreases the CNS toxicity of bupivacaine and by

the convulsive dose and threshold plasma concentrations for convulsions

Another animal study(Rats) suggest that Dexmedetomidine the cocaine-induced seizure threshold possibly via a mechanism related to the attenuation of the extracellular dopaminergic neurotransmitter response to cocaine.

Dexmedetomidine & Cardiovascular System

Dexmedetomidine may the risk of ventricular tachycardia and hyperglycemia. Thus, Dexmedetomidine could be a safe and efficacious sedative agent in cardiac surgical patients.

Perioperative Dexmedetomidine use was associated with a in postoperative mortality up to 1 year and incidence of postoperative complications and delirium in patients undergoing cardiac surgery

6 Final Points

1. Dexmedetomidine has a mechanism of action that is different from that of benzodiazepines and Propofol. It has greater selectivity for alpha-2 receptors than Clonidine, suggesting the potential for a lower risk of hemodynamic adverse events.

6 Final Points

2. The nature of the sedation induced by Dexmedetomidine is different to that of established agents, although the depth of the sedation is comparable between the agents. Patients being treated with Dexmedetomidine are responsive to stimuli, and in clinical trials, nurses noted better co-operation and communication with patients treated with Dexmedetomidine compared with Midazolam and Propofol.

6 Final Points

3. Importantly, delirium is less frequent with Dexmedetomidine treatment than midazolam and propofol, and the time to extubation is shorter than with either midazolam or propofol.

6 Final Points

4. Dexmedetomidine is not believed to cause

respiratory depression.

6 Final Points

5. Consistent with its pharmacology, cardiovascular

adverse events are the most commonly reported

in clinical trials.

However, in clinical trials, the overall frequency of discontinuation due to adverse events was similar for Dexmedetomidine, Midazolam and Propofol.

6 Final Points

6. In clinical trials, Dexmedetomidine was noninferior to other sedating agents

and offered a different quality of sedation to other

agents.