The Art of Sedation in ICU Yasser Zaghloul MD PhD, FCARCSI (Ireland)

Sedation comes from the Latin word sedare. Sedare = to calm or to allay fear Hypnosis Analgesia ± Muscle Relaxation

Sedation comes from the Latin word sedare. Sedare = to calm or to allay fear Hypnosis Analgesia ± Muscle Relaxation

Why sedation is necessary? To improve patient comfort. Reduce stress. Facilitate interventions. Allow effective ventilation. Encourage sleep. ?? Prevent post-ICU psychosis.

Inadequate Sedation All ICU patients suffer from severe sleep deprivation. REM sleep is 6% ( Normal 25 %). Stress  neuroendocrine response ( ACTH, GH, Aldosterone, Adrenaline, .....) Release of cytokines  inflammatory response.

Non-pharmacological interventions Good nursing. Psychological: - Explanation. - Reassurance. Physical: - Touching & message. - Environment - Prevent constipation - Physiotherapy. - Tracheostomy.

Sedation-Analgesia Medications IV Anaesthetics: - Prpofol - Thiopentone. - Ketamine - Etomidate. Benzodiazepines: - Midazolam. - Lorazepam

Sedation-Analgesia Medications Opiodis: - Morphine - Fentanyl. - Remifentanil α-2 receptors agonists: Clonidine. Dexmedetomidine .

Sedation-Analgesia Medications Others: - Inhalation anaesthetics (Sevoflurane). - Phenothiazines. - Butyrophenones (Haloperidol). - Local Anaesthetics.

Choice of the sedative drug Short-term Vs long-term sedation. Pain & painful Procedures. Organ problems (Renal, hepatic, brain, CVS). Drug withdrawal (Alcohol, heroin, .....) Prescriber & Prescription.

Which Medication? Soliman et al, Brit J Anaesth 2001;87:186-92

IV Anaesthetics; Thiopentone Acts on the GABAA. Zero order kinetics (accumulation). Provides a cerebral protection effect. Main uses in ICU: - High ICP. - Status epilepticus

IV Anaesthetics; Propofol (CH3)2CH CH(CH3)2 OH 2,6 di-isopropyl phenol Short-term sedation (< 48 h)

IV Anaesthetics; Propofol Mechanisms of actions: - Acts on GABAA receptors in the hippocampus. - Inhibits of NMDA.  IOP, ICP & CMRO2.

IV Anaesthetics; Propofol Decreases (10 – 30%): - HR. - SBP, DBP & MAP. - SVR. - CI. - SV.

Target concentrations with ‘Diprifusor’ TCI Full ‘Diprivan’ PFS is loaded correctly Finger grip Tag = PMR (Programmaable Magnetic Resonance*) Aerial ‘Diprifusor’ TCI Subsystem Recognition software/electronics ‘Diprifusor’ TCI Software/ 2 microprocessors Pump software Pump hardware

Target concentrations with ‘Diprifusor’ TCI 38 Target concentrations with ‘Diprifusor’ TCI 1200 ↑ Tc End 8 Calculated concentration (automatic calculation and display by system) Target concentration (selected by anaesthetist, displayed) Titration 5 6 6 2 3 Age Wt. Tc 4 4 Infusion rate (ml/h) 100 Blood concentration (µg/ml) 4 1 Start ‘Diprifusor’ TCI with initial target concentration of 6 mg/ml Rapid bolus (1,200 ml/h) to reach target 2 Variable-rate infusion to maintain initial target 3 10 minutes, select lower target of 4 mg/ml (titrate downwards) Infusion stops until blood concentration falls to lower target Resumption of infusion at decreased rate to maintain new target 4 20 minutes, select higher target of 6 mg/ml (titrate upwards) Another bolus to reach new target Resumption of infusion at increased rate to maintain higher target 5 30 minutes, end of ‘Diprifusor’ TCI Blood concentration falls ... What happens when an initial target concentration has been set? A ‘Diprifusor’ System can be considered as a “smart pump”. ‘Diprifusor’ TCI Software “commands” the syringe pump to deliver a rapid infusion at a rate of 1,200 ml/h until the pharmacokinetic model calculates that the selected target concentration has been reached. Variable-rate infusions are then provided automatically to maintain the selected target concentration. The target concentration can be changed at any time by the anaesthetist — and is displayed. Selection of a higher target concentration results in administration of a bolus followed by infusion at an increased rate. Selection of a lower target concentration results in a temporary discontinuation of infusion followed by resumption at a lower rate. The calculated concentration is displayed continuously both during and after stopping drug infusion. The display of both the selected target concentration and the calculated concentration provides feedback to the anaesthetist. These principles apply to the commercially-available pumps that incorporate ‘Diprifusor’ as well as to the ‘Diprifusor’ System used for clinical trials. 50 2 1 4 8 12 16 20 24 28 Start; 6µg/ml Time (hours)

IV Anaesthetics; Propofol Propofol infusion syndrome: - Rare but fatal. - 1st described in children. - Infusion ≥ 5 mg/kg/hr or ≥ 48 hours.

Propofol Infusion Syndrome Clinical features: - Cardiomyopathy with acute cardiac failure. - Myopathy. - Metabolic acidosis, K+ - Hepatomegaly. Inhibition of FFA entry into mitochondria  failure of its metabolism.

IV Anaesthetics - Ketamine

IV Anaesthetics - Ketamine Phencyclidine derivative. High lipid solubility (5–10 times > thiopental) crosses BBB faster. Non-competitive antagonism at NMDA receptor

IV Anaesthetics - Ketamine  HR, BP.  CBF, ICP & CMRO2. Bronchial smooth muscle relaxant. Excellent analgesic. Dose: 5-30 µg/kg/min.

Opioids; Morphine Isolated in 1803 by the German pharmacist Friedrich Adam. Named it 'morphium' after Morpheus, the Greek god of dreams.

Opioids - Morphine Plasma levels do not correlate with clinical effect. Low lipid solubility causes slow equilibration across BBB. Metabolized in the liver by conjugation. Morphine-6-glucuronide (active).

Remifentanil Piperidine derivative. Selective mu-receptor agonist. Potency similar to fentanyl. Terminal half-life < 10 min. Rapid blood-brain equilibrium. Metabolised by non-specific esterases.

Remfentnil Acid 95% 1.5%

Plasma concentration after long term infusion After 240 min Context –sensitive half-time Fentanyl 262 min 100 75 Alfentanil 59 min Time to 50% drop in concentration at effect site (minutes) Sufentanil 34 min 50 25 Remifentanil 3.7 min 100 200 300 400 500 600 Duration of infusion (minutes)

Unwanted side-effects of opioids Vasodilation Confusion Respiratory depression Gut motility depression

Benzodiazepines

Benzodiazepines; Midazolam Water-soluble  lipid soluble in the body. Produces sedation, anxiolysis and amensia. Withdrawal agitation.

α2-Adrenergic agonists Clonidine Dexmedetomidine

α2 – agonists Sedation-hypnosis: Analgesia: by an action on α2-receptors in the locus ceruleus. Analgesia: by an action on α2-receptors within the locus ceruleus and the spinal cord

α2 – agonists; Dexmedetomidine 94% protein bound. Narrow therapeutic range (0.5 - 1.0 ng/mL) It undergoes conjugation & N-methylation. Approved only for sedation ≤ 24 h.

α2 – agonists Haemodynamics Effects: No respiratory depression -  heart rate. - Initial  then  BP. -  SVR. -  CO No respiratory depression

Unwanted side-effects of sedative agents General Over sedation Delayed awakening/extubation Benzodiazepines Hypotension Respiratory depression Agitation/Confusion 2-agonists Hypotension Bradycardia Propofol Hypertriglyceridemia CVS depression Hypotension Ketamine Hypertension Secretions Dysphoria

Drug Elimination h1/2 (h) Prpofol 4 – 7 Dexmedetomidine 2 - 3 Ketamine 2.5 – 2.8 Midazolam 1.7 – 2.6

Assessment of Sedation Ramsay Sedation Score. Motor Activity Assessment Scale Richmond Agitation–Sedation Scale. Sedation – Agitation Score. Modified Glasgow Coma Score.

Ramsay Sedation Score Level 1 Level 2 Level 3 Level 4 Level 5 Level 6 Awake, anxious, agitated, restlessness Level 2 Awake, cooperative, tranquil. Level 3 Respond to commands. Level 4 Asleep, brisk response to stimuli. Level 5 Asleep, sluggish response to stimuli. Level 6 Asleep, no response

Bispectral Index

Is any place for neuro-muscular Blockers in ICU?

Mehta S et al. Crit Care Med 2006; 34: 374

The Art of Sedation * Under sedation: * Over sedation: Fighting the ventilator. V/Q mismatch. Accidental extubation. Catheter displacement. CV stress  ischemia. Anxiety, awareness. Post-traumatic stress disorder. * Over sedation: Tolerance, tachyphylaxis. Withdrawal syndrome. Delirium. Prolonged ventilation. CV depression.  neuro testing. Sleep disturbance.

Thank You Yasser Zaghloul