1. Sedation & Analgesia PICU Resident Talk Stanford School of Medicine Pediatric Critical Care Medicine June 2010

2. Objectives After this lesson, the participant will be able to: Differentiate between sedation and analgesia. Develop an appropriate sedation/analgesia plan, taking into consideration: airway, depth of sedation needed, time to onset of drug effect, duration of sedation/analgesia effect. Describe the differences between distribution half life, elimination half-life and context sensitive half life.

3. Questions to ask yourself Does patient need pain control or sedation? How can you tell which one? Why does patient need sedation or pain control? Could the objective be achieved without it? Might agents for sedation or pain control make the patient worse (ie delirium)? How quickly do you need effect? How long do you need effect? At what risk to the patient? Are you prepared? Airway, BP support

4. Definitions Sedation--Reduction of anxiety, stress, irritability, or excitement by administration of a sedative agent or drug Analgesia--the relief of pain

5. Levels of Sedation Minimal Sedation (anxiolysis) – Normal response to verbal stimulus Moderate Sedation (conscious sedation) – Depressed consciousness but response to verbal commands Deep Sedation – Difficult to arouse – May need assistance w/ airway patency & ventilation General Anesthesia – Not able to arouse even by painful stimulation – Impaired airway, ventilation & possibly cardiovascular function

6. Commonly used agents Analgesics Acetaminophen NSAIDS/ketorolac Opioids (morphine, fentanyl, dilaudid) Sedatives Chloral Hydrate Benzodiazepines (midazolam, lorazepam, diazapam) Propofol Barbituates (methohexital, thiopental, phenobarbital, pentabarbital) Etomidate Analgesic and Sedative Effects Ketamine Dexmedetomidine Remifentanil

7. Opioids Mediate pain by binding to the mu, kappa, and delta receptors. Dose dependent sedative effect via kappa receptor Dose dependent respiratory depression and decrease in blood pressure Reversal agent: Naloxone

8. Opioids AgentPotencyPeak effectActive Metabolite Adverse reactions Morphine1Peak effect 20 minutes Yes (Renal)Histamine effects Hydro- Morphone 5-7Peak effect 8-10 minutes NoNo Histamine effects, no rigid chest Fentanyl75-100Peak effect 5 minutes NoRigid chest if given rapidly

9. Minutes since bolus injection 05101520 Percent of peak effect site concentration 0 20 40 60 80 100 Fentanyl Hydromorphone Morphine Comparitive Onset of Opioids

10. Benzodiazepines GABA agonist Causes sedation/hypnosis, anxiolysis, amnesia No analgesia Dose dependent respiratory depression and decrease in blood pressure Reversal agent: flumazenil

11. Benzodiazepines AgentPotencyOnsetActive Metabolites Adverse Reactions Midazolam½ as potent as lorazepam 1-5 minutesYesParadoxical effects Lorazepam2 times as potent as midazolam 5-15 minutesNoParadoxical effects (less than midazolam)

12. Chloral Hydrate Sedative-hypnotic Onset of action: 10-20 minutes Peak action: 60 minutes Duration 4-8 hours No reversal agent Unreliable in children over 3 years of age (Krauss Lancet 2006)

13. Propofol GABA agonist—binds alpha subunit Sedative only, no analgesic effects Rapid onset and offset and no withdrawal Onset: within 30 seconds Duration: 3-10 minutes but depends on duration of infusion PK follows 3 compartment model – Rapid distribution from blood into tissues – Rapid metabolic clearance from blood Hepatic + extra-hepatic metabolism – Slow return to blood from peripheral compartment

14. Propofol Propofol infusion syndrome—most often lactic acidosis, rhabdomyolysis, and circulatory collapse (Wysowski Anesthesia 2006, Cremer Critical Care 2009) Propofol infusion syndrome typically occurs when high doses (greater than 67-83mcg/kg/min) are given for long periods of time (greater than 24 hours). (Roberts Critical Care Med 2009, Cremer Lancet 2001 and Cornfield Pediatrics 2002) Not indicated for sedation in the PICU according to product label

15. Ketamine “Dissociative” anesthetic Works at multiple receptors—NMDA receptor antagonist, opiate receptor agonist Bronchodilation effects (Hemmingsen Am J Emerg Med 1994) Associated with hemodynamic stability and sometimes hypertension Respiratory effort and airway reflexes maintained Onset of action: 30 seconds to 1 minute Duration of action: 5-30 minutes Adverse effects: increased secretions, dysphoria, pychosis (may be improved with midazolam premedication)

16. Dexmedetomidine Alpha-2 adrenergic agonist Has both sedative and analgesic properties Adverse effects: bradycardia, may excacerbate heart block, hypertension, hypotension

17. Etomidate Sedative-hypnotic Used primarily for procedures; doesn’t cause hemodynamic instability Onset of action: 5-30 seconds Peak action: 1 minute Duration of action: 2-10 minutes Adverse effect: Transient adrenal suppression (Wagner New England Journal 1984)

18. Barbiturates Methohexital, thiopental, pentobarbital GABA receptor agonist Rarely used in PICU because of hemodynamic effects and because there is no reversal agent Used for seizure burst suppression

19. Elimination Half Life versus Context Sensitive Half Life Distribution half life (t1/2  ): the time required for plasma conc. to drop by 50% due to movement from central to peripheral compartment Elimination half life (t1/2  ): the time necessary to metabolize/excrete 50% of the drug from the body after IV injection Context Sensitive half life: Time for plama drug concentration to decrease by 50% after cessation of an infusion. Incorporates effects of redistribution into and out of peripheral compartments (3 compartment model).

21. Summary of Key Points Be prepared to manage adverse effects when you give a sedative or analgesic drug Have a plan! Know what is needed to achieve your goals. Understand the pharmacokinetics

22. Cases 1 year old intubated for ALI and pneumonia who needs sedation for arterial line placement. 5 year old with elevated WBC count and mediastinal mass on Chest X-ray and oncology wants a chest CT. 4 year old returns from OR after undergoing LTR. Needs to be sedated for a week.