SEDATION & NEUROMUSCULAR BLOCKADE

1. SEDATION & NEUROMUSCULAR BLOCKADE NGA B. PHAM, MD, FAAP CHOA & EMORY UNIVERSITY MARCH 2008

2. Pain in ICU: • Disease process or painful procedures • Exacerbated by emotional distress and anxiety • Goals: provide anxiolysis, loss of consciousness, cooperation, amnesia and immobility • All nerve pathways are formed by 24 wk EGA, so babies do feel pain

3. Pain Measurement tools • Oucher Scale by Judy Beyer, modified by Wong • Pain physiologic responses – observational pain scales (OPS) • HR & BP • Measuring levels of adrenal stress hormones

4. Sedation Measurement tools • Michigan sedation scale for procedures • COMFORT scores: both behaviors & physiologic markers • Sedation-Agitation scale • Ramsey Sedation Score: 1-6 scores • Brussels sedation scale: 1-5 scores • Bis: bispectral Index 0-100 correlates to measure of cerebral electrical activity • 60- no recall in surgical patient • State behavioral scales

5. DEFINITIONS - Pharmaco-dynamics: relationship of concentration at the site & physiologic response - Pharmacokinetics: drug disposition in the body over time: routes, absorption, distribution & elimination

6. Definitions • Absorption: • “First pass effect” in oral meds • Distribution • Transportation & movement throughout the body • Altering factors: poor perfusion, change receptor binding via edema, malnutrition, uremic toxins, down regulation, change in plasma protein binding • Metabolism & Elimination • Physical and chemical alteration to detox parent molecules, change from fat soluble to water soluble to be eliminated by the kidneys • Most drugs metabolize in the liver using the cytochrome P450 system (CYP)

7. Phase I Drug Metabolites I Oxidation Hydroxylation Hydrolysis Reduction Glucuronidation Glycosilation Sulphation Methylation Acetylation Glutathione Amino Acid Fatty acids Phase II Phase II Metabolites II Phase III: metabolized by blood & tissue esterases

8. Sedation & Pain • Analgesia • Sedation & Anxiolytic • Neuromuscular blockade

9. Analgesia • Antipyretic & Non-opioids • Opioids • Methadone • Local anesthetic

10. AnalgesiaAntipyretic or non-opioids • Inhibit cyclo-oxygenase (COX) 1,2,3, blocking both periph & central prostaglandins production • Cox 1: synth. protective Prostaglandins to preserve gastric lining integrity & maintain normal renal fxn • Cox 2: inducible by pro-inflammatory cytokines & growth factors; present in the brain and spinal cord acting as nerve transmission particularly for pain & fever • Useful for inflammatory, bony and rheumatic pain

11. Analgesia-Antipyretic or non-oipoids • Aspirin: • Not use due to increase risk of Rye syndrome • Altered plt fxn; caused gastric irritant • Ketorolac • Serious risk of GI bleeding due to plt dysfxn • Trilisate • Choline magnesium trisalicylate: aspirin like compound • Do not bind to platelet • Use in post op pain & cancer patients • Paracetamone • No anti-inflammatory activity • Central Cox 3 • Naproxen • Cox 1 inhibitor

12. AnalgesiaOpioids • Terms • Agonist: bind receptor, trigger pharmacologic effect • Antagonist: bind receptor, silence • Partial agonist: bind receptor causing less than max response; acts as antagonist by blocking receptors from other agonists. • Receptors: µΚδσ • Inhibit synaptic transmission in CNS & myenteric plexus • Found in pre-synaptic, dec. release of excitatory neurotransmitter for norciceptice stim. • Coupling w/ G-protein, reg. transmembrane signaling by reg. cAMP

13. AnalgesiaOpiate receptors

14. AnalgesiaOpioids - Morphine • Sedation, analgesia, anxiolysis and euphoria: acting via peri-aquaductal gray matter, ventromedial medulla & spinal cord • Inc. sensory threshold for pain • Resp depression: dec. RR, MV and response to elevation of PCO2 • Pupillary constriction: central effect on oculomotor nucleus • Uncertain response of N&V: acting on chemotrigger zone + depress vomiting center • Dec. stress hormones: ACTH, ADH, prolactin, GH & epinephrine

15. AnalgesiaOpioids - Morphine • Smooth ms relaxation: acts both centrally via vagus n. & direct sm. ms. relaxation • Inc. biliary tract tone causing biliary colic • Urinary retention via inc. bladder detrusor ms. & vesical sphincter • Histamine release can cause CV collapse & bronchospasm • Met. via glucuronide to M3G (excreted) & M6G (active metabolites)

16. AnalgesiaOpioids - Fentanyl • Mainlyµ agonist, 100X more potent • Block syst. & pulm hemodynamic effect of pain • Prevents biochemical & endocrine stress (catabolic) • Lipophilic: rapid onset, short duration due to rapid redistribution • SE: • Glottic & chestwall rigidity w/rapid infusion (>5mcg/kg) • Bradycardia

17. AnalgesiaOpoids - Others • MEPERIDINE • More CNS excitatory effects: tremors, ms spasm, myoclonus, psychiatric changes & sz secondary to serotoninergic effect. • Metabolized to Normeperidine-twice as toxic • Local anesthetic properties – surgical spinal analgesia • Small dose (0.125-0.25mg/kg) for post op shivering • CODEIN • Equivalent of PO morphine • Preserve pupillary signs • Constipation • Can use for cough suppressant

18. AnalgesiaOpioids - Others • SUFENTANIL • 5-10X > Fentanyl, most potent opioid in clinical practice • Smaller volume of distribution, more rapid recovery after prolonged infusion • ALFENTANIL • 5X < Fentanyl, short duration of action 5-10 min • Useful in intubation with high ICP • REMIFENTANIL • Met. by plasma esterases w/short t1/2 remains constant at 8min, “context sensitive half-life” • Potent Mu with mild Kappa & Delta effects, potent resp. depression, no histamine release • Similar kinetics in neonates & adults • Very expensive

19. Commonly used Opioids

20. AnalgesiaOpioids - Others • HYDROMORPHONE • Hydrogenated ketone of morphine, 7X > morphine • Less histamine release • TRAMADOL • Binding to opiate receptors AND inhibiting NE & serotonin • Adjusting for renal & hepatic insufficiency, poorly removed by dialysis (7%) • Sz w/high dose, w/epilepsy, w/monoamine oxidase (MAO) inhibitors and neuroleptics (lower sz threshold) • Can cause withdrawal sx, slow wean

21. AnalgesiaOpiate Antagonists • Naloxone: most common use • T ½ 30-81 min • 1-10 mcg/kg • Nalmafene • Longer acting with T ½ 41 min

22. AnalgesiaMethadone • Slow elimination, long duration T ½ 19 hrs (80-90% principal metabolite is Morphine) • Can be used as analgesic • Use in weaning from Narc dependency, use concomitantly w/α2 agonist , clonidine • Morphone:methadone 1:0.25-0.1 • Incomplete cross tolerance, acts as antogonist onN-methyl-D-aspartate

23. AnalgesiaLocal Anesthetic • Differential nerve block: dilute concentration to block sensory/motor, maintain proprioceptor & light touch • Add vasoconstrictor (Epi) to dec. absorption of anest. • Bupivacaine toxicity can cause electrical asystole, refractory to treatment • Lidocaine: anti-arrhythmia, neuropathic pain by blocking conduction of Na channels in periph & central neurons

24. AnalgesiaEpidural • Bupivacaine & lidocaine • Additional analgesia w/addition of opioids & α2 agonist, watch for syst effect of opioids

25. Narcotic Withdrawal • Signs & symptoms • Neurologic excitability Sleep disturbances Agitation Tremors, Seizures Choreoartheroid mov’ts • GI disturbances Vomiting & diarrhea Autonomic dysfunction • Hypertension (>150mmHg) Tachycardia (>150> Tachypnea (>40) Fever (>38.5) Frequent yawning Sweating or goose flesh Mottling

26. Narcotic Withdrawal • Methadone: • Equipotent to Morphine, ¼ potent with fentanyl after prolonged infusion • 80-90% bio-availability compare to morphine • Long T ½ • No sign of respiratory depressant with good analgesic • rec: start IV methadone 48 hours prior, dec fentanyl inf by 50% in 2 consecutive days then d/c. If no sign of withdrawal, convert to PO

27. Narcotic Withdrawal • Clonidine • Effective in the management of nicotine, opiate, and alcohol withdrawal • Dec. sympathetic outflow + synergistic effect for analgesia both central and spinal • Patch applied 12 hours prior to extubate dec the need for opiate • Leave on for 7 days • Dose 6mcg/kg/day

28. Sedation • Sedatives interfere w/normal sleep architectures causing the inc. need for more sedation • Spectrum: wake, anxiolysis, moderate (conscious) sedation, deep sedation, coma

29. SedationBenzodiazepines • Augment GABA & glycin transmission: binding to receptors causing influx of Cl, hyper-polarization causing resistance to neuronal excitation • GABA: major inhibitory neurotransmitter in brain • Glycin: major inhibitory neurotransmitter in spinal cord & brain stem • Dec. CRMO2 and CBF • Impair anterograde amnesia, maintain retrograde • Affect vent. response to both hypoxia & hypercapnea • Dec. both preload & after-load, MAP with min effect on CO

30. SedationBenzodiazepines

31. SedationBenzodiazepines • Flumazenil: antagonist by competitively binding to the receptors; • Solvents (diazepam & lorazepam) w/propylene glycol & sodium benzoate can cause metabolic acidosis & toxicity to newborns

32. SedationBarbiturates • Can be anti-analgesic in small dose • All are potent AED except Methohexital, all cause hypnosis, sedation • Causing dec. CBF & cerebral metabolism • SE: myocardium depression, hypotension • Thiopental pH>10, can cause catastrophic damage if given intra arterially

33. SedationPropofol • 10% soybean oil, 2.25% glycerol, 1.2 % egg phosphatide • Bind to GABA a receptor, inhibit synaptic activity • Rapid clearance from vasculature system • Dose: load 3-5mg/kg, infusion 25-150 mcg/kg/min • Side effects • Pain on injection, pro bacterial growth, green urine • Negative inotrope, potent vasodilatation, bradycardia (dec. atrial conduction), Potent resp. depressant • Deplete trace element esp. zinc in prolonged infusion • Low dose: pro-convulsant “herky jerky” myotonic movement • “Propofol infusion synd”: refractory met. , lipemia, acidosis or rhabdomyolysis, enlarged liver (w/8mg/kg/hr for 70 hrs). • “Gasping synd”: benzyl alcohol becomes benzoic a. – fatal in neonates: Met. acid., resp. distress, gasping respiration, CNS dysfnx, hypotension & CV collapse

34. SedationKetamine • Structurally similar to PCP • NMDA antagonist: hallucination, amnesia & analgesia; • Inc. catechols release & cholinergic receptor stim. – bronchodilator, rhonchorhea, inc. SVR, HR & CO • Negative inotrope • Inc. CBF & CMRO2 • Metabolized to Norketamine to excrete in urine • Loading IV 0.5-1mg/kg; infusion 0.5-2mg/kg/hr

35. Sedation- Chloral Hydrate Alcohol dehydrogenase Trichloroethanol (TCE) Chloral Hydrate T ½ 8-12hr 45% protein bound 30-60 min peak Glucuronidation Trichloroacetate (TCA) • Side Effects: • CV: dec. myocardial contractility, • Shortened refractory period • Inc. sensitivity of heart to catechols • GI: gastristis, N&V • Overdose: severe hemorrhagic gastritic T ½ 67 hrs Inc. 3-4X in neonates Displace bili from albumin CNS depression

36. Sedationα-Adrenergic Agonists • Alpha2a- sedation, sleep, analgesia, sympatholysis • Alpha2b – vasoconstriction, anti-shivering, endogenous analgesia • 1- Clonidine: 200:1 • Large volume of distribution, long T ½ 12-24 hrs • Acts on receptors in the locus caerulues; Prevent pre-synaptic release of of NE in the sympathetic nervous systemanti-hypertensive • Acts on peripheral α2  vasoconstriction

37. Sedationα-Adrenergic Agonists • 2- Dexmetomidine • α2:α1 1600:1 • T ½ 1.5-3 hrs, ½ excreted unchanged in urine • Highly lipophilic, cross BBB • Loading 1mcg/kg/min, infusion 0.2-0.7 mcg/kg/hr • Reduced sympathetic activity, dropped BP & HR • Rapid infusion causes hypertension due to activation of α1 • Sedated yet easily aroused

38. BZD Withdrawal • Signs & Symptoms • Anxiety, insomnia, nightmares, seizures, psychosis, & hyper-reflexia • Post midazolam infusion phenomenon: poor social interactions, decreased eye contact, & dec. interest in the surrounding, choreoathetotic movement • Rec. to slow taper of 10% of dose daily with long acting like Diazepam

39. NMB • Large highly charged water-soluble molecules at physiologic pH can’t cross BBB, placenta, GI • Onset is more rapid & less intense at the laryngeal ms (vocal cord) & peripheral ms • Diaphragm is the most resistant to paralysis • Type: • Depolarizing: mimic action of Acetylcholine • Non-depolarizing: competitively block ACH receptors • Classifications • Short: Succinylcholine, mivacurium • Intermediate: Atracurium, Vecuronium, Rocuronium, Cisatracurium • Long: Pancuronium, Doxacurium, Pipecuronium

40. Degrees of Neuromuscular Blockade Furhman, 3rd Edition

41. NMBDepolarizing – Succinylcholine • Bind to ACH receptors non-competitively  depol.  ms fasciculation (not in children<4yrs) • Metab. by pseudo-cholinesterase, short duration due to high volume of distribution • Prolonged & repeat exposure memb can repol. but remains refractory to subsequent depol  “Phase II block”, clinical resemblance to non-depol. agents. • Prolonged effects in Hepatic dysfunction, hyper-magnesia & pregnancy

42. NMBDepolarizing – Succinylcholine • Stim all cholinergic autonomic & nicotinic receptors of both sympathetic & parasympathetic ganglia. Also muscarinic receptors of SA noded  negative inotropic and chronotropic • SE: • Dysrhythmias • Pulmonary edema & hemorrhage • Hyperkalemia (0.5 mEq/kg)in muscular dystrophy, spinal cord trauma, muscular disease, 3rd degree unhealed burns • Myoglobinemia • Masseter spasm, trismus • Trigger Malignant Hyperthermia

43. NMBNon-Depolarizing • Low plasma protein binding capacity • 4 routes of elimination: renal excretion, Hepatic excretion, biotransformation, tissue binding • Renal clearance does not exceed the GFR • Types • Short: Mivacurium • Intermediate: atracurium, Vecuronium, Rocuronium, cisatrocurium • Long: d-tubocurarine, pancuronium, pipecuronium, doxacurium

45. NMBReversal • Abx, hypotension, hypothermia, acidosis & hypocalcemia prolong or potentiate NMB • Duration of reversals are the same in all 3 classes • Neostigmine • 25-70 mcg/kg • Edrophonium • Faster acting • 125-250 mcg/kg