SEDATION & NEUROMUSCULAR BLOCKADE

1. SEDATION & NEUROMUSCULAR BLOCKADE Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta

2. Objectives • Definition • Signs & Symptoms • Categories • Shock physiology • Treatments

3. Myths • Children don’t feel pain/anxiety; underestimation of pain • Masking symptoms of progressing injury • Side effects: respiratory depression & cardiovascular compromise • Addiction

4. Truths - Pain • Pathophysiology of pain Tissue damage  release local mediators (bradykinin, substance P, prostoglandins, K+)  heighten nociception  facilitate the communication of painful sensations to the spinal cord & brain Tissue injury  release of histamine & serotonin  increase pain sensitivity in areas surrounding the site of initial injury

5. Truths - Pain • All nerve pathways for the conduction of painful stimuli & awareness of pain are functional by 24 wk EGA • Failure to manage painful stimuli increases perception of pain for future painful events • Lack of pain control increases the stress responses • Simons SH, van Dijk M. van Lingen RA et al: Randomized controlled trial evaluation effects of morphine on plasma adrenaline/noradrenaline concentration in newborns. Arch. Dis Child Fetal Neonatal Ed. 2005; 90: F36-F40

6. Truths – Side Effects • Respiratory & hemodynamic compromises • Potentiates with combination with other sedatives & analgesics • Understanding the pharmacokinetics and effects of these agents

7. Truths - Addiction • Definitions: • Addiction • Tolerance • Dependence • Dependence: • 1/3 pts who received tx>4wks • Continuous infusion: tolerance develops within days • Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (Aug 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics.". Acta Neurol Scand118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004 • Risk factors: • Dependent personality • Short acting benzo • Long-term use of benzo

8. Sedation – A Continuum • Analgesia • Minimal sedation • Moderate sedation • Deep sedation • General anesthesia

9. Sedation – A Continuum • Awake/ Drowsy/ Gen. Anest. • Baseline Anxiolysis • Moderate Deep • sedation sedation

10. Sedation Measurement Tools • Modified Ramsey Score • 0 – unresponsive • 1 – responsive to noxious stimuli • 2 – responsive to touch or name • 3 – calm & cooperative • 4 – restless & cooperative • 5 – agitated • 6 – dangerously agitated & uncooperative

11. Sedation Measurement Tools • Bispectral Index (Bis) • Measure level of consciousness by algorithmic analysis of EEG • Scale 0 (silent EEG) to 100 (fully awake) • Good tools to use for deep sedation/anesthesia, doesn’t differentiate level of consciousness for moderate to deep sedation • Mason KP et all: Value of bispectral index monitor in defferentiating between moderate and deep Ramsay Sedation Scores in children. Paediatr Anaesth. 2006 Dec; 16 (12):1226-31

12. Sedative - Hypnotic • Sedation, motion control, and anxiolysis • NO analgesia • Classes • Benzodiazepines • Barbiturates • Chloral hydrate • Diprivan • α –adrenergic agonists

13. Sedation Neurotransmitters • GABA: inhibitory neurotransmitter in the brain • Glycin: inhibitory neurotransmitter in the spinal cord & brain stem • Glutamate: excitatory receptors

14. Sedation - Benzodiazepines • Augment GABA & glycin transmission  binding to receptors  influx Cl-  hyper-polarization  resistance to neuronal excitation • BZD bind to receptor complex  enhance GABA binding to its receptors  increase in GABA efficiency • BZD increase the frequency of Cl- channel opening  increase GABA potency

15. Sedation - Benzodiazepines • Effects: anxiolytic, amnestic, anti-convulsant, hypnotic, sedative, skeletal muscle relaxant • Decrease CMRO2 & CBF • Impair anterograde amnesia, • Affect ventilatory response to both hypoxia & hypercapnea • Potentiate effect with alcohol & narcotics • Decrease both pre & after-load  decrease MAP with min effect on CO

16. Sedation - Benzodiazepines • Tolerance involves GABAA receptor • Down regulation • Alterations to the subunit configuration • Uncoupling & internalizing of the BZD binding site • Change in gene expression • Others • Paradoxical reaction – disinbition usually in children or older adults with h/o alcohol abuse or ones with underlying aggressive behavior • Rebound insomnia & anxiety after only 7 days • Long lasting memory deficit with long term use • Worsening of depression

17. Sedation - Benzodiazepines • Withdrawal syndrome • Anxiety, insomnia, nightmares, seizures, psychosis, hyper-reflexia • Post midazolam infusion phenomenon • Slow tapering to decrease withdrawal

18. Sedation - Benzodiazepines

19. BZD - Midazolam • Most commonly used sedative • Water soluble (less thrombophlebitis)  less pain with injection • IV, IM, PO, IN, PR, Buccal • Metabolized by P450 (CYP) enzymes & by glucuronide conjugation • Side effects: • Post midazolam infusion phenomenon • A “midazolam infusion syndrome”: delayed arousal hrs to days after discontinuation, associated with high dose infusion • “Hang over”: psychomotor & cognitive function impairment to the next day

20. BZD - Lorazepam • Highly protein bound, extensively metabolized into inactive forms • Lipophobic  confine in the vascular space • IV, IM, PO, SL • Solvent: polyethylene & propylene glycol hyperosmolar metabolic acidosis with prolonged infusion • Injectable solution contains benzyl alcohol • Uses: • Status epilepticus • Alcohol withdrawal syndrome, catatonia • Anti-emetic

21. BZD - Diazepam • IV, IM, PO (100% bio-availability), PR (90%) • Highly protein bound, cross BBB & placenta, excrete in stools • Lipophilic  evenly distributed  accumulative effect with repeat doses • High risk of thrombophlebitis, pain with injection • P450 + glucuronidation in liver long t ½ metabolite • Uses: anxiety, insomia, seizure, muscle spasm, restless leg syndrome, alcohol and BZD withdrawal

22. Sedation - Barbiburates • GABAA receptor (different from BZD)  increases duration of Cl- channel opening  increases GAGA efficacy • Block AMPA receptor (glutamate subtype) • Decrease CMRO2 & CBF • Side effects: myocardial depression, hypotension • Effects: CNS depressants (mild sedation  anesthesia); anxiolytic, hypnotic, anti-convulsants (except Methohexital) • Uses: • Surgical anesthesia • Delirium tremens • Seizures • Insomnia

23. Sedation - Barbiburates

24. Sedation - Chloral Hydrate • Sedative & hypnotic: short term use for insomnia • Enhance GABA receptor complex • Tolerance with long term use • Overdose: N/V, convulsion, confusion, irregular breathing, arrhythmias, coma • SV, junctional or ventricular arrhythmias including torsades de pointes • Side effects: rash, gastric discomfort, myocardial depression, hepatic failure • Hyperbilirubinemia: displace bilirubin from albumin sites

25. Sedation - Chloral Hydrate Alcohol dehydrogenase Chloral Hydrate Trichloroethanol (TCE) T ½ 8-12hr 45% protein bound 30-60 min peak Glucuronidation Trichloroacetate (TCA) T ½ 67 hrs Inc. 3-4X in neonates Displace bili from albumin CNS depression

26. Sedation - Diprivan • 10% soybean oil, 2.25% glycerol, 1.2% egg phosphatide • Protein bound; metabolized by conjugation in liver + extra hepatic elimination • Potentiate GABAA receptor activity  slow the closing of the Cl-channels • Rapid distribution to peripheral tissue  ultra short effects • T ½ 2-24 hrs

27. Sedation - Diprivan • Adverse effects: • Pain with injection, pro-bacterial growth, produce green urine • Negative inotrope, potent vasodilitation, bradycardia • Potent respiratory depressant • Deplete trace element (Zinc) in prolonged infusion • “Propofol infusion syndrome” • “Gasping syndrome”

28. Sedation - α-adrenergic Agonists • α-1 agonist: stimulates phospholipase C activity • Vasoconstriction, mydriasis • Use a vasopressrs, nasal decongestants, eye exam • α-2 agonist: inhibits adenylyl cyclase activity • Reduce brainstem vasomotor center-mediated CNS activation • Use: anti-hypertensive, sedative, opiate & alcohol withdraw • α-2a: sedation, sleep, analgesia, sympatholysis • α-2b: vasoconstriction, anti-shivering, endogenous analgesia

29. Sedation - α-adrenergic Agonists • Clonidine: α-2: α-1 = 200:1 • Large volume of distribution, long T½ 12-24 hrs • Acts on receptors in the locus coeruleus (stress & panic) • Prevent pre-synaptic release of NE in the sympathetic nervous system  anti-hypertensive • Acts on peripheral α-2  vasoconstriction • Dexmetomidine: α-2: α-1 = 1600:1 • T½ 1.5-3 hrs, ½ excrete unchanged in urine • Min respiratory depression, sedated yet easily aroused • Highly lipophilic, cross BBB • Effective in CV symptoms for cocaine intoxication • Reduce sympathetic activity  decrease HR & BP • Rapid infusion  hypertension due to activation of α-1

30. Sedation - Ketamine • Dissociate anesthesia (similar in structure of PCP)  hallucigenic, analgesic, amnestic • NMDA (glutamate) antagonist  analgesic; • Binds to opioid receptors (μ & sigma) in high dose • Increases catecholamines release & cholinergic receptor stimulation  bronchodilator, mucous production, increase SVR, HR, CO • Increasse CBF & CRMO2 • Metabolized to Norketamine to excrete in urine

31. Analgesia • Oucher Scale by Judy Beyer, modified by Wong: self report with faces & numerical pain scale • Pain physiological responses – observational pain scale (OPS) • HR & BP • Measuring level of adrenal stress hormone • COMFORT score: • Behaviors: alertness, facial tension, muscle tone, agitation, movement • Physiologic responses: HR, respiration, BP

32. Analgesia • Anti-pyretic & non-opioid • Opiod • Methadone

33. Analgesia – Antipyretic or Non-opioid • Cyclo-oxygenase (COX) 1,2,3: inhibit prostaglandins production (peripheral & central) • Cox 1:protective prostaglandins  preserve gastric lining integrity; maintain normal renal function • Cox 2: inducible by pro-inflammatory cytokines & growth factors; in both brain & spinal cord: nerve transmission for pain & fever • Useful for inflammatory processes (bony or rheumatic)

34. Analgesia – Antipyretic or Non-opioid • Aspirin: • Alter platelet function; can cause gastric irritant • Ketorolac • Platelet dysfuncion  serious risk of GI bleeding • Trilisate (choline magnesium trisalicylate; ASA like compound) • No SE on platelet • Use in post-op pain or cancer patients • Paracetamone • Central Cox 3, no anti-inflammatory activity • Naproxen • Cox 1 inhibitor

35. Analgesia - Opioids • Terms: • Agonist • Antagonist • Partial agonist • Receptors: µΚδσ • Inhibit synaptic transmission in CNS and myenteric plexus • Found in pre-synaptic, decrease release of excitatory neurotransmitter for nociceptive stimuli • Coupling with G-protein, regulate trans-membrane signaling by regulate cAMP

37. Analgesia – Morphine • µ2 agonist: analgesia, sedation, euphoria, resp. depression • K and δ agonist: spinal analgesia, miosis, psychomimetic effects • Glucuronide metabolism  M3G (exrete) & M6G (active metabolites) • Poor lipid solubility, protein binding • SQ, IV, IT, epidural

38. Analgesia – Morphine • Increase in sensory threshold for pain • Respiratory depression: decrease RR, MV & response to CO2 • Miosis: pupillary constriction via oculomotor nucleus • Decrease stress hormones: ACTH, ADH, prolactin, GH & epi • Uncertain response to N/V: act on chemo-trigger zone + depress vomiting center • Smooth muscle relaxation: directly or via vagus nerve • Increase biliary tract tone  biliary colic • Urinary retention via increase tone in bladder detrusor muscle or vesical sphincter • Histamine release  bronchospasm or CV collapse

39. Analgesia - Fentanyl • 100X >morphine • Strong agonist at the µ and K • Lipophilic: cross BBB  rapid onset with short duration 2/2 rapid redistribution • Block systemic & pulmonary hemodynamic effect of pain • Prevent biochemical & endocrine stress (catabolic) • Adverse effects: N/V, constipation, dry mouth, somnolence, confusion, anesthesia (weakness), sweating Severe AE: glottic & chest wall rigidity with rapid infusion (>5mcg/kg)

40. Analgesia – Other Fentanyls • Sufentanil • 5-10x > Fentanyl, most potent opioid in clinical practice • Smaller volume of distribution, faster recovery after prolonged infusion • Alfentanil • 5x < Fentanyl, short duration 5-10 min • Useful for RSI with ICP • Remifentanil • Metabolized by plasma esterase with short t ½ • Potent µ with mild K & δ effects, potent respiratory depression, no histamine release • Similar kinetics in neonates & adults • Very expensive

41. Analgesia – Other Opioids • Meperidine • K receptor agonist; strong opioidergic, anticholinergic and antispasmodic; Local anesthetic properties – surgical spinal analgesia • Superior to Morphine for billiary spasm or renal colic • Metabolized to normeperidine - twice as toxic • “Serotonin syndrome” with CNS excitatory effects: tremors, ms spasm, myoclonus, psychiatric changes & seizure • Interact with MAOIs  agitation, delirium, headache, convulsions, hyperthermia (Libby Zion Law) • Contraindicated in liver, kidney disease, seizure disorder, enlarged prostate or urinary retention, hypothyroidism, asthma, Addison’s disease.

42. Analgesia – Other Opioids • Codein • Methylmorphine: analgesic, anti-tussive, anti-diarrheal • Alkaloid found in opium poppy (papaveraceae) • Convert to morphine in the liver by P450 and to active metabolites • Prolonged use  physical dependence & psychologically addictive; mild withdrawal symptoms • Preserve pupillary signs

43. Analgesia – Other Opioids • Tramadol (Ultram, Tramal) • Weak µ agonist, release serotonin, inhibits reuptake of norepinephrine • Therapy for most neuralgia and chronic pain • Hard to wean due to effects on opioid, serotonin/NE activity • Decrease seizure threshold • Hydromorphone (Dilaudid) • Centrally acting opioid class on µ receptor, 8x > morphine • Water soluble with quick onset • Lack of toxic metabolite, lower dependency, less nausea • Brief but intense withdrawal

45. Analgesia – Opioid Antagonist • Naloxone • Competitive antagonist with high affinity for µ receptor in CNS  rapid onset of withdrawal • IV with fast onset of action; T½ 30-81 min

46. Analgesia – Other • Methadone • Acts on opioid receptors without the euphoric effects  prevent narcotic withdrawal syndrome • Binds on NMDA (N-methyl-D-aspartate) antagonist against glutamate  decrease craving for opioids & tolerance

47. Analgesia – Withdrawal • Neurologic excitability: Sleep disturbances, agitation, tremors, seizures, choreoartheroid movements • GI disturbances: V/D • Autonomic dysfunction: hypertension, tachycardia, tachypnea, fever, frequent yawning, sweating or goose flesh,

48. Neuromuscular Blockade • Large highly charged water - soluble molecules at physiologic pH can’t cross BBB, placenta, GI • Onset is more rapid & less intense at the laryngeal muscle (vocal cord) & peripheral muscle • Diaphragm is the most resistant to paralysis

49. Neuromuscular Blockade • Types • Depolarizing: mimic action of acetylcholine • Non-depolarizing: competitively block ACH receptors • Classifications • Short: succinylcholine, mivacurium • Intermediate: atracurium, vecuronium, rocuronium, cisatracurium • Long: pancuronium, doxacurium, pipecuronium

50. Furhman, 3rd Edition