SEDATION NEUROMUSCULAR BLOCKADE

1. SEDATION & NEUROMUSCULAR BLOCKADE  Author: Nga Pham, MDAuthor: Nga Pham, MD

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

3. 3 Myths Children don�t feel pain/anxiety; underestimation of pain Masking symptoms of progressing injury Side effects: respiratory depression & cardiovascular compromise Addiction - Children�s inability to qualify or quantify pain- Children�s inability to qualify or quantify pain

4. 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. 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. 6 Truths � Side Effects Respiratory & hemodynamic compromises Potentiates with combination with other sedatives & analgesics Understanding the pharmacokinetics and effects of these agents

7. 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 Scand 118 (2): 69�86. doi:10.1111/j.1600-0404.2008.01004 Risk factors: Dependent personality Short acting benzo Long-term use of benzo Addiction: �need� or craving along with physical finding of withdrawing Tolerance: decrease effect with same dose (esp. with long term infusion) Dependence: physical sx of withdrawal with removal of the medicationAddiction: �need� or craving along with physical finding of withdrawing Tolerance: decrease effect with same dose (esp. with long term infusion) Dependence: physical sx of withdrawal with removal of the medication

8. 8 Sedation � A Continuum Analgesia Minimal sedation Moderate sedation Deep sedation General anesthesia analgesia: relief of pain without intentionally producing a sedated states. AMS as secondary SE Minimal sedation: responds normally to verbal commands. Impaired cognitive and coordination, no vent or CV effects Moderate: responds purposefully to verbal commands either alone or with light touch. Maintains airway and adequate ventilation, same as CV Deep sedation: cannot be easily aroused but responds purposefully to noxious stimulation. May need assistance for airway or ventilation. CV usually normal General anesthesia: Cannot be aroused. Requires assistance to maintain airway & pos press ventilation. CV may be impairedanalgesia: relief of pain without intentionally producing a sedated states. AMS as secondary SE Minimal sedation: responds normally to verbal commands. Impaired cognitive and coordination, no vent or CV effects Moderate: responds purposefully to verbal commands either alone or with light touch. Maintains airway and adequate ventilation, same as CV Deep sedation: cannot be easily aroused but responds purposefully to noxious stimulation. May need assistance for airway or ventilation. CV usually normal General anesthesia: Cannot be aroused. Requires assistance to maintain airway & pos press ventilation. CV may be impaired

9. 9 Sedation � A Continuum

10. 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 Many sedation scores, mostly relying on observation/behavioral scores CHOA uses modified Ramsey Score: desired level is 0-3Many sedation scores, mostly relying on observation/behavioral scores CHOA uses modified Ramsey Score: desired level is 0-3

11. 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. 12 Sedative - Hypnotic Sedation, motion control, and anxiolysis NO analgesia Classes Benzodiazepines Barbiturates Chloral hydrate Diprivan a �adrenergic agonists

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

14. 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. 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 CMRO2: cerebral metabolism rate CBF: cerebral blood flow CMRO2: cerebral metabolism rate CBF: cerebral blood flow

16. 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 Long lasting memory deficit with only partial recovery after 6 months of stoppingLong lasting memory deficit with only partial recovery after 6 months of stopping

17. 17 Sedation - Benzodiazepines Withdrawal syndrome Anxiety, insomnia, nightmares, seizures, psychosis, hyper-reflexia Post midazolam infusion phenomenon Slow tapering to decrease withdrawal Post midazolam infusion phenomenon: poor social interactions, decreased eye contact, decrease interest in the surrounding, choreoathetotic movement Taper; 10% daily dose with long acting BZD (Diazepam)Post midazolam infusion phenomenon: poor social interactions, decreased eye contact, decrease interest in the surrounding, choreoathetotic movement Taper; 10% daily dose with long acting BZD (Diazepam)

18. Sedation - Benzodiazepines

19. 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. 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 Superior to diazepam in status Anti-emetic: in chemo or cyclic vomiting syndrome Superior to diazepam in status Anti-emetic: in chemo or cyclic vomiting syndrome

21. 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 � metabolite Uses: anxiety, insomia, seizure, muscle spasm, restless leg syndrome, alcohol and BZD withdrawal Metabolites: desmethyldiazepam Metabolites: desmethyldiazepam

22. 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. 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 Arrhythmias: alteration of the automaticity of the pacemaker cells by the metabolites and sensitization to catecholamines. Treatments: lidocaine, phenytoi, and beta blockersArrhythmias: alteration of the automaticity of the pacemaker cells by the metabolites and sensitization to catecholamines. Treatments: lidocaine, phenytoi, and beta blockers

26. 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 � 2-24 hrs

27. 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� Propofol infusion syndrome: refractory metabolic acidosis, lipemia, rhabdomyolysis, enlarged liver; associated with 8mg/kg/hr x 70 hrs, can occur with lower rate or shorter time �Gasping syndrome�: benzyl alcohol ? severe metabolic acidosis, respiratory distress, gasping respiration, CNS dysfunction, hypotenstion & CV collapsePropofol infusion syndrome: refractory metabolic acidosis, lipemia, rhabdomyolysis, enlarged liver; associated with 8mg/kg/hr x 70 hrs, can occur with lower rate or shorter time �Gasping syndrome�: benzyl alcohol ? severe metabolic acidosis, respiratory distress, gasping respiration, CNS dysfunction, hypotenstion & CV collapse

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

29. 29 Sedation - a-adrenergic Agonists Clonidine: a-2: a-1 = 200:1 Large volume of distribution, long T� 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 a-2 ? vasoconstriction Dexmetomidine: a-2: a-1 = 1600:1 T� 1.5-3 hrs, � 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 a-1

30. 30 Sedation - Ketamine Dissociate anesthesia (similar in structure of PCP) ? hallucigenic, analgesic, amnestic NMDA (glutamate) antagonist ? analgesic; Binds to opioid receptors (� & 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. 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. 32 Analgesia Anti-pyretic & non-opioid Opiod Methadone

33. 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. 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. 35 Analgesia - Opioids Terms: Agonist Antagonist Partial agonist Receptors: �?ds 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. 37 Analgesia � Morphine �2 agonist: analgesia, sedation, euphoria, resp. depression K and d agonist: spinal analgesia, miosis, psychomimetic effects Glucuronide metabolism ? M3G (exrete) & M6G (active metabolites) Poor lipid solubility, protein binding SQ, IV, IT, epidural �2 receptors are discretely distributed in human brain.�2 receptors are discretely distributed in human brain.

38. 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. 39 Analgesia - Fentanyl 100X >morphine Strong agonist at the � 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. 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 � Potent � with mild K & d effects, potent respiratory depression, no histamine release Similar kinetics in neonates & adults Very expensive

41. 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. 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. 43 Analgesia � Other Opioids Tramadol (Ultram, Tramal) Weak � 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 � receptor, 8x > morphine Water soluble with quick onset Lack of toxic metabolite, lower dependency, less nausea Brief but intense withdrawal

45. 45 Analgesia � Opioid Antagonist Naloxone Competitive antagonist with high affinity for � receptor in CNS ? rapid onset of withdrawal IV with fast onset of action; T� 30-81 min

46. 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. 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. 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. 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

52. 52 NMB: Depolarizing Succinylcholine Stimulates all cholinergic receptors Binds directly to the postsynaptic ACH receptors Metabolized by pseudocholinesterase Also binds to muscarinic receptors of SA node ? negative inotrope and chronotrope Short duration due to high volume of distribution Prolonged & repeat exposure ?membrane can repolarize but remain refractory to subsequent depolarization ? �Phase II block�, clinical resemblance to non-depolarizing agents. Prolonged effects in hepatic dysfunction, hyper-magnesia & pregnancy Both sympathetic and parasympathetic - continuous stimulation of these receptors ? transient fasciculation followed by muscular paralysisBoth sympathetic and parasympathetic - continuous stimulation of these receptors ? transient fasciculation followed by muscular paralysis

53. 53 NMB: Depolarizing Succinylcholine Contraindications History of malignant hyperthermia (personal or family) Neuromuscular disease involving denervation Muscular dystrophy Stroke over 72 hours old Rhabdomyolysis Burn over 72 hours old Significant hyperkalemia

54. 54 NMB: Depolarizing Succinylcholine Malignant hyperthermia: Myopathic metabolic disorder Autosomal dominant Sympathetic hyperactivity, mucular rigidity acidosis and hyperthermia Uncontrolled increase in skeletal muscle oxidative metabolism ? hypoxia, hypercapnea and hyperthermia Treatment: dantrolene, cooling and sedation

55. 55 NMB: Depolarizing Succinylcholine Side effects Trismus: masseter muscle spasm (can associate with MH) Fasciculations: via nicotinic activation Bradycardia: via muscarinic activation at SA node especially children; can occur in adults in repeated dose or infusion Rhabdomyolysis and muscle pain Transient ocular hypertension: safe in open globe injury if use in conjunction with sedation Mild increase in intra cranial pressure

56. 56 NMB: Non-Depolarizing Competitively inhibits the postsynaptic Ach receptors of the neuromuscular motor endplate Prevents depolarization & inhibits all muscle function Categories Benzylisoqyinolinium: atracurium, mivacurium Histamine release Can cause autonomic ganglionic blockade Aminosteroids: rocuronium, vecuronium, pancuronium

57. 57 NMB: Non-Depolarizing Low plasma protein binding capacity 4 routes of elimination: renal excretion, hepatic excretion, biotransformation, tissue binding Types Short: Mivacurium Intermediate: atracurium, Vecuronium, Rocuronium, cisatrocurium Long: d-tubocurarine, pancuronium, pipecuronium, doxacurium

58. 58 NMB: Non-Depolarizing reversal 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