SEDATION & NEUROMUSCULAR BLOCKADE Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta Objectives • • • • • Definition Signs & Symptoms Categories Shock physiology Treatments.
Download ReportTranscript SEDATION & NEUROMUSCULAR BLOCKADE Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta Objectives • • • • • Definition Signs & Symptoms Categories Shock physiology Treatments.
SEDATION & NEUROMUSCULAR BLOCKADE Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta Objectives • • • • • 2 Definition Signs & Symptoms Categories Shock physiology Treatments Myths • Children don’t feel pain/anxiety; underestimation of pain • Masking symptoms of progressing injury • Side effects: respiratory depression & cardiovascular compromise • Addiction 3 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 4 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 5 Truths – Side Effects • Respiratory & hemodynamic compromises – Potentiates with combination with other sedatives & analgesics – Understanding the pharmacokinetics and effects of these agents 6 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 7 Sedation – A Continuum • • • • • 8 Analgesia Minimal sedation Moderate sedation Deep sedation General anesthesia Sedation – A Continuum Awake/ Baseline Drowsy/ Anxiolysis Moderate sedation 9 Gen. Anest. Deep sedation Sedation Measurement Tools • Modified Ramsey Score – – – – – – – 10 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 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 11 Sedative - Hypnotic • Sedation, motion control, and anxiolysis • NO analgesia • Classes – – – – – 12 Benzodiazepines Barbiturates Chloral hydrate Diprivan α –adrenergic agonists Sedation Neurotransmitters • GABA: inhibitory neurotransmitter in the brain • Glycin: inhibitory neurotransmitter in the spinal cord & brain stem • Glutamate: excitatory receptors 13 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 14 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 15 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 16 Sedation - Benzodiazepines • Withdrawal syndrome – Anxiety, insomnia, nightmares, seizures, psychosis, hyper-reflexia – Post midazolam infusion phenomenon – Slow tapering to decrease withdrawal 17 Sedation - Benzodiazepines T½ Hr Protein Binding Active metab. Metabolism Midazolam 1-4 94% alpha1hydroxymidazolam P450 Glucoronide conjugation Lorazepam 14.5 91% None Hepatic glucuronidation Diazepam 46.6 97.8% Desmethyl diazepam (t½ 48-96 hrs) Liver 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: 19 – 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 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 20 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 21 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: 22 – – – – Surgical anesthesia Delirium tremens Seizures Insomnia Sedation - Barbiburates Types Names T½ Long acting Phenobarbital 24-96 hrs Medium acting Pentobarbital Secobarbital 20-45 hrs Ultra short acting Thiopental Methohexital 4-24 hours 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 24 Sedation - Chloral Hydrate Alcohol dehydrogenase Chloral Hydrate Trichloroethanol (TCE) Glucuronidation Trichloroacetate (TCA) T ½ 67 hrs Inc. 3-4X in neonates Displace bili from albumin CNS depression T ½ 8-12hr 45% protein bound 30-60 min peak 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 26 Sedation - Diprivan • Adverse effects: – – – – – – 27 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” 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 – – – – 28 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 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 29 – – – – – – 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 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 30 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 31 Analgesia • Anti-pyretic & non-opioid • Opiod • Methadone 32 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) 33 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 34 – Cox 1 inhibitor 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 35 SUBTYPE PROTOTYPIC DRUGS ACTIONS Mu1 µ1 Opiates & most opiate peptides Supraspinal analgesia Prolactin release Acetylcholine turnover in brain Mu2 µ2 Morphine Respiratory depression; GI transit Dopamine turnover in brain Most CV effects Delta δ Enkephalins Spinal analgesia Dopamine turnover Kappa Κ Dynorphin Spinal analgesia; sedation Inhibition of ADH Sigma σ N-allynormetazocine Psychotomimetic effects 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 37 Analgesia – Morphine • • • • • • • • 38 • 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 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) 39 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 40 – 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 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. 41 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 42 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) – – – – 43 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 RELATIVE POTENCY T½ (Hr) ACTIVE METABOLITES MORPHINE 1 2.2 MORPHINE-6GLUCURONIDE MEPERIDINE 0.1 3.2 NORMEPERIDINE T1/2 15 HRS FENTANYL 100 4 NONE HYDROMORPHONE 7 SUFENTANIL 500 REMIFENTANIL N/A ALFENTANIL 10 1.2 NONE METHADONE 1 19 NONE NONE 2.7 NONE NONE 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 45 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 46 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, 47 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 48 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 49 % of Blockade Clinical Relaxation Ventilation None; TOF > 0.7 Tetanus sust. @ 50Hz Normal 25 Poor; inadequate head lift & leg flexion Slightly to moderate. Diminished VC 50 Fair Mod. to markedly diminished VC TV may be adequate 75 Good TV diminished 90 Good TV inadequate 95 Very good; adequate for tracheal intubation under light anesthesia Some diaphragmatic motion 100 Excellent; very good for tracheal intubation Apnea 0 Inspiratory force > 50cm H2O Furhman, 3rd Edition Metab./ excretion Succinylcholine Pseudocholinest. Onset (min) Duration (min) Dosage (mg/kg) 1 3-4 IV- 1-2 IM-3-4 Infusion Mivacurium Plasma Cholinester. 1-3 9-12 0.2 10-14 mcg/kg/min Atracurium Hoffmann 1-4 20-35 0.3-0.4 0.6-1.2 mg/kg/hr Cisatracurium Hoffmann 2-3 35-45 0.1-0.2 0.06-0.24 mg/kg/hr Vecuronium Liver Renal exc. 1-3 30-40 0.1 0.06-0.15 mg/kg/hr Rocuronium Liver Renal exc. 1 30-90 0.5-1 10-20 mcg/kg/min Pancuronium Liver Renal exc. 2-3 40-60 0.1 0.02-0.1 mg/kg/hr Pipecuronium Liver Renal exc. Doxacurium Renal 5-11 30 0.03-0.05 6-12 mcg/kg/hr 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 52 NMB: Depolarizing Succinylcholine Contraindications – – – – – – – 53 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 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 54 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 55 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 56 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 57 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 58