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SEDATION & NEUROMUSCULAR BLOCKADE. Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta. Objectives. Definition Signs & Symptoms Categories Shock physiology Treatments. Myths. Children don’t feel pain/anxiety; underestimation of pain

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Sedation neuromuscular blockade

SEDATION & NEUROMUSCULAR BLOCKADE

Pediatric Critical Care Medicine

Emory University

Children’s Healthcare of Atlanta


Objectives
Objectives

  • Definition

  • Signs & Symptoms

  • Categories

  • Shock physiology

  • Treatments


Myths
Myths

  • Children don’t feel pain/anxiety; underestimation of pain

  • Masking symptoms of progressing injury

  • Side effects: respiratory depression & cardiovascular compromise

  • Addiction


Truths pain
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


Truths pain1
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


Truths side effects
Truths – Side Effects

  • Respiratory & hemodynamic compromises

    • Potentiates with combination with other sedatives & analgesics

    • Understanding the pharmacokinetics and effects of these agents


Truths addiction
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


Sedation a continuum
Sedation – A Continuum

  • Analgesia

  • Minimal sedation

  • Moderate sedation

  • Deep sedation

  • General anesthesia


Sedation a continuum1
Sedation – A Continuum

  • Awake/ Drowsy/ Gen. Anest.

  • Baseline Anxiolysis

  • Moderate Deep

  • sedation sedation


Sedation measurement tools
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


Sedation measurement tools1
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


Sedative hypnotic
Sedative - Hypnotic

  • Sedation, motion control, and anxiolysis

  • NO analgesia

  • Classes

    • Benzodiazepines

    • Barbiturates

    • Chloral hydrate

    • Diprivan

    • α –adrenergic agonists


Sedation neurotransmitters
Sedation Neurotransmitters

  • GABA: inhibitory neurotransmitter in the brain

  • Glycin: inhibitory neurotransmitter in the spinal cord & brain stem

  • Glutamate: excitatory receptors


Sedation benzodiazepines
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


Sedation benzodiazepines1
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


Sedation benzodiazepines2
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


Sedation benzodiazepines3
Sedation - Benzodiazepines

  • Withdrawal syndrome

    • Anxiety, insomnia, nightmares, seizures, psychosis, hyper-reflexia

    • Post midazolam infusion phenomenon

    • Slow tapering to decrease withdrawal


Sedation benzodiazepines4
Sedation - Benzodiazepines


Bzd midazolam
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


Bzd lorazepam
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


Bzd diazepam
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


Sedation barbiburates
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


Sedation barbiburates1
Sedation - Barbiburates


Sedation chloral hydrate
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


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


Sedation diprivan
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


Sedation diprivan1
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”


Sedation adrenergic agonists
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


Sedation adrenergic agonists1
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


Sedation ketamine
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


Analgesia
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


Analgesia1
Analgesia

  • Anti-pyretic & non-opioid

  • Opiod

  • Methadone


Analgesia antipyretic or non opioid
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)


Analgesia antipyretic or non opioid1
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


Analgesia opioids
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


Analgesia morphine
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


Analgesia morphine1
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


Analgesia fentanyl
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)


Analgesia other fentanyls
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


Analgesia other opioids
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.


Analgesia other opioids1
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


Analgesia other opioids2
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


Analgesia opioid antagonist
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


Analgesia other
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


Analgesia withdrawal
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,


Neuromuscular blockade
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


Neuromuscular blockade1
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


Furhman, 3rd Edition


Nmb depolarizing
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


Nmb depolarizing1
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


Nmb depolarizing2
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


Nmb depolarizing3
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


Nmb non depolarizing
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


Nmb non depolarizing1
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


Nmb non depolarizing reversal
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


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