SEDATION

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SEDATION NEUROMUSCULAR BLOCKADE
Pediatric Critical Care Medicine Emory
University Childrens Healthcare of Atlanta
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Objectives

• Definition
• Signs Symptoms
• Categories
• Shock physiology
• Treatments

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Myths

• Children dont feel pain/anxiety underestimation
  of pain
• Masking symptoms of progressing injury
• Side effects respiratory depression
  cardiovascular compromise
• Addiction

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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

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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

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Truths Side Effects

• Respiratory hemodynamic compromises
• Potentiates with combination with other sedatives
  analgesics
• Understanding the pharmacokinetics and effects of
  these agents

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Truths - Addiction

• Definitions
• Addiction
• Tolerance
• Dependence
• Dependence
• 1/3 pts who received txgt4wks
• 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) 6986. doi10.1111/j.1600-0404.2008.01004
• Risk factors
• Dependent personality
• Short acting benzo
• Long-term use of benzo

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Sedation A Continuum

• Analgesia
• Minimal sedation
• Moderate sedation
• Deep sedation
• General anesthesia

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Sedation A Continuum

• Awake/ Drowsy/ Gen. Anest.
• Baseline Anxiolysis
• Moderate Deep
• sedation sedation

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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

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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,
  doesnt 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

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Sedative - Hypnotic

• Sedation, motion control, and anxiolysis
• NO analgesia
• Classes
• Benzodiazepines
• Barbiturates
• Chloral hydrate
• Diprivan
• a adrenergic agonists

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Sedation Neurotransmitters

• GABA inhibitory neurotransmitter in the brain
• Glycin inhibitory neurotransmitter in the spinal
  cord brain stem
• Glutamate excitatory receptors

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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

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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

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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

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Sedation - Benzodiazepines

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

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Sedation - Benzodiazepines
T ½ Hr Protein Binding Active metab. Metabolism
Midazolam 1-4 94 alpha1-hydroxymidazolam P450 Glucoronide conjugation
Lorazepam 14.5 91 None Hepatic glucuronidation
Diazepam 46.6 97.8 Desmethyl diazepam (t½ 48-96 hrs) Liver
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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

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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

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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

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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

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Sedation - Barbiburates
Types Names T ½
Long acting Phenobarbital 24-96 hrs
Medium acting Pentobarbital Secobarbital 20-45 hrs
Ultra short acting Thiopental Methohexital 4-24 hours
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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

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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
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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

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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

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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

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Sedation - a-adrenergic Agonists

• Clonidine a-2 a-1 2001
• 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 a-2 ? vasoconstriction
• Dexmetomidine a-2 a-1 16001
• 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 a-1

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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

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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

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Analgesia

• Anti-pyretic non-opioid
• Opiod
• Methadone

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Analgesia Antipyretic or Non-opioid

• Cyclo-oxygenase (COX) 1,2,3 inhibit
  prostaglandins production (peripheral central)
• Cox 1protective 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)

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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

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Analgesia - Opioids

• Terms
• Agonist
• Antagonist
• Partial agonist
• Receptors µ?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

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SUB-TYPE 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 d Enkephalins Spinal analgesia Dopamine turnover
Kappa ? Dynorphin Spinal analgesia sedation Inhibition of ADH
Sigma s N-allynormetazocine Psychotomimetic effects
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Analgesia Morphine

• µ2 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

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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

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Analgesia - Fentanyl

• 100X gtmorphine
• 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 (gt5mcg/kg)

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Analgesia Other Fentanyls

• Sufentanil
• 5-10x gt Fentanyl, most potent opioid in clinical
  practice
• Smaller volume of distribution, faster recovery
  after prolonged infusion
• Alfentanil
• 5x lt 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 d effects, potent
  respiratory depression, no histamine release
• Similar kinetics in neonates adults
• Very expensive

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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, Addisons disease.

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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

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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 gt
  morphine
• Water soluble with quick onset
• Lack of toxic metabolite, lower dependency, less
  nausea
• Brief but intense withdrawal

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RELATIVE POTENCY T½ (Hr) ACTIVE METABOLITES
MORPHINE 1 2.2 MORPHINE-6- GLUCURONIDE
MEPERIDINE 0.1 3.2 NORMEPERIDINE T1/2 15 HRS
FENTANYL 100 4 NONE
HYDROMORPHONE 7 NONE
SUFENTANIL 500 2.7 NONE
REMIFENTANIL N/A NONE
ALFENTANIL 10 1.2 NONE
METHADONE 1 19 NONE
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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

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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

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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,

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Neuromuscular Blockade

• Large highly charged water - soluble molecules at
  physiologic pH ?cant 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

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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

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of Blockade Clinical Relaxation Ventilation
0 None TOF gt 0.7 Tetanus sust. _at_ 50Hz Normal Inspiratory force gt 50cm H2O
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
Furhman, 3rd Edition
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Metab./ excretion Onset (min) Duration (min) Dosage (mg/kg) Infusion
Succinylcholine Pseudo-cholinest. 1 3-4 IV- 1-2 IM-3-4
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
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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

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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

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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

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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

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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

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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

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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