Pediatric Pharmacology Update: Perioperative Medications in Infants and Children

 
Pharmacology
for Infants &
Children
 
Martina Downard, MD
Wake Forest Baptist Health,
Brenner Children’s Hospital
 
Updated 7/2019
 
Learning Objectives
 
1.
Increase understanding of
frequently used medications in the
perioperative period in infants and
children
2.
Review mechanisms, effects and
doses of commonly used anesthesia
medications in children
 
Disclosures
 
No relevant financial relationships
 
Outline
 
1.
Pharmacokinetics and pharmacodynamics
2.
Inhalation anesthetic agents
3.
IV anesthetics
4.
Neuromuscular blocking drugs and antagonists
5.
Opioids
6.
NSAIDs & acetaminophen
7.
Sedatives: benzodiazepines, dexmedetomidine and
chloral hydrate
8.
Opioid & benzodiazepine antagonists
 
Pharmacokinetics & Pharmacodynamics
 
Pharmacokinetics
: 
How the 
patient/body affects
 the drug
or how 
drug concentrations in the body change over time
-
Altered by immature kidney or liver function
-
Altered by protein binding
-
Altered by body composition (fat/muscle/total body
fluid/ volume of distribution)
 
Pharmacodynamics
: How the 
drug affects
 the
patient/body
 
Drug distribution in neonates
 
Remember:
Acidic
 
drugs bind mostly to 
albumin
, 
e.g
diazepam or 
barbiturates
Basic
 drugs bind to globulins, lipoproteins, and
plasma alpha-1-acid glycoproteins, 
e.g.
lidocaine or alfentanil
 
Drug distribution in neonates
 
Neonates have 
reduced total protein & albumin
levels – 
result
: 
increase
 levels & effect from
“unbound” medications
Neonates have 
reduced clearance 
of drugs from
decreased renal/hepatic clearance – 
result
: 
increase
medication levels
Neonates have 
increased volume of distribution 
of
drugs (increase in total body water) – 
result
: 
decrease
medication levels
 
Drug distribution
 
Medications can compete
 with bilirubin to 
bind
to albumin
, causing hyperbilirubinemia or
kernicterus in neonates
Ex. phenytoin, salicylate, caffeine, ceftriaxone,
Hypaque (diatrizoate)
Changes in tissue binding 
with maturation
Ex. digoxin, opioids
 
Body composition
 
Preterm & term infants have larger % body water
than older children
-
Result - overall, 
increased loading dose
-
larger 
distribution volumes for 
water-soluble
 drugs &
smaller
 for 
lipophilic
 drugs
Preterm and term infants have less muscle & fat
-
Less area for redistribution = 
prolonged peak blood
concentrations
-
Example: opioids with prolonged sedation/respiratory
depression
 
Absorption
 
Slower enteral absorption until 8 months old
Larger skin surface area to body size
 = increased
skin absorption
-
EMLA
 more likely to cause
methemoglobinemia
 (prilocaine)
-
Iodine
 antiseptics likely to cause
hypothyroidism
 
Metabolism
 
Reduced function & blood flow to liver in infants
Drugs dependent on 
liver
 glucuronidation:
-
Morphine, acetaminophen, dexmedetomidine,
lorazepam
-
Clearance reaches 
adult levels ~ 5 - 6 months 
of age
Extrahepatic
-
Nonspecific esterases
 in tissues & erythrocytes are
mature at birth
-
No change in remifentanil and succinylcholine clearance
 
Renal Excretion
 
Glomerular filtration & tubular function fully 
mature by 12 to
24 months of age
Aminoglycoside & cephalosporin antibiotics have
prolonged duration of action in neonates
 
Pharmacokinetics & Pharmacodynamics
 SUMMARY
 
Decreased circulating protein levels,
metabolism and
 excretion – 
suggest
decreasing
 drug dose
Increased volume of distribution & total
body water – 
suggest 
increasing
 drug
dose
REALITY
dosing of 
medications in
neonates & children requires 
careful
titration
 
Inhalation agents - MAC
 
MAC
 = minimum alveolar anesthetic
concentration at which 50% patients
don’t move to noxious stimuli.
 
Why is MAC altered in children?
1.
Change in cerebral blood flow?
2.
GABA receptors?
3.
Regulation of chloride
transporters?
 
** Except Sevoflurane! Peak
MAC as full term neonate
.
 
Inhalation agents
 
Wash-in 
= ratio of alveolar to inspired anesthetic partial pressure (
FA/FI)
Faster Wash-In in neonates 
than in adults:
Greater 
alveolar ventilation (VA) to functional residual capacity
(FRC) 
in neonates (5:1) than in adults (1.5:1)
Greater percent of 
cardiac output
 distributed to vessel-rich
groups (brain, heart, kidney, organs) in neonates
Neonates have ½ the 
tissue/blood solubility 
of adults
Reduced 
blood/gas solubility 
in neonates
 
Inhalation agents
 
Second gas effect
-
When two anesthetics given simultaneously, small
concentration of 1 may increase the uptake of the 2
nd
anesthetic.  E.g. nitrous oxide & sevoflurane/isoflurane
-
Weak effect, if at all
Speed of induction
 determined by:
-
Solubility of agent – less soluble = faster induction
-
Rate of increase of inspired concentration
-
Max inspired concentration
-
Respirations
 
Inhalation agents
 
Cardiovascular effects: Volatile agents decrease
the calcium influx by inhibiting sodium-calcium
pumps
Neonates more commonly have 
bradycardia & hypotension
 with
increasing volatile % compared to adults
Immature sarcoplasmic reticulum
 in cardiac cells leading to poor
calcium retention and release
Increased sensitivity/dependence on calcium
 for contractility
Fewer & 
less organized 
contractile elements
 
Inhalation agents
 
Side effects by volatile agent:
Halothane
 – depression of sinoatrial
node, slowing myocardial conduction,
predispose to ventricular arrhythmias by
sensitizing heart to adrenaline
Isoflurane
 & 
Sevoflurane
 – decrease SVR
to decrease BP, blunt baroreceptor
responses, no effect on arrhythmias
 
IV Anesthetic agents
 
Propofol
Contains: soybean oil,
 egg lecithin (yolk), 
glycerol, EDTA
Pediatric IV induction dose: 3-4 mg/kg
Pediatric maintenance infusion rate: 200-250 mcg/kg/min
Highly lipophilic, pain on injection (“warmth” or “sunshine on your
arm”)
Rapid re-distribution, hepatic and extrahepatic clearance (lung,
kidney)
Associated with less emergence delirium than inhalational agents
Associated with a decreased incidence of nausea and vomiting
 
IV Anesthetic agents
 
Methohexital (brevital)
Short-acting barbiturate
IV induction dose: 1-2 mg/kg
Side effects:
-
Pain on injection
-
Hiccups
-
Seizure-like
 
activity
Can also be given rectally as a premedication
 
IV Anesthetic agents
 
Thiopental
Binds GABA
A
 receptors to prolong chloride
channel opening
IV induction 3-4 mg/kg
Myocardial depressant & weak vasodilator
 
IV anesthetic agents: Ketamine
 
Ketamine: NMDA receptor Antagonist
Effects:
-
Analgesic & amnestic
, dissociative amnesia
-
Increased HR & BP, little effect on pulmonary artery pressure
-
Direct cardiac depressant
-
Bronchodilator
May precipitate seizures in susceptible children
Side effects: 
nystagmus
, increased secretions, 30% increase intraocular
pressure, 
increased intracranial pressure
 (cerebral vasodilation) &
CMRO
2
1 - 3 mg/kg IV, 5-10 mg/kg intramuscular
-
Doses typically larger in children due to greater clearance than adults
-
IM dose useful for combative larger children
 
IV anesthetic agents
 
Etomidate: steroid based hypnotic induction agent
0.2 - 0.3 mg/kg IV, typically 
30% increase dose in children
due to increased volume of distribution
Effects:
-
No effect on hemodynamics
-
Great for head injury or unstable CV status!
Side effects:
-
Adrenal suppression
-
Pain on injection
-
Emesis
 
Neuromuscular blocking agents
 
Neonates 
have 
increased sensitivity
-
Neuromuscular transmission 
immature until 2 months old
-
Reduction in acetylcholine released
-
Reduced muscle mass
-
Reduced clearance
Neonate 
diaphragm function
 may be more preserved
-
Type 1 (slow twitch) diaphragm muscle fibers most sensitive to NMBDs
-
Preterm neonate has only ~10% type 1 fibers
-
Therefore, 
diaphragm function may recover earlier than peripheral
muscles
Infants
 require 
larger dose
 than adults
-
Larger volume of distribution due to greater total body water &
extracellular fluid
Neonates
 - 
faster onset
 due to greater cardiac output
 
Neuromuscular blocking drugs
 
Succinylcholine: depolarizing muscle relaxant
Infants more resistant
 than adults
-
Rapid redistribution in extracellular fluid volume
-
Dose: infants ~ 3mg/kg IV/ 5mg/kg IV; children ~1.5 mg/kg IV/
4mg/kg IM
Possible side effects:
-
Increased masseter muscle tone
 when given with halothane -
masseter spasm potential sign of malignant hyperthermia
-
Arrhythmia - 
bradycardi
a due to choline metabolites; more likely
with 2
nd
 dose
-
Hyperkalemia
 - normal increase K
+
~ 1 mEq/L; higher in burns,
motor neuron lesions & neuromuscular disease
-
Increased intraocular pressure
-
Fasciculations
 
Neuromuscular blocking agents
 
Suggested intubating doses:
 
Cote & Lerman’s A Practice of Anesthesia for Infants and Children, 5th edition. p122.
 
Neuromuscular blocking agents-
non- depolarizing relaxants
 
Cisatracurium
-
Spontaneous degradation
 not dependent on plasma cholinesterase
-
Faster recovery in children due to greater volume of distribution & total
body clearance
Vecuronium
-
Metabolized by liver, excreted in bile
-
No CV effects
Rocuronium
-
Fastest onset
 of non-depolarizing relaxants
-
Can be used for rapid sequence intubation
-
Metabolized in liver, excreted in urine
Pancuronium
-
Long-acting
-
> 50% excreted in urine unchanged, 10% in bile
-
Side effect: 
tachycardia
 - blocks presynaptic noradrenaline uptake
 
Antagonism of muscle relaxants
 
Neonates at greater risk for residual neuromuscular
blockade:
-
Immature neuromuscular system
-
Greater elimination half-life of relaxants
-
Reduced type 1, fatigue resistant, muscle fibers in diaphragm
-
Closing lung volume occurs within tidal volume in neonate (increased alveoli
closure)
Suggested doses for reversal:
-
Neostigmine
 (0.07mg/kg) with 
atropine
 (10-20 mcg/kg) or glycopyrrolate 5-
10 mcg/kg
-
Always give atropine or glycopyrolate 1st 
to avoid bradycardia & ↓ cardiac
output
or
-
Sugammadex
 (2-16 mg/kg) which encapsulates rocuronium to reverse
neuromuscular blockade
-
Limited use due to 
expense $$$$
 
Opioids
 
Morphine
Analgesic effect by activating 
μ
1 
receptor
Water soluble, poor lipid soluble
High hepatic clearance - metabolized into morphine-3-glucuronide
(M3G) & morphine-6-glucuronide (M6G). 
M6G causes respiratory
suppression
Reduced liver and renal function causes M3G & M6G accumulation,
leading to 
increased respiratory suppression in children & neonates
relative to adults
Side effects: itching, nausea
Dose: 0.05 - 0.2 mg/kg
 
 
 
Opioids
 
Meperidine
Weak opioid, 1/10
th
 strength of morphine
Prolonged elimination ½ time in neonates
Mainly used to stop shivering
Metabolite, 
normeperidine
, causes 
seizures
No longer recommended for use in children
 
Hydromorphone
Synthetic opioid, 5-7.5 more potent than morphine
Dose 0.01-0.02 mg/kg IV
Metabolites do not cause respiratory suppression
 
Opioids
 
Methadone
Synthetic opioid, similar potency to morphine but 
greater ½
life
Highly variable elimination ½ life in neonates 3.8 - 62 hours
Analgesic effect by activating 
μ
1 
receptor & NMDA receptor
antagonist
Dose ~0.1-0.2mg/kg
Lipid soluble - penetrates blood brain barrier
May cause QT prolongation
 
Opioids
 
Fentanyl
Rapid onset, short duration, lipid soluble
Potent 
μ
 
receptor
 agonist 70 - 125 times morphine
Most commonly used narcotic in infants & children
Metabolized by CYP3A4 in liver to non-active metabolites
Clearance reduced 70-80% compared to adults
May cause chest wall or glottic rigidity after IV push
Dose 1-3 mcg/kg 
(minor surgery) to 100 mcg/kg (cardiac surgery)
 
 
Opioids - infusions
 
Sufentanil
-
5-10 times more potent than fentanyl
-
Common infusion for cardiac & spine surgery
-
Metabolized by CYP3A4
-
Dose 0.3 mcg/kg/
hour
Alfentanil
-
¼ potency of fentanyl
-
Rapid onset, brief duration of action, more protein bound than fentanyl
-
May also cause chest wall rigidity
-
Dose 0.5-3 mcg/kg/
min 
or 10 mcg/kg for intubation
Remifentanil
-
Rapid onset, brief ½ life (3-6 minutes!!)
-
Metabolized by 
nonspecific blood esterases 
that are 
mature at birth
-
Flat context-sensitive ½ time
-
Dose 0.05-0.3 mcg/kg/
min
 
Opioids
 
Codeine
Weak, 1/10
th
 potency of morphine BUT 
~10% metabolized
into morphine
Analgesia depends on how much is metabolized into
morphine
Metabolized by CYP2D6 which has many 
polymorphisms
:
-
poor metabolizers
-
intermediate metabolizers
-
ultra-rapid metabolizers (produces the most morphine)
May lead to accidental overdose
, respiratory suppression to
cause death
Not recommended for children
 
Relative Opioid Potencies
 
Acetaminophen & NSAIDS
 
Acetaminophen/tylenol/paracetamol
-
Inhibits prostaglandin H2 synthetase (PGHS) - 
no anti-inflammatory
effect
-
Doses: 10 - 15 mg/kg PO or IV, 20 - 40 mg/kg PR
-
Toxic metabolite NAPQI
 binds hepatic macromolecules to cause
necrosis
NSAIDS
-
Heterogeneous group that all have antipyretic, analgesic and     
anti-
inflammatory effects
-
Inhibit COX-1, COX-2 or both
-
COX-1 - protects gastric mucosa, regulate renal blood flow, induce platelet
aggregation
-
COX-2 - inflammatory pathway
 
NSAIDS
 
Ketorolac
Analgesia similar to low-dose morphine
No respiratory suppression
Side effects:
-
Inhibits platelet function
 & increases bleeding
time
-
Altered bone healing if given in high doses
-
Bradycardia after rapid IV administration
 
Sedatives
 
Benzodiazepines: GABA receptor agonists
Midazolam
-
Antegrade amnesia
-
Water soluble, no pain on injection
-
Possible respiratory depression & hypotension with             co-
administration of fentanyl
-
Dose: 0.1 mg/kg IV, 0.5 - 0.75 mg/kg PO, 0.2 mg/kg nasal
 Diazepam
-
Reduces seizures & muscle spasms
-
Pain on injection
-
Prolonged ½ life in neonates & infants
-
Dose: 0.2 - 0.3 mg/kg IV
 
Sedatives
 
Dexmedetomidine
𝜶
2
-agonist
, affinity 1600:1 specificity ratio for 
𝜶
2
: 𝜶
1
7-8 x more affinity than clonidine
Decreases sympathetic outflow from CNS by hyperpolarization of
noradrenergic neurons in the locus coeruleus
No ventilatory depression
Shorter elimination ½ life than clonidine, 2 hours vs. 8 hours
Effects:
-
Anxiolysis, analgesia, decrease HR, decrease emergence delirium
-
Dose: loading IV 1 mcg/kg, infusion 0.5 - 2.0 mcg/kg/hour*
-
Can be given intranasal 1 - 2 mcg/kg for sedation
 
Sedatives
 
Chloral hydrate
Activates GABA to produce sedation
Dose 20-75 mg/kg PO or PR
Side effects: airway obstruction, apnea, bradycardia,
hypotension
Metabolites may be carcinogenic/toxic, leading to
metabolic acidosis, renal failure & hypotonia
Interferes with bilirubin binding to albumin in neonates
Long ½ life - 
may have re-sedation
No longer produced in USA
 
 
Antagonists
 - when your dose goes to far ….
 
Naloxone
-
Opioid antagonist
, greatest affinity at 𝜇-receptor
-
Rapid onset ~30 seconds
-
Longer ½ life in neonates of 3 hours vs. 1-1.5 hours in adults
-
Dose: IV 0.25  -0.5 mcg/kg (mild overdose) to 10-100 mcg/kg (severe)
-
If treating opioid induced respiratory depression, 
must observe respiratory
status minimum of 2 hours after naloxone administration
Flumazenil
-
Competitive antagonist at GABA
A
 receptor to 
reverse BZD
-
Why reverse? excessive sedation or paradoxical response to BZD
-
Dose: 10 - 25 mcg/kg IV
-
Short ½ life: ~35 min
 
Conclusions:
 
Volume of distribution and clearance
vary with age
Drug doses are frequently age and
weight dependent in neonates and
children
Anesthesia management of infants and
children involve careful knowledge of
pharmacology and physical development
 
References:
 
1.
Cote & Lerman’s A Practice of Anesthesia for Infants and Children, 5th
edition. P 77-149.
2.
Smith’s Anesthesia for Infants and Children, 8th edition. p 179-261.
3.
Mason KP, et al. Incidence and predictors of hypertension during high-
dose dexmedetomidine sedation for pediatric MRI. Paediatr Anaesth.
2010 Jun;20(6):516-23.
4.
Mason KP, et al. High dose dexmedetomidine as the sole sedative for
pediatric MRI. Paediatr Anaesth. 2008 May;18(5):403-11.
5.
Wu J, et al. Comparison of propofol and dexmedetomidine techniques
in children undergoing magnetic resonance imaging. Paediatr Anaesth
2014 Aug;24(8):813-8.
 
 
 
 
Slide Note
Embed
Share

Gain insights on frequently used medications in the perioperative period for infants and children, including anesthesia medications. Explore pharmacokinetics, drug distribution in neonates, and the effects of common anesthesia agents on pediatric patients. Understand how immature kidney or liver function, protein binding, and body composition can alter drug responses. Learn about drug interactions with bilirubin and the impact on neonatal health.


Uploaded on Jul 29, 2024 | 0 Views


Download Presentation

Please find below an Image/Link to download the presentation.

The content on the website is provided AS IS for your information and personal use only. It may not be sold, licensed, or shared on other websites without obtaining consent from the author. Download presentation by click this link. If you encounter any issues during the download, it is possible that the publisher has removed the file from their server.

E N D

Presentation Transcript


  1. Pharmacology for Infants & Children Updated 7/2019 Martina Downard, MD Wake Forest Baptist Health, Brenner Children s Hospital

  2. Learning Objectives 1. Increase understanding of frequently used medications in the perioperative period in infants and children 2. Review mechanisms, effects and doses of commonly used anesthesia medications in children

  3. Disclosures No relevant financial relationships

  4. Outline 1. Pharmacokinetics and pharmacodynamics 2. Inhalation anesthetic agents 3. IV anesthetics 4. Neuromuscular blocking drugs and antagonists 5. Opioids 6. NSAIDs & acetaminophen 7. Sedatives: benzodiazepines, dexmedetomidine and chloral hydrate 8. Opioid & benzodiazepine antagonists

  5. Pharmacokinetics & Pharmacodynamics Pharmacokinetics: How the patient/body affects the drug or how drug concentrations in the body change over time - Altered by immature kidney or liver function - Altered by protein binding - Altered by body composition (fat/muscle/total body fluid/ volume of distribution) Pharmacodynamics: How the drug affects the patient/body

  6. Drug distribution in neonates Remember: Acidic drugs bind mostly to albumin, e.g diazepam or barbiturates Basic drugs bind to globulins, lipoproteins, and plasma alpha-1-acid glycoproteins, e.g. lidocaine or alfentanil

  7. Drug distribution in neonates Neonates have reduced total protein & albumin levels result: increase levels & effect from unbound medications Neonates have reduced clearance of drugs from decreased renal/hepatic clearance result: increase medication levels Neonates have increased volume of distribution of drugs (increase in total body water) result: decrease medication levels

  8. Drug distribution Medications can compete with bilirubin to bind to albumin, causing hyperbilirubinemia or kernicterus in neonates Ex. phenytoin, salicylate, caffeine, ceftriaxone, Hypaque (diatrizoate) Changes in tissue binding with maturation Ex. digoxin, opioids

  9. Body composition Preterm & term infants have larger % body water than older children - Result - overall, increased loading dose - larger distribution volumes for water-soluble drugs & smaller for lipophilic drugs Preterm and term infants have less muscle & fat - Less area for redistribution = prolonged peak blood concentrations - Example: opioids with prolonged sedation/respiratory depression

  10. Absorption Slower enteral absorption until 8 months old Larger skin surface area to body size = increased skin absorption - EMLA more likely to cause methemoglobinemia (prilocaine) - Iodine antiseptics likely to cause hypothyroidism

  11. Metabolism Reduced function & blood flow to liver in infants Drugs dependent on liver glucuronidation: - Morphine, acetaminophen, dexmedetomidine, lorazepam - Clearance reaches adult levels ~ 5 - 6 months of age Extrahepatic - Nonspecific esterases in tissues & erythrocytes are mature at birth - No change in remifentanil and succinylcholine clearance

  12. Renal Excretion Glomerular filtration & tubular function fully mature by 12 to 24 months of age Aminoglycoside & cephalosporin antibiotics have prolonged duration of action in neonates

  13. Pharmacokinetics & Pharmacodynamics SUMMARY Decreased circulating protein levels, metabolism and excretion suggest decreasing drug dose Increased volume of distribution & total body water suggest increasing drug dose REALITY dosing of medications in neonates & children requires careful titration

  14. Inhalation agents - MAC MAC = minimum alveolar anesthetic concentration at which 50% patients don t move to noxious stimuli. ** Except Sevoflurane! Peak MAC as full term neonate. Why is MAC altered in children? 1. Change in cerebral blood flow? 2. GABA receptors? 3. Regulation of chloride transporters?

  15. Inhalation agents Wash-in = ratio of alveolar to inspired anesthetic partial pressure (FA/FI) Faster Wash-In in neonates than in adults: Greater alveolar ventilation (VA) to functional residual capacity (FRC) in neonates (5:1) than in adults (1.5:1) Greater percent of cardiac output distributed to vessel-rich groups (brain, heart, kidney, organs) in neonates Neonates have the tissue/blood solubility of adults Reduced blood/gas solubility in neonates

  16. Inhalation agents Second gas effect - When two anesthetics given simultaneously, small concentration of 1 may increase the uptake of the 2nd anesthetic. E.g. nitrous oxide & sevoflurane/isoflurane - Weak effect, if at all Speed of induction determined by: - Solubility of agent less soluble = faster induction - Rate of increase of inspired concentration - Max inspired concentration - Respirations

  17. Inhalation agents Cardiovascular effects: Volatile agents decrease the calcium influx by inhibiting sodium-calcium pumps Neonates more commonly have bradycardia & hypotension with increasing volatile % compared to adults Immature sarcoplasmic reticulum in cardiac cells leading to poor calcium retention and release Increased sensitivity/dependence on calcium for contractility Fewer & less organized contractile elements

  18. Inhalation agents Side effects by volatile agent: Halothane depression of sinoatrial node, slowing myocardial conduction, predispose to ventricular arrhythmias by sensitizing heart to adrenaline Isoflurane & Sevoflurane decrease SVR to decrease BP, blunt baroreceptor responses, no effect on arrhythmias

  19. IV Anesthetic agents Propofol Contains: soybean oil, egg lecithin (yolk), glycerol, EDTA Pediatric IV induction dose: 3-4 mg/kg Pediatric maintenance infusion rate: 200-250 mcg/kg/min Highly lipophilic, pain on injection ( warmth or sunshine on your arm ) Rapid re-distribution, hepatic and extrahepatic clearance (lung, kidney) Associated with less emergence delirium than inhalational agents Associated with a decreased incidence of nausea and vomiting

  20. IV Anesthetic agents Methohexital (brevital) Short-acting barbiturate IV induction dose: 1-2 mg/kg Side effects: - Pain on injection - Hiccups - Seizure-like activity Can also be given rectally as a premedication

  21. IV Anesthetic agents Thiopental Binds GABAAreceptors to prolong chloride channel opening IV induction 3-4 mg/kg Myocardial depressant & weak vasodilator

  22. IV anesthetic agents: Ketamine Ketamine: NMDA receptor Antagonist Effects: - Analgesic & amnestic, dissociative amnesia - Increased HR & BP, little effect on pulmonary artery pressure - Direct cardiac depressant - Bronchodilator May precipitate seizures in susceptible children Side effects: nystagmus, increased secretions, 30% increase intraocular pressure, increased intracranial pressure (cerebral vasodilation) & CMRO2 1 - 3 mg/kg IV, 5-10 mg/kg intramuscular - Doses typically larger in children due to greater clearance than adults - IM dose useful for combative larger children

  23. IV anesthetic agents Etomidate: steroid based hypnotic induction agent 0.2 - 0.3 mg/kg IV, typically 30% increase dose in children due to increased volume of distribution Effects: No effect on hemodynamics Great for head injury or unstable CV status! Side effects: Adrenal suppression Pain on injection Emesis - - - - -

  24. Neuromuscular blocking agents Neonates have increased sensitivity - Neuromuscular transmission immature until 2 months old - Reduction in acetylcholine released - Reduced muscle mass - Reduced clearance Neonate diaphragm function may be more preserved - Type 1 (slow twitch) diaphragm muscle fibers most sensitive to NMBDs - Preterm neonate has only ~10% type 1 fibers - Therefore, diaphragm function may recover earlier than peripheral muscles Infants require larger dose than adults - Larger volume of distribution due to greater total body water & extracellular fluid Neonates - faster onset due to greater cardiac output

  25. Neuromuscular blocking drugs Succinylcholine: depolarizing muscle relaxant Infants more resistant than adults - Rapid redistribution in extracellular fluid volume - Dose: infants ~ 3mg/kg IV/ 5mg/kg IV; children ~1.5 mg/kg IV/ 4mg/kg IM Possible side effects: - Increased masseter muscle tone when given with halothane - masseter spasm potential sign of malignant hyperthermia - Arrhythmia - bradycardia due to choline metabolites; more likely with 2nddose - Hyperkalemia - normal increase K+~ 1 mEq/L; higher in burns, motor neuron lesions & neuromuscular disease - Increased intraocular pressure - Fasciculations

  26. Neuromuscular blocking agents Suggested intubating doses: Infants (mg/kg) Children (mg/kg) muscle relaxant: succinylcholine 3 1.5-2 rocuronium 0.25 - 0.5 0.6 - 1.2 (1.2 for RSI) vecuronium 0.07 - 0.1 0.1 pancuronium 0.1 0.1 cisatracurium 0.1 0.1 - 0.2 atracurium 0.5 0.5 Cote & Lerman s A Practice of Anesthesia for Infants and Children, 5th edition. p122.

  27. Neuromuscular blocking agents- non- depolarizing relaxants Cisatracurium - Spontaneous degradation not dependent on plasma cholinesterase - Faster recovery in children due to greater volume of distribution & total body clearance Vecuronium - Metabolized by liver, excreted in bile - No CV effects Rocuronium - Fastest onset of non-depolarizing relaxants - Can be used for rapid sequence intubation - Metabolized in liver, excreted in urine Pancuronium - Long-acting - > 50% excreted in urine unchanged, 10% in bile - Side effect: tachycardia - blocks presynaptic noradrenaline uptake

  28. Antagonism of muscle relaxants Neonates at greater risk for residual neuromuscular blockade: - - - - Immature neuromuscular system Greater elimination half-life of relaxants Reduced type 1, fatigue resistant, muscle fibers in diaphragm Closing lung volume occurs within tidal volume in neonate (increased alveoli closure) Suggested doses for reversal: - Neostigmine (0.07mg/kg) with atropine (10-20 mcg/kg) or glycopyrrolate 5- 10 mcg/kg Always give atropine or glycopyrolate 1st to avoid bradycardia & cardiac output - or - Sugammadex (2-16 mg/kg) which encapsulates rocuronium to reverse neuromuscular blockade Limited use due to expense $$$$ -

  29. Opioids Morphine Analgesic effect by activating 1 receptor Water soluble, poor lipid soluble High hepatic clearance - metabolized into morphine-3-glucuronide (M3G) & morphine-6-glucuronide (M6G). M6G causes respiratory suppression Reduced liver and renal function causes M3G & M6G accumulation, leading to increased respiratory suppression in children & neonates relative to adults Side effects: itching, nausea Dose: 0.05 - 0.2 mg/kg

  30. Opioids Meperidine Weak opioid, 1/10thstrength of morphine Prolonged elimination time in neonates Mainly used to stop shivering Metabolite, normeperidine, causes seizures No longer recommended for use in children Hydromorphone Synthetic opioid, 5-7.5 more potent than morphine Dose 0.01-0.02 mg/kg IV Metabolites do not cause respiratory suppression

  31. Opioids Methadone Synthetic opioid, similar potency to morphine but greater life Highly variable elimination life in neonates 3.8 - 62 hours Analgesic effect by activating 1 receptor & NMDA receptor antagonist Dose ~0.1-0.2mg/kg Lipid soluble - penetrates blood brain barrier May cause QT prolongation

  32. Opioids Fentanyl Rapid onset, short duration, lipid soluble Potent receptor agonist 70 - 125 times morphine Most commonly used narcotic in infants & children Metabolized by CYP3A4 in liver to non-active metabolites Clearance reduced 70-80% compared to adults May cause chest wall or glottic rigidity after IV push Dose 1-3 mcg/kg (minor surgery) to 100 mcg/kg (cardiac surgery)

  33. Opioids - infusions Sufentanil - - - - Alfentanil - - - - Remifentanil - Rapid onset, brief life (3-6 minutes!!) - Metabolized by nonspecific blood esterases that are mature at birth - Flat context-sensitive time - Dose 0.05-0.3 mcg/kg/min 5-10 times more potent than fentanyl Common infusion for cardiac & spine surgery Metabolized by CYP3A4 Dose 0.3 mcg/kg/hour potency of fentanyl Rapid onset, brief duration of action, more protein bound than fentanyl May also cause chest wall rigidity Dose 0.5-3 mcg/kg/min or 10 mcg/kg for intubation

  34. Opioids Codeine Weak, 1/10thpotency of morphine BUT ~10% metabolized into morphine Analgesia depends on how much is metabolized into morphine Metabolized by CYP2D6 which has many polymorphisms: - poor metabolizers - intermediate metabolizers - ultra-rapid metabolizers (produces the most morphine) May lead to accidental overdose, respiratory suppression to cause death Not recommended for children

  35. Relative Opioid Potencies Drug Potency morphine 1 methadone 1 meperidine 0.1 hydromorphone 5 - 7.5 alfentanil 40 fentanyl 150 sufentanil 1500

  36. Acetaminophen & NSAIDS Acetaminophen/tylenol/paracetamol Inhibits prostaglandin H2 synthetase (PGHS) - no anti-inflammatory effect Doses: 10 - 15 mg/kg PO or IV, 20 - 40 mg/kg PR Toxic metabolite NAPQI binds hepatic macromolecules to cause necrosis - - - NSAIDS Heterogeneous group that all have antipyretic, analgesic and anti- inflammatory effects Inhibit COX-1, COX-2 or both - COX-1 - protects gastric mucosa, regulate renal blood flow, induce platelet aggregation - COX-2 - inflammatory pathway - -

  37. NSAIDS Ketorolac Analgesia similar to low-dose morphine No respiratory suppression Side effects: - Inhibits platelet function & increases bleeding time - Altered bone healing if given in high doses - Bradycardia after rapid IV administration

  38. Sedatives Benzodiazepines: GABA receptor agonists Midazolam Antegrade amnesia Water soluble, no pain on injection Possible respiratory depression & hypotension with co- administration of fentanyl Dose: 0.1 mg/kg IV, 0.5 - 0.75 mg/kg PO, 0.2 mg/kg nasal Diazepam Reduces seizures & muscle spasms Pain on injection Prolonged life in neonates & infants Dose: 0.2 - 0.3 mg/kg IV - - - - - - - -

  39. Sedatives Dexmedetomidine ?2-agonist, affinity 1600:1 specificity ratio for ?2: ?1 7-8 x more affinity than clonidine Decreases sympathetic outflow from CNS by hyperpolarization of noradrenergic neurons in the locus coeruleus No ventilatory depression Shorter elimination life than clonidine, 2 hours vs. 8 hours Effects: - Anxiolysis, analgesia, decrease HR, decrease emergence delirium - Dose: loading IV 1 mcg/kg, infusion 0.5 - 2.0 mcg/kg/hour* - Can be given intranasal 1 - 2 mcg/kg for sedation

  40. Sedatives Chloral hydrate Activates GABA to produce sedation Dose 20-75 mg/kg PO or PR Side effects: airway obstruction, apnea, bradycardia, hypotension Metabolites may be carcinogenic/toxic, leading to metabolic acidosis, renal failure & hypotonia Interferes with bilirubin binding to albumin in neonates Long life - may have re-sedation No longer produced in USA

  41. Antagonists - when your dose goes to far . Naloxone - Opioid antagonist, greatest affinity at ?-receptor - Rapid onset ~30 seconds - Longer life in neonates of 3 hours vs. 1-1.5 hours in adults - Dose: IV 0.25 -0.5 mcg/kg (mild overdose) to 10-100 mcg/kg (severe) - If treating opioid induced respiratory depression, must observe respiratory status minimum of 2 hours after naloxone administration Flumazenil - Competitive antagonist at GABAAreceptor to reverse BZD - Why reverse? excessive sedation or paradoxical response to BZD - Dose: 10 - 25 mcg/kg IV - Short life: ~35 min

  42. Conclusions: Volume of distribution and clearance vary with age Drug doses are frequently age and weight dependent in neonates and children Anesthesia management of infants and children involve careful knowledge of pharmacology and physical development

  43. References: 1. Cote & Lerman s A Practice of Anesthesia for Infants and Children, 5th edition. P 77-149. 2. Smith s Anesthesia for Infants and Children, 8th edition. p 179-261. 3. Mason KP, et al. Incidence and predictors of hypertension during high- dose dexmedetomidine sedation for pediatric MRI. Paediatr Anaesth. 2010 Jun;20(6):516-23. 4. Mason KP, et al. High dose dexmedetomidine as the sole sedative for pediatric MRI. Paediatr Anaesth. 2008 May;18(5):403-11. 5. Wu J, et al. Comparison of propofol and dexmedetomidine techniques in children undergoing magnetic resonance imaging. Paediatr Anaesth 2014 Aug;24(8):813-8.

Related


More Related Content

giItT1WQy@!-/#giItT1WQy@!-/#giItT1WQy@!-/#giItT1WQy@!-/#giItT1WQy@!-/#giItT1WQy@!-/#