growing pains – neonatal analgesia€¦ · - tracheoesophageal fistula repair - many more…...
TRANSCRIPT
Emily Rodman, PharmD, BCPPSClinical Pharmacy Specialist - Neonatology
Growing Pains –Neonatal Analgesia
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Objectives• Recall how physiological differences affect pharmacokinetic parameters (absorption, distribution, metabolism, elimination) of medications in the neonate - with a focus on medications used in pain
•Apply developmental pharmacology concepts to medication dosing in the neonate
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Pain in Neonates•Increased sensitivity to pain
•Pain sensitivity may not be clinically evident in premature neonates and critically ill neonates
•Neonates exhibit greater hormonal, metabolic, and cardiovascular responses to procedures compared with older children (short term physiologic instability)
•Changes in white matter microstructure and altered cognitive development
Page GG. J Perinat Educ. 2004;13(3):10-7.Lago P. Acta Paediatrica. 2009; 932-9.
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Conditions of Pain• Diagnostic
- Arterial puncture
- Bronchoscopy
- Endoscopy
- Heel lancing
- Lumbar puncture
- Retinopathy of prematurity examination
- Suprapubic bladder puncture
- Venipuncture
• Therapeutic- Bladder cath
- Central line placement
- Chest tube insertion
- Dressing change
- Gavage tube insertion
- Intramuscular injections
- Removal of adhesive tape
- Suture removal
- Tracheal intubation/extubation
- Tracheal suctioning
• Surgical- Circumcision
- Incision and drainage of abscess
- Venous and arterial cutdown
- Patent ductus arteriosusligation
- Bowel resection
- Tracheoesophageal fistula repair
- Many more…
Khurana S, Whit Hall R, Anand KJS. NeoReviews Feb 2005, 6 (2) e76-e86
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Nonpharmacologic Treatment•Environmental
- Decrease bright lights
- Avoid loud noises
- Cluster care- Undisturbed rest
•Positioning- Swaddling/containment
- Facilitated tucking
•Touch- Stroking/caressing
- Massaging
- Holding- Kangaroo care
•Distraction- Music
- Rhythmic rocking
- Soft, smoothing voice
•Nonnutritive sucking- Pacifier
- Nonlactating nipple
- + sucrose
Khurana S, Whit Hall R, Anand KJS. NeoReviews Feb 2005, 6 (2) e76-e86Committee on Fetus and Newborn. Pediatrics. 2016 Feb;137(2):e20154271.
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Pharmacotherapy•Neonatal Challenges -
-Over 90% of FDA approved drugs DO NOT have neonatal labeling
-Results of tragic lessons from the past
• Grey baby syndrome (Chloramphenicol)
• Kernicterus (Trimethoprim/Sulfamethoxazole)
- Lack of safety and efficacy data
•Lack of neonatal dosing guidelines
•Lack of commercially available formulations
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Developmental Pharmacokinetics•Most dramatic changes occur during the first 12 months of life•Ongoing process throughout infancy, childhood and adolescence
Adapted from Kearns GL, et al. N Engl J Med 2003
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Absorption
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Gastric Emptying Time•Absorption at the small intestine
-Motility is irregular à difficult to predict the extent or time for peak drug absorption
•Factors affecting gastric emptying time
-Gestational age, disease states
• Reaches adult values at 6-8 months of age
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Intestinal Integrity•Immature or altered permeability of intestinal mucosa ↑
drug absorption
•GI integrity is influenced by drug osmolality
-Can cause diarrhea, cramping, abdominal distension and
vomiting
-↑ Osmolality destroys GI integrity
-↑ Risk of necrotizing enterocolitis
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Absorption: Morphine •Oral bioavailability is 35% in adults due to first-pass effect
•Adults require higher mg/kg/dose for oral vs IV route
•Neonates believed to not need as high of a conversion as older children
Pediatric Dosing:
Neonatal Dosing:
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IM Administration•Factors influencing absorption
-Skeletal muscle blood flow
-Muscle size
-Muscle activity
•IM fentanyl-Longer onset and duration of action
•IV is preferred over IMTayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/appdx-full-d.pdf
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Transdermal Administration•Factors influencing absorption
-Skin thickness, skin hydration, surface area of skin, skin damage
•Concern for increased absorption
-Newborn’s ratio of skin surface area to body weight is approximately 3 times that of an adult
•Possible systemic toxicity -Fentanyl, corticosteroids, alcohol, diphenhydramine
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Distribution
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Distribution•Volume of distribution (Vd) is a concept used to explain the drug concentrations in the blood stream
•Magnitude of Vd provides insight into drug distribution
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Fluid Compartments
Age TBW (%)Extracellular Water (%)
Adipose Tissue
(%)
Preterm 87 50 1-5
Term 77 45 12-16
3 months
73 33
1 year 59 28
Adult 55 20 20
Adapted from Clinical Pharmacy 1987; 6: 549
and Clinical Therapeutics 1991; 13: 526
DECR
EASE
INCR
EASE
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What does this mean?•Increased %TBW and extracellular water in pediatric patients
•Larger doses of hydrophilic and smaller doses of lipophilic drugs are required in neonates
C = dose
volume
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Gentamicin: Volume of Distribution
Stolk LM, Ther Drug Monit. 2002;24:27-31.Van den Anker J. Red Book: 2018 Report of the Committee on Infectious Diseases. 31th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2018.
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Lorazepam: Volume of Distribution
Age Vd (L/kg)Neonates 0.76 ± 0.37 (range: 0.14 to 1.3)
5 months to < 3 years 1.62 (range: 0.67 to 3.4)
3 to <13 years 1.5 (range: 0.49 to 3)
13 to <18 years 1.27 (range: 1 to 1.54)
Adults 1.3
McDermott CA, et al. J Pediatr. 1992 Mar;120(3):479-83. Chamberlain JM, et al. J Pediatr. 2012 Apr;160(4):667-672.e2.
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Plasma Protein Binding•Only unbound drug is pharmacologically active
•Neonatal patients have qualitative and quantitative differences in protein binding
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What does this mean?↓ Protein Binding = ↑ Free Drug
% Protein Bound
Drug Neonates Adults
Morphine 18-22 33-37
Phenobarbital 28-43 45-50
Phenytoin 70-90 89-93
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Blood Brain Barrier•Medication uptake dependent on lipid solubility and blood flow
-However, may be easier to cross in the newborn period
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Metabolism & Elimination
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Phase I Reactions: Oxidation•Cytochrome P450 system
•Different developmental patternsKearns GL, et al. N Engl J Med. 2003 Sep 18;349(12):1157-67. Review.
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Metabolism: Fentanyl •Metabolized by CYP3A4 into nor-fentanyl
•Only a small percentage is eliminated unchanged
•Other drugs metabolized by CYP3A4 may compete for clearance and increase fentanyl plasma concentrations
Pacifici GM. Pediatr Neonatol. 2015 Jun;56(3):143-8.
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Phase II Reactions: Glucuronidation•Uridine diphosphate (UDP)-glucuronosyltransferase (UGT)
- Activity reduced at birth- Reached adult levels around 6 – 18 months
•Bilirubin, morphine, APAP, corticosteroids and lorazepamundergo glucuronidation
•Historical example: Chloramphenicol tragedy
Tayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84.
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Metabolism: Morphine •M3G: opioid antagonist, respiratory stimulant, contributes to development of tolerance
•M6G: potent opioid agonist, respiratory depressant
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Phase II Reactions: Glycine Conjugation•Decreased in newborns
•Increases to adult levels by approximately 8 weeks of age
•Historical example: Neonatal gasping syndrome
Tayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84.
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Metabolism: Benzyl Alcohol
•Caution: neonatal gasping syndrome, deathBenzyl Alcohol Metabolism. Wikimedia Commons. Website. 11 Sept 2017 <https://commons.wikimedia.org/wiki/File:Benzyl_Alcohol_Metabolism_Scheme.png>
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Phase II Reactions: Sulfation•Sulfotransferase system is fairly well developed at birth
•May compensate for limited function of other pathways
•Clinical example: APAP
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Metabolism: Acetaminophen •Metabolized via sulfation rather than glucuronidation as in adults
Age Half-life
Neonates 7 hours (range: 4 to 10 hours)
Infants ~4 hours (range: 1 to 7 hours)
Children 3 hours (range: 2 to 5 hours)
Adolescents ~3 hours (range: 2 to 4 hours)
Adults 2 hours (range: 2 to 3 hours)
Acetaminophen Metabolism. Wikimedia Commons. Website. 11 Sept 2017 <http://upload.Wikimedia.org/Wikipedia/commons/1/12/paracetamol_metabolism.svg>
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Elimination: Creatinine Clearance
Gallini. Pediatr Nephrol (2000) 15:119–124
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Elimination: Serum Creatinine
Gallini. Pediatr Nephrol (2000) 15:119–124
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Gabapentin•Observational evaluation
- 22 NICU pts received gabapentin
- 10.2 mg/kg/day mean starting dose
- 25.5 mg/kg/day maximum dose
- N-PASS score decreased in most patients from median of 3.1 to 0
- It also reduced the need for analgesic or sedative medications
- Well tolerated
•Highly lipophilic/penetrates well through the BBB
•Not metabolized
•PK data- Neonates: plasma half-life of 14 hours (adults 5-7 hours)
- Eliminated unchanged via the kidneys
Sacha GL, et al. J Pediatr Pharmacol Ther. 2017 May-Jun;22(3):207-211.
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Elimination: Morphine•Reaches 80% of adult values by 6 months of age
Age Clearance (L/h/kg)24-27 weeks 0.136
28-31 weeks 0.193
Term neonate 0.44
3 months 1.14
6 months 1.43
Age Half-life (hr)Preterm 10-20
Neonates 7.6
6 months 2.9
Anand KJ. J Perinatol. 2007 May;27 Suppl 1:S4-S11. Review.McRorie TI, et al. Am J Dis Child. 1992 Aug;146(8):972-6.
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Elimination: Morphine
Bouwmeester 2004.
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Elimination: Fentanyl
Age ClearancePreterm 2 – 85 mL/min/kgNeonates < 1 week old 7.4 mL/min/kgNeonates 7 – 14 days old 23.6 mL/min/kgInfants post abdominal surgery 0 to 9 mL/min/kgAdults 0.4 to 1.5 L/min
Saarenmaa E, et al. J Pediatr. 1999 Feb;134(2):144-50.
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Opioid Conversions“The potency ratio of
fentanyl compared to morphine is
different in adults (80 to 100 times) as compared to infants
(13 to 20 times).”Anand. Journal of
Perinatology (2007)27.
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Summary•Decreased Vd for lipophilic medications, increased for hydrophilic medications
•Decreased protein binding
•Increased blood brain barrier penetration
•Decreased metabolism
•Decreased elimination
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Children are NOT just small adults!
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Questions?