Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Propofol

Generic name
Propofol
Brand name
ATC Code
N01AX10

Pharmacokinetics in children

Propofol is 98% bound to plasma proteins. Propofol is widely distributed and rapidly cleared from the body. Clearance occurs via metabolic processes, mainly in the liver, and is there dependent on blood flow to form inactive conjugates of propofol and its metabolite quinol, which are excreted in the urine [SmPC Propol Lipuro].

After a single dose of 3 mg/kg administered intravenously, propofol clearance per kg body weight with increase in age as follows: The mean clearance was in neonates < 1 month (n=25) (20 mL/kg/min) significantly lower compared with older children (n=36, age between 4 months – 7 years). In addition, interindividual variability was significant in neonates (3.7-78 mL/kg/min). In older children, the mean propofol clearance after a single bolus injection of 3 mg/kg was 37.5 ml/min/kg (4-24 months) (n=8), 38.7 ml/min/kg (11-43 months) (n=6), 48 ml/min/kg (1-3 years) (n=12), 28.2 ml/min/kg (4-7 years) (n=10) compared with 23.6 ml/min/kg in adults (n=6) [SmPC Propol Lipuro].

In (premature) neonates, the following median (range) pharmacokinetic parameters were found after an IV bolus of 3 mg / kg (Allegaert, de Hoon et al. 2007, Allegaert, Peeters, et al. 2007):

  Allegaert, de Hoon et al 2007 (n=9) Allegaert, Peeters et al. 2007 (n=25)
Cl (ml/min/kg) 13,6 (3,7-78,2) 19,6
Vd (l/kg) 3,7 (1,33-7,96) 5,56

The following average pharmacokinetic parameters were found in older children (4 months to 12 years) (Murat et al. 1996, Raoof et al. 1995, Saint-Maurice et al. 1989):

t½ (min) 100-141
Cl (ml/min/kg) 30.6-49
Vd (l/kg) 2.4-10.9

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

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Available formulations

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Dosages

Short term anaesthesia (as used in intubation)
  • Intravenous
    • Preterm neonates Gestational age < 37 weeks
      • In minimal invasive surfactant administration (MIST/ LISA): 0.5 mg/kg/dose, once only.
    • Term neonate
      • 1 - 2 mg/kg/dose, as required 2 single doses.
    • Preterm neonates Gestational age < 37 weeks
      [10]
      • In minimal invasive surfactant administration (MIST/ LISA): 0.5 mg/kg/dose, once only.
    • Term neonate
      [10]
      • 1 - 2 mg/kg/dose, as required 2 single doses.
Anaesthesia, general
  • Intravenous
    • 1 month up to 18 years
      [9]
      • Initial dose: Induction of anaesthesia: 2.5 - 4 mg/kg/dose, bolus.
      • Maintenance dose: 9 - 15 mg/kg/hour, continuous infusion. Maintenance dosing depending on the anaesthesia.
        • Use for prolonged periods (> 6 hours) is not recommended.
        • titrate slowly  based on clinical response until clinical signs indicate the onset of anesthesia
        • In younger children (1 month – 3 years), higher doses within the range may be necessary.
Sedation of ventilated patients in the ICU
  • Intravenous
    • ≥ 16 years
      • 0.3 - 4 mg/kg/hour, continuous infusion.

      • Cave propofol infusion syndrome in this indication (see warnnings and precautions)
Sedation for diagnostic and surgical procedures, alone or combined with local or regional anaesthesia
  • Intravenous
    • 1 month up to 18 years
      [9]
      • Initial dose: 1 - 2 mg/kg/dose, bolus.
      • Maintenance dose: 1.5 - 9 mg/kg/hour, continuous infusion.

      • Extra bolus up to 1 mg/kg can be administerred if stronger sedation is required.

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Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

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The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

When used as a sedative in children less than 16 years of age, serious side effects such as metabolic acidosis, hyperlipidemia, rabdomyolysis and heart failure have been reported, sometimes with fatal outcome. These side effects may occur together in the context of ‘’propofol infusion syndrome’’.

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The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications in children

Propofol product information lists hypersensitivity to soy and peanut as a contraindication. The literature indicates that allergic reactions to propofol are rare, the amounts of food proteins in a propofol product are negligible, and a history of food allergy is not a predictor of propofol allergy [Sommerfield 2019; Murphy 2011; Bagley 2021; Wiskin 2015; Gelberg 2019]

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Cavebloodpressure drop with rapid injection. Painful when administered: possibly add lidocaine. Propofol lipuro is less painful when injected than propofol.

Propofol is a lipid formulation. This can cause hyperlipidemia. Children are at greater risk for "fat overload" syndrome (pay particular attention when on a ketogenic diet). Monitor plasma lipid levels.

Cave propofol infusion syndrome:
The use of propofol emulsion infusions for sedation in intensive care has been associated with various metabolic disorders and organ failure, which can lead to death. There have been reports of metabolic acidosis, rhabdomyolysis, hyperkalemia, hepatomegaly, renal failure, hyperlipidemia, cardiac arrhythmias, Brugada-type ECG arrhythmias (elevated ST segment and coved T wave), and rapidly progressive heart failure that was usually unresponsive to inotropic support.
Combinations of these side effects are referred to as propofol infusion syndrome (PIS). This mainly (but not exclusively) affected patients with severe head injuries and increased intracranial pressure (ICP) and children with respiratory tract infections who received doses higher than those recommended for adults for sedation in intensive care.
The use of doses higher than 4 mg/kg/hour and/or use for longer than 48 hours is not recommended in children. [SmPC, Meyers 2020]

Be reluctant in children with (suspicion of) mitochondrial disorders, severe cachexia and hemodynamic instable patients.

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Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

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Halogenated hydrocarbons
N01AB07
N01AB06
N01AB08
Barbiturates, plain
N01AF03
Opioid anesthetics
N01AH02
N01AH01
N01AH06
N01AH03
Other general anesthetics
N01AX01
N01AX14
N01AX07

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References

  1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
  2. Bray RJ., Propofol infusion syndrome in children., Paediatr Anaesth, 1998, 8(6), 491-9
  3. Hatch DJ, Propofol infusion syndrome in children, Lancet, 1999, 353:, 1117-8
  4. Wolf A, et al, Impaired fatty acid oxidation in propofol infusion syndrome, The Lancet, 2001, 357, 606-607
  5. Wolf A et al, Propofol infusion in children: when does an anesthetic tool become an intensive care liability?, Pediatric anesthesia, 2004, 14, 435-438
  6. Vasile B et al, The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome, Intensive Care Med, 2003, 29, 1417-1425
  7. B. Braun Melsungen AG, SPC Propofol Lipuro 10 mg/ml (RVG 24720) 09-01-2019, www.geneesmiddeleninformatiebank.nl
  8. Bayer BV, SPC Recofol (RVG 103669), www.cbg-meb.nl, Geraadpleegd 27 oktober 2010, http://db.cbg-meb.nl/IB-teksten/h103669.pdf
  9. AstraZeneca BV, SmPC Diprivan (RVG 11549) 08-06-2023, www.geneesmiddeleninformatiebank.nl
  10. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie,, Expert opinie, 13 november 2018
  11. Dekker, J. et al, Sedation during minimal invasive surfactant therapy: a randomised controlled trial., Arch Dis Child Fetal Neonatal Ed, 2019, 104(4), F378-F383
  12. Dekker, J. et al., Sedation during Minimal Invasive Surfactant Therapy in Preterm Infants, Neonatology, 2016, 109(4), 308-13
  13. Ghanta, S., et al, Propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation: a randomized, controlled trial, Pediatrics, 2007, 119(6), e1248-55
  14. Murat, I. et al, Pharmacokinetics of propofol after a single dose in children aged 1-3 years with minor burns. Comparison of three data analysis approaches., Anesthesiology, 1996, A84(3), 526-32
  15. Raoof, A. A.et al, Propofol pharmacokinetics in children with biliary atresia., Br J Anaesth, 1995, 74(1), 46-9
  16. Saint-Maurice, C. et al, Pharmacokinetics of propofol in young children after a single dose, Br J Anaesth, 1989, 63(6), 667-70
  17. Allegaert, K., Peeters M. et al, Inter-individual variability in propofol pharmacokinetics in preterm and term neonates., Br J Anaesth, 2007, 99(6), 864-70
  18. Welzing, L. et al, Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates, Paediatr Anaesth, 2010, 20(7), 605-11
  19. Smits, A. et al, Propofol Dose-Finding to Reach Optimal Effect for (Semi-)Elective Intubation in Neonates., J Pediatr., 2016, 179, 54-60 e9
  20. Simons, S. H. et al, Clinical evaluation of propofol as sedative for endotracheal intubation in neonates., Acta Paediatr, 2013, 102(11), e487-92
  21. Penido, M. G. et al, Propofol versus midazolam for intubating preterm neonates: a randomized controlled trial., J Perinatol, 2011, 31(5), 356-60
  22. Papoff, P. et al, Effectiveness and safety of propofol in newborn infants., Pediatrics, 2008, 121(2), 448; author reply 448-9
  23. Nauta, M. et al, Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm infants, Paediatr Anaesth, 2011, 21(6), 711-2
  24. Descamps, C. S. et al, Propofol for sedation during less invasive surfactant administration in preterm infants., Arch Dis Child Fetal Neonatal Ed, 2017, 102(5), F465
  25. Allegaert, K., de Hoon, J. et al, Maturational pharmacokinetics of single intravenous bolus of propofol., Paediatr Anaesth, 2007, 17(11), 1028-34
  26. Wiskin AE, et al., Propofol anaesthesia is safe in children with food allergy undergoing endoscopy. , Br J Anaesth., 2015, 115(1), 145-6.
  27. Sommerfield DL, et al, Propofol use in children with allergies to egg, peanut, soybean or other legumes., Anaesthesia, 2019, 74(10), 1252-1259
  28. Murphy A, et al., Allergic reactions to propofol in egg-allergic children., Anesth Analg, 2011, 113(1), 140-4
  29. Gelberg J, et al, Safety of propofol use in patients allergic to soy or peanut: A retrospective observational cohort study., Eur J Anaesthesiol., 2019, 36(4), 311-312
  30. Bagley L, et al, Food allergy history and reaction to propofol administration in a large pediatric population., Paediatr Anaesth, 2021, 31(5), 570-577
  31. Wiskin AE, et al., Propofol anaesthesia is safe in children with food allergy undergoing endoscopy., Br J Anaesth., 2015, 115(1), 145-6.
  32. Murphy A, et al., Allergic reactions to propofol in egg-allergic children., Anesth Analg, 2011, 113(1), 140-4
  33. Meyers RS, et al., Key Potentially Inappropriate Drugs in Pediatrics: The KIDs List, J Pediatr Pharmacol Ther, 2020, 25(3), 175-191

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