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

Interactions
PK
Renal impairment
References

Esketamine

Generic name
Esketamine
Brand name
ATC Code
N01AX14

Pharmacokinetics in children

PK-Data during sevoflurane anaesthesia in 20 children (1–7 years) administration of esketamine 2 mg/kg/dose  (Weber 2004)

  Esketamin Esnorketamin
  Cmax (ng/ml) Tmax (min) Cmax (ng/ml) Tmax (min)
Intranasal mean ± SD (range) 355 ± 172(152-732) 18 ± 13 (2-40) 90 ± 128 (8-425) 50 ± 11 (40-60)
IV: mean ± SD (range) 1860 ± 883 (1078--4035) 3 ± 1 (2-5) 429 ± 277 (62-1033) 40 ± 16 (20-60)

One child in the intranasal group experienced rapid and high level s-ketamine absorption with a peak plasma concentration of 732 ng/ml after 2 min, which decreased to 274 ng/ml  after 60 min.  
 
PK-Data during prolonged sedation at the pediatric intensive care unit  after a loading dose of 0.5-2mg/kg i.v.-push and maintenance dose in neonates  of 0.1-1.8 mg/kg/hour and in infants: 0.3-3.6 mg/kg/hour  (Flint 2017)(8) were as follows: 

  Estimated Vd (V1) central compartment Estimated Vd (V2) peripheral compartment Estimated Cl (esketamin) Estimated Cl (esnorketamin) 
IV 7,73 L/70 kg 545 L/70 kg 112 L/h/70 kg 53,2 L/h/70 kg

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

No information is present at this moment.

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Available formulations

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Dosages

Procedural Sedation and Analgesia
  • Intravenous
    • 1 month up to 18 years
      [1] [12] [13] [22] [28] [29] [30]
      • 0.125 - 0.5 mg/kg/dose, once only slow IV.

      • Titrate to effect, if needed: lower doses are related to analgesia and higher dosages to procedural sedation 

    • Term neonate
      [1] [2] [18] [19]
      • 0.125 - 0.5 mg/kg/dose slow injection.
        • Use for procedural sedation in neonates only if alternatives are contraindicated due to potential neurotoxicity
        • Titrate if needed based on the desired effect: lower doses are related to analgesia and higher dosages to procedural sedation 
  • Nasal
Analgosedation in the ICU and Anesthesia in the OR
  • Intravenous
    • Term neonate
      [1] [15] [20] [24]
      • Initial dose: 0.5 - 1 mg/kg/dose, once only.
      • Maintenance dose: 0.25 - 0.5 mg/kg/dose every 10-15 minutes. ALTERNATIVE: 0.5 - 3 mg/kg/hour, continuous infusion.

      • Repeat the initial dose if needed to achieve intended effect. 

    • 1 month up to 18 years
      [1] [8] [9] [13] [22] [28] [29] [30]
      • Initial dose: 0.5 - 1 mg/kg/dose, bolus.
      • Maintenance dose: 0.25 - 0.5 mg/kg/dose every 10-15 minutes. ALTERNATIVE: 0,5 - 3 mg/kg/hour, continuous infusion .

      • Repeat the initial dose if needed to achieve the desired effect.

  • Intramuscular
    • 1 month up to 18 years
      [1]
      • 2 - 4 mg/kg/dose single dose. Repeated dosing: if indicated half of the initial dose can be administerred every 10-15 minutes.
Postoperative analgesia additional to other analgesics (ventilated and non-ventilated patients)
  • Intravenous
    • 1 month up to 18 years
      [1] [10]
      • Initial dose: 0.25 mg/kg/dose, bolus.
      • Maintenance dose: 0.2 - 0.5 mg/kg/hour, continuous infusion. Maximum dose for ventilated patients: 1,5 mg/kg/hour.
        • Titrate based on desired effect
    • Term neonate
      [1]
      • Initial dose: 0.25 mg/kg/dose, bolus.
      • Maintenance dose: 0.2 - 0.5 mg/kg/hour, continuous infusion. Maximum dose in ventilated patients: 1,5 mg/kg/hour.
        • Titrate based on desired effect

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Renal impaiment in children > 3 months

No information available on dose adjustment in renal impairment.

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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

Stimulation of the respiration and heart function. Increases the intracranial and intraocular pressure. Dysphoria. Causes saliva production. When using in diagnostic or therapeutic procedures in the upper respiratory tract, laryngeal spasms and other forms of airway obstruction as well as hyperreflexia have been reported in children in particular. During the recovery phase, psychological disorders can occur (unpleasant dreams with or without psychomotor activity, irrational behaviour, confusion). In children up to the age of 15 years, this occurs less often than in adults.

In neonates, potential neurotoxic effects have been reported (Dong 2013), Choudhury 2021

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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

No information available on specific contra indications in children.

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

Always use in combination with atropine due to saliva production.

During diagnostic and therapeutic procedures in the area of the upper respiratory tract, an increase in reflexes (hyperreflexia) and spasm of the glottis (laryngospasm) can be expected, especially in children. During interventions on the pharynx, larynx and bronchial tree, muscle relaxation with appropriate ventilation may therefore be necessary. (SmPC Esketamin Inresa 09/2022) 

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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
N01AB06
N01AB08
Other general anesthetics
N01AX10

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References

  1. Inresa Arzneimittel GmbH, SmPC, Esketamin Inresa 5/25 mg/ml Injektionslösung (2201536.00.00), 09/2022
  2. Elalouf C, et al., Prospective follow-up of a cohort of preterm infants<33 WG receiving ketamine for tracheal intubation in the delivery room: Neurological outcome at 1 and 2 years., Arch Pediatr., 2018, 25(4), 295-300
  3. Pfizer Pharma PFE GmbH, SmPC Ketanest® S 5/25 mg/ml Injektionslösung (37086.00.00),, 07/2021
  4. Xin, N., et al, Comparison between dexmedetomidine and esketamine in pediatric dentistry surgery., Transl Pediatr, 2021, 10(12), 3159-3165
  5. Eurocept International B.V., SmPC Esketiv Injektionslösung (2200304.00.00 en 2200305.00.00), 12/2020
  6. Dong, C. and K. J. Anand , Developmental neurotoxicity of ketamine in pediatric clinical use, Toxicol Lett, 2023, 220(1), 53-60
  7. Alp, H.,et al, Comparison of intranasal midazolam, intranasal ketamine, and oral chloral hydrate for conscious sedation during paediatric echocardiography: results of a prospective randomised study, Cardiol Young, 2019, 29(9), 1189-1195
  8. Liu, W., et al , Effects of preoperative nasal spray esketamine on separation anxiety and emergence agitation in pediatric strabismus surgery: A randomized clinical trial., Medicine (Baltimore) , 2022, 101(51), e32280.
  9. Sauer, H., et al, Bone marrow aspirations in oncological patients: experience from an in-house standard in paediatrics, Wien Med Wochenschr, 2019, 169(3-4), 82-86
  10. Xu Y, et al., Safety and efficacy of esketamine for postoperative analgesia in pediatric patients with hypospadias., Front Surg, 2023, 10, 1131137
  11. Choudhury, D., et al, Ketamin: Neuroprotective or Neurotoxic, Front Neurosci , 2021, 15, 672526.
  12. Zheng, X., ED(50) and ED(95) of propofol combined with different doses of esketamine for children undergoing upper gastrointestinal endoscopy: A prospective dose-finding study using up-and-down sequential allocation method, J Clin Pharm Ther, 2022, 47(7), 1002-1009
  13. Eich, C., et al, Low-dose S-ketamine added to propofol anesthesia for magnetic resonance imaging in children is safe and ensures faster recovery--a prospective evaluation, Paediatr Anaesth, 2011, 21(2), 176-178
  14. Sado-Filho, J., et al, Randomized clinical trial on the efficacy of intranasal or oral ketamine-midazolam combinations compared to oral midazolam for outpatient pediatric sedation, PLoS One, 2019, 14(3), e0213074
  15. Flint, R. B., et al , Pharmacokinetics of S-ketamine during prolonged sedation at the pediatric intensive care unit, Paediatr Anaesth, 2017, 27(11), 1098-1107.
  16. Huang J,et al , Median effective dose of esketamine for intranasal premedication in children with congenital heart disease, BMC Anesthesiol, 2023, Apr 19;23(1), 129
  17. Zhang, Y., et al, Efficacy and safety of the combination of propofol and S(+)-ketamine for procedural sedation in pediatric patients undergoing totally implantable venous access port implantation: A prospective randomized controlled study., Front Pediatr, 2022, 10, 974917
  18. Madathil, S.,et al, NOPAIN-ROP' trial: Intravenous fentanyl and intravenous ketamine for pain relief during laser photocoagulation for retinopathy of prematurity (ROP) in preterm infants: A randomised trial., BMJ Open, 2021, 11(9), e046235
  19. Pees, C., et al, Comparison of analgesic/sedative effect of racemic ketamine and S(+)-ketamine during cardiac catheterization in newborns and children., Pediatr Cardiol, 2003, 24(5), 424-429
  20. Van de Bunt, J. A., et al, Effects of esketamine sedation compared to morphine analgesia on hydrostatic reduction of intussusception: A case-cohort comparison study., Paediatr Anaesth, 2017, 27(11), 1091-1097
  21. Wang, J., et al, Sedative effect and safety of different doses of S-ketamine in combination with propofol during gastro-duodenoscopy in school-aged children: a prospective, randomized study, BMC Anesthesiol, 2022, 22(1), 346
  22. Su M, et al. , Median effective dose (ED(50)) of esketamine combined with propofol for children to inhibit response of gastroscope insertion., BMC Anesthesiol. , 2023, 23(1), 240
  23. Weber, F., et al, S-ketamine and s-norketamine plasma concentrations after nasal and i.v. administration in anesthetized children, Paediatr Anaesth , 2004, 14(12), 983-988
  24. Zhang, Y., et al, Efficacy and safety of the combination of propofol and S(+)-ketamine for procedural sedation in pediatric patients undergoing totally implantable venous access port implantation: A prospective randomized controlled study, Front Pediatr, 2022, 10, 974917
  25. Lu X, et al., A Comparison of Intranasal Dexmedetomidine, Esketamine or a Dexmedetomidine-Esketamine Combination for Induction of Anaesthesia in Children: A Randomized Controlled Double-Blind Trial., Front Pharmacol. , 2012, 12, 808930
  26. Wang J, et al., Intranasal esketamine combined with oral midazolam provides adequate sedation for outpatient pediatric dental procedures: a prospective cohort study, Int J Surg, 2023, 109(7), 1893-9
  27. Xin, N., et al, Comparison between dexmedetomidine and esketamine in pediatric dentistry surgery, Transl Pediatr, 2021, 10(12), 3159-3165
  28. Xu SX, et al., Effect of esketamine vs dexmedetomidine adjunct to propofol sedation for pediatric 3Tesla magnetic resonance imaging: a randomized, double-blind, controlled trial., Eur J Med Res, 2022, 27(1), 258
  29. Zheng X, et al., Efficacy and safety comparison of esketamine-propofol with nalbuphine-propofol for upper gastrointestinal endoscopy in children: a multi-center randomized controlled trial., Front Pediatr, 2023, 11, 1126522
  30. Zhong Y, et al., Evaluating efficacy and safety of sub-anesthetic dose esketamine as an adjuvant to propofol/remifentanil analgosedation and spontaneous respiration for children flexible fibreoptic bronchoscopy: <...>., Front Pharmacol, 2023, 14, 1184663

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