Skip to main content
Log in

Ketamine Infusion as a Counter Measure for Opioid Tolerance in Mechanically Ventilated Children: A Pilot Study

  • Original Research Article
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

Background

Drug rotation to prevent opioid tolerance is well recognized in chronic pain management. However, ketamine infusion as a counter measure for opioid tolerance is rarely described in mechanically ventilated children developing tolerance from prolonged opioid infusion.

Patients and Methods

We performed a retrospective study in a 14-bed medical-surgical-cardiac pediatric intensive care unit. Thirty-two mechanically ventilated children who had developed tolerance from prolonged intravenous infusion of opioids received a continuous intravenous infusion of ketamine as an opioid substitute for more than 2 days, scheduled in a drug rotation protocol.

Results

Thirty-two children (median age 2.5 years, range 0.1–16.0; weight 11.2 kg [3.8–62.0]) were included. Patients had received continuous intravenous infusion of opioids and benzodiazepines for 16.0 days (4.0–34.0) when drug rotation was started. The median dose of continuous intravenous infusion of ketamine was 4.0 mg·kg−1·h−1 (1.8–6.0) and the median duration was 3.0 days (2.0–6.0). After having restarted opioids, fentanyl doses were significantly lower compared with the time before the drug rotation began (after, 2.9 µg·kg−1·h−1 [0.8–4.9] vs before, 4.15 µg·kg−1·h−1 [1.2–10.0]; p < 0.001). Continuous intravenous infusion of midazolam and clonidine were unchanged during drug rotation. COMFORT-B scoring was significantly lower after having started drug rotation (after, 14.5 [8–19] vs before, 16 [11–22]; p < 0.001).

Conclusion

Drug rotation with ketamine in mechanically ventilated children with opioid tolerance is feasible and seems to reduce the rate of fentanyl infusion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Jenkins IA, et al. Current United Kingdom sedation practice in pediatric intensive care. Paediatr Anaesth. 2007;17(7):675–83.

    Article  PubMed  Google Scholar 

  2. Anand KJ, et al. Summary proceedings from the neonatal pain-control group. Pediatrics. 2006;117(3 Pt 2):S9–22.

    Article  PubMed  Google Scholar 

  3. Anand KS. Relationships between stress responses and clinical outcome in newborns, infants, and children. Crit Care Med. 1993;21(9 Suppl):S358–9.

    Article  CAS  PubMed  Google Scholar 

  4. Simons SH, Anand KJ. Pain control: opioid dosing, population kinetics and side-effects. Semin Fetal Neonatal Med. 2006;11(4):260–7.

    Article  PubMed  Google Scholar 

  5. Anand KJ, et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics. 2010;125(5):e1208–25.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bardo MT, Hughes RA. Single-dose tolerance to morphine-induced analgesic and hypoactive effects in infant rats. Dev Psychobiol. 1981;14(5):415–23.

    Article  CAS  PubMed  Google Scholar 

  7. Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000;28(6):2122–32.

    Article  CAS  PubMed  Google Scholar 

  8. Katz R, Kelly HW. Pharmacokinetics of continuous infusions of fentanyl in critically ill children. Crit Care Med. 1993;21(7):995–1000.

    Article  CAS  PubMed  Google Scholar 

  9. Schulz S, Hollt V. Opioid withdrawal activates MAP kinase in locus coeruleus neurons in morphine-dependent rats in vivo. Eur J Neurosci. 1998;10(3):1196–201.

    Article  CAS  PubMed  Google Scholar 

  10. Avidor-Reiss T, et al. Opiate-induced adenylyl cyclase superactivation is isozyme-specific. J Biol Chem. 1997;272(8):5040–7.

    Article  CAS  PubMed  Google Scholar 

  11. Celerier E, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000;92(2):465–72.

    Article  CAS  PubMed  Google Scholar 

  12. Mauermann E, et al. Does fentanyl lead to opioid-induced hyperalgesia in healthy volunteers? A double-blind, randomized, crossover trial. Anesthesiology. 2016;124(2):453–63.

    Article  CAS  PubMed  Google Scholar 

  13. Kissin I, Bright CA, Bradley EL Jr. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg. 2000;91(6):1483–8.

    Article  CAS  PubMed  Google Scholar 

  14. Luginbuhl M, et al. Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg. 2003;96(3):726–32.

    Article  PubMed  Google Scholar 

  15. Playfor SD, Thomas DA, Choonara I. Sedation and neuromuscular blockade in paediatric intensive care: a review of current practice in the UK. Paediatr Anaesth. 2003;13(2):147–51.

    Article  PubMed  Google Scholar 

  16. Cunliffe M, McArthur L, Dooley F. Managing sedation withdrawal in children who undergo prolonged PICU admission after discharge to the ward. Paediatr Anaesth. 2004;14(4):293–8.

    Article  CAS  PubMed  Google Scholar 

  17. Ista E, et al. Assessment of sedation levels in pediatric intensive care patients can be improved by using the COMFORT “behavior” scale. Pediatr Crit Care Med. 2005;6(1):58–63.

    Article  PubMed  Google Scholar 

  18. Playfor S, et al. Consensus guidelines on sedation and analgesia in critically ill children. Intensive Care Med. 2006;32(8):1125–36.

    Article  CAS  PubMed  Google Scholar 

  19. Anand KJ, et al. Opioid analgesia in mechanically ventilated children: results from the multicenter measuring opioid tolerance induced by Fentanyl study. Pediatr Crit Care Med. 2013;14(1):27–36.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Neunhoeffer F, et al. Nurse-driven pediatric analgesia and sedation protocol reduces withdrawal symptoms in critically ill medical pediatric patients. Paediatr Anaesth. 2015;25(8):786–94.

    Article  PubMed  Google Scholar 

  21. Vet NJ, et al. Optimal sedation in pediatric intensive care patients: a systematic review. Intensive Care Med. 2013;39(9):1524–34.

    Article  CAS  PubMed  Google Scholar 

  22. Cohen SP, et al. Ketamine in pain management. Adv Psychosom Med. 2011;30:139–61.

    Article  PubMed  Google Scholar 

  23. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004;99(2):482–95.

    Article  CAS  PubMed  Google Scholar 

  24. Park GR, et al. Ketamine infusion. Its use as a sedative, inotrope and bronchodilator in a critically ill patient. Anaesthesia. 1987;42(9):980–3.

    Article  CAS  PubMed  Google Scholar 

  25. Jin HS, et al. The efficacy of the COMFORT scale in assessing optimal sedation in critically ill children requiring mechanical ventilation. J Korean Med Sci. 2007;22(4):693–7.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Miller AC, Jamin CT, Elamin EM. Continuous intravenous infusion of ketamine for maintenance sedation. Minerva Anestesiol. 2011;77(8):812–20.

    CAS  PubMed  Google Scholar 

  27. Atangana R, et al. Morphine versus morphine–ketamine association in the management of post operative pain in thoracic surgery. Acta Anaesthesiol Belg. 2007;58(2):125–7.

    CAS  PubMed  Google Scholar 

  28. Bossard AE, et al. Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers. Pain. 2002;98(1–2):47–57.

    Article  CAS  PubMed  Google Scholar 

  29. Lauretti GR, et al. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology. 1999;90(6):1528–33.

    Article  CAS  PubMed  Google Scholar 

  30. Huang C, et al. Ketamine enhances the efficacy to and delays the development of tolerance to electroacupuncture-induced antinociception in rats. Neurosci Lett. 2005;375(2):138–42.

    Article  CAS  PubMed  Google Scholar 

  31. Shimoyama N, et al. Ketamine attenuates and reverses morphine tolerance in rodents. Anesthesiology. 1996;85(6):1357–66.

    Article  CAS  PubMed  Google Scholar 

  32. Ikonomidou C, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70–4.

    Article  CAS  PubMed  Google Scholar 

  33. Moryl N, et al. Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain. Pain. 2002;96(3):325–8.

    Article  CAS  PubMed  Google Scholar 

  34. Drake R, Longworth J, Collins JJ. Opioid rotation in children with cancer. J Palliat Med. 2004;7(3):419–22.

    Article  PubMed  Google Scholar 

  35. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev 2004(3):CD004847.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Felix Neunhoeffer.

Ethics declarations

Ethics

The study protocol was approved by the Ethics Committee of Tuebingen University Hospital (634/2011BO1).

Funding

No funding was received for the conduct of this study.

Conflict of interest

Felix Neunhoeffer, Anja Hanser, Martin Esslinger, Vanja Icheva, Matthias Kumpf, Ines Gerbig, Michael Hofbeck and Jörg Michel declare that they have no conflict of interest that might be relevant to the contents of this manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental: Drug Rotation Protocol (DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neunhoeffer, F., Hanser, A., Esslinger, M. et al. Ketamine Infusion as a Counter Measure for Opioid Tolerance in Mechanically Ventilated Children: A Pilot Study. Pediatr Drugs 19, 259–265 (2017). https://doi.org/10.1007/s40272-017-0218-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-017-0218-4

Keywords

Navigation