Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations
Abstract
Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated.
Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS).
Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations.
Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.
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References
2. MacKenzie M, Zed PJ, Ensom MHH. Opioid pharmacokinetics-pharmacodynamics: clinical implications in acute pain management in trauma. Ann Pharmacother. 2016;50:209–18. doi: 10.1177/1060028015625659
3. Minto CF, Schnider TW. Contributions of PK/PD modeling to intravenous anesthesia. Clin Pharmacol Ther. 2008;84:27–38. doi: 10.1038/clpt.2008.100
4. Hannivoort LN, Absalom AR, Struys M. The role of pharmacokinetics and pharmacodynamics in clinical anaesthesia practice. Curr Opin Anaesthesiol. 2020;33:483–9. doi: 10.1097/aco.0000000000000881
5. Gerlach AT, Murphy CV. Sedation with dexmedetomidine in the intensive care setting. Open Access Emerg Med. 2011;3:77–85. doi: 10.2147/oaem.S17429
6. Swart EL, et al. Population pharmacodynamic modelling of lorazepam- and midazolam-induced sedation upon long-term continuous infusion in critically ill patients. Eur J Clin Pharmacol. 2006;62:185–94. doi: 10.1007/s00228-005-0085-8
7. Frenkel C, Schuttler J, Ihmsen H, Heye H, Rommelsheim K. Pharmacokinetics and pharmacodynamics of propofol/alfentanil infusions for sedation in ICU patients. Intensive Care Med. 1995;21:981–8. doi: 10.1007/bf01700659
8. Tse AHW, Ling L, Lee A, Joynt GM. Altered pharmacokinetics in prolonged infusions of sedatives and analgesics among adult critically ill patients: a systematic review. Clin Ther. 2018;40:1598–615.e1592. doi: 10.1016/j.clinthera.2018.07.021.
9. Yogaratnam D, Ditch K, Medeiros K, Miller MA, Smith BS. The impact of liver and renal dysfunction on the pharmacokinetics and pharmacodynamics of sedative and analgesic drugs in critically ill adult patients. Crit Care Nurs Clin North Am. 2016;28:183–94. doi: 10.1016/j.cnc.2016.02.009.
10. Fujita Y, et al. A comparison between dosages and plasma concentrations of dexmedetomidine in clinically ill patients: a prospective, observational, cohort study in Japan. J Intensive Care. 2013;1:15. doi: 10.1186/2052-0492-1-15
11. Masica AL, et al. Clinical sedation scores as indicators of sedative and analgesic drug exposure in intensive care unit patients. Am J Geriatr Pharmacother. 2007;5:218–31. doi: 10.1016/j.amjopharm.2007.10.005
12. Kollef MH, et al. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998;114:541–8. doi: 10.1378/chest.114.2.541
13. Porhomayon J, Joude P, Adlparvar G, El-Solh AA & Nader ND. The impact of high versus low sedation dosing strategy on cognitive dysfunction in survivors of intensive care units: a systematic review and meta-analysis. J Cardiovasc Thorac Res. 2015;7:43–8. doi: 10.15171/jcvtr.2015.10
14. Schulz M, Schmoldt A, Andresen-Streichert H, Iwersen-Bergmann S. Revisited: therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics. Crit Care. 2020;24:195. doi: 10.1186/s13054-020-02915-5
15. Launiainen T, Ojanperä I. Drug concentrations in post-mortem femoral blood compared with therapeutic concentrations in plasma. Drug Test Anal. 2014;6:308–16. doi: 10.1002/dta.1507
16. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–4. doi: 10.1001/jama.2013.281053.
17. Metnitz PG, et al. SAPS 3 – from evaluation of the patient to evaluation of the intensive care unit. Part 1: objectives, methods and cohort description. Intensive Care Med. 2005;31:1336–44. doi: 10.1007/s00134-005-2762-6
18. Moreno RP et al. SAPS 3 – from evaluation of the patient to evaluation of the intensive care unit. Part 2: development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med. 2005;31:1345–55. doi: 10.1007/s00134-005-2763-5
19. Roman M, Ström L, Tell H, Josefsson M. Liquid chromatography/time-of-flight mass spectrometry analysis of postmortem blood samples for targeted toxicological screening. Anal Bioanal Chem. 2013;405:4107–25. doi: 10.1007/s00216-013-6798-0
20. Johansson A, et al. Quantitation of seven sedative and analgesic drugs in whole blood from intensive care patients using liquid chromatography mass spectrometry. Toxicol Anal Clin. 2021;33:327–37. doi: 10.1016/j.toxac.2021.08.016
21. Barr J. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41:263–306. doi: 10.1097/CCM.0B013E3182783B72
22. Ely EW, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003;289:2983–91. doi: 10.1001/jama.289.22.2983
23. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs. 2005;14:798–804. doi: 10.1111/j.1365-2702.2005.01121.x
24. Gill KV, Voils SA, Chenault GA, Brophy GM. Perceived versus actual sedation practices in adult intensive care unit patients receiving mechanical ventilation. Ann Pharmacother. 2012;46:1331–39. doi: 10.1345/aph.1R037
25. Sharma S, Hashmi MF, Valentino JD. Sedation Vacation in the ICU. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
26. Iirola T, et al. Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients. Br J Anaesth. 2012;108:460–8. doi: 10.1093/bja/aer441.
27. Nies RJ, et al. Monitoring of sedation depth in intensive care unit by therapeutic drug monitoring? A prospective observation study of medical intensive care patients. J Intensive Care. 2018;6:62. doi: 10.1186/s40560-018-0331-7
28. Bremer F, Reulbach U, Schwilden H, Schüttler J. Midazolam therapeutic drug monitoring in intensive care sedation: a 5-year survey. Ther Drug Monit. 2004;26:643–649. doi: 10.1097/00007691-200412000-00010
29. Kirwan CJ et al. Using midazolam to monitor changes in hepatic drug metabolism in critically ill patients. Intensive Care Med. 2009;35:1271–5. doi: 10.1007/s00134-009-1430-7
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