Optimizing Drug Dosing in the ICU

  • X. Liu
  • P. Kruger
  • M. S. Roberts


Patients admitted to the intensive care unit (ICU) may exhibit multiple organ dysfunctions and usually require treatment with a wide range of drugs such as sedatives, analgesics, neuromuscular blockers, and antimicrobials [1]. Recommendations for the dosing regimens in ICU patients are often extrapolated from clinical trials in healthy volunteers or non-ICU patients. This extrapolation assumes similar drug behavior (pharmacokinetics and pharmacodynamics) among ICU and other patients or healthy volunteers. However, it is well described that many drugs used in critically ill patients may have alterations of the pharmacokinetic and pharmacodynamic properties due to pathophysiological changes or drug interactions [1, 2, 3, 4]. These changes may occur even within a single patient at varying stages of their illness and, therefore, critically ill patients offer unique challenges in drug dosing.


Intensive Care Unit Intensive Care Unit Patient Continuous Renal Replacement Therapy Hepatic Blood Flow Bayesian Forecast 
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  1. 1.
    Power BM, Forbes AM, van Heerden PV, Ilett KF (1998) Pharmacokinetics of drugs used in critically ill adults. Clin Pharmacokinet 34: 25–56CrossRefPubMedGoogle Scholar
  2. 2.
    Boucher BA, Wood GC, Swanson JM (2006) Pharmacokinetic changes in critical illness. Crit Care Clin 22: 255–271CrossRefPubMedGoogle Scholar
  3. 3.
    Lipman J (2000) Towards better ICU antibiotic dosing. Crit Care Resusc 2: 282–289PubMedGoogle Scholar
  4. 4.
    Wagnerand BK, O’Hara DA (1997) Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet 33: 426–453CrossRefGoogle Scholar
  5. 5.
    Benko R, Matuz M, Doro P, et al (2007) Pharmacokinetics and pharmacodynamics of levofloxacin in critically ill patients with ventilator-associated pneumonia. Int J Antimicrob Agents 30: 162–168CrossRefPubMedGoogle Scholar
  6. 6.
    Fish DN, Teitelbaum I, Abraham E (2005) Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother 49: 2421–2428CrossRefPubMedGoogle Scholar
  7. 7.
    Johnston AJ, Steiner LA, O’Connell M, Chatfield DA, Gupta AK, Menon DK (2004) Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients. Intensive Care Med 30: 45–50CrossRefPubMedGoogle Scholar
  8. 8.
    Vincent JL, Spapen HD, Creteur J, et al (2006) Pharmacokinetics and pharmacodynamics of once-weekly subcutaneous epoetin alfa in critically ill patients: results of a randomized, double-blind, placebo-controlled trial. Crit Care Med 34: 1661–1667CrossRefPubMedGoogle Scholar
  9. 9.
    Mohr JF, Wanger A, Rex JH (2004) Pharmacokinetic/pharmacodynamic modeling can help guide targeted antimicrobial therapy for nosocomial gram-negative infections in critically ill patients. Diagn Microbiol Infect Dis 48: 125–130CrossRefPubMedGoogle Scholar
  10. 10.
    de Wildt SN, de Hoog M, Vinks AA, van der Giesen E, van den Anker JN (2003) Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Crit Care Med 31: 1952–1958CrossRefPubMedGoogle Scholar
  11. 11.
    Herfindaland ET, Gourley DR (2000) Textbook of Therapeutics: Drug and Disease Management. Lippincott Williams and Wilkins, PhiladelphiaGoogle Scholar
  12. 12.
    Siebert GA, Hung DY, Chang P, Roberts MS (2004) Ion-trapping, microsomal binding, and unbound drug distribution in the hepatic retention of basic drugs. J Pharmacol Exp Ther 308: 228–235CrossRefPubMedGoogle Scholar
  13. 13.
    Laznicekand M, Laznickova A (1995) The effect of lipophilicity on the protein binding and blood cell uptake of some acidic drugs. J Pharm Biomed Anal 13: 823–828CrossRefGoogle Scholar
  14. 14.
    Herve F, Urien S, Albengres E, Duche JC, Tillement JP (1994) Drug binding in plasma. A summary of recent trends in the study of drug and hormone binding. Clin Pharmacokinet 26: 44–58CrossRefPubMedGoogle Scholar
  15. 15.
    Martyn JA, Abernethy DR, Greenblatt DJ (1984) Plasma protein binding of drugs after severe burn injury. Clin Pharmacol Ther 35: 535–539PubMedGoogle Scholar
  16. 16.
    Hammons KB, Edwards RF, Rice WY (2006) Golf-inhibiting gynecomastia associated with atorvastatin therapy. Pharmacotherapy 26: 1165–1168CrossRefPubMedGoogle Scholar
  17. 17.
    Benet LZ, Hoener BA (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71: 115–121CrossRefPubMedGoogle Scholar
  18. 18.
    Vrhovac B, Sarapa N, Bakran I, et al (1995) Pharmacokinetic changes in patients with oedema. Clin Pharmacokinet 28: 405–418CrossRefPubMedGoogle Scholar
  19. 19.
    Barlage S, Frohlich D, Bottcher A, et al (2001) ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response. J Lipid Res 42: 281–290PubMedGoogle Scholar
  20. 20.
    Sampliner R, Perrier D, Powell R, Finley P (1984) Influence of ascites on tobramycin pharmacokinetics. J Clin Pharmacol 24: 43–46PubMedGoogle Scholar
  21. 21.
    Buijk SL, Gyssens IC, Mouton JW, Van Vliet A, Verbrugh HA, Bruining HA (2002) Pharmacokinetics of ceftazidime in serum and peritoneal exudate during continuous versus intermittent administration to patients with severe intra-abdominal infections. J Antimicrob Chemother 49: 121–128CrossRefPubMedGoogle Scholar
  22. 22.
    Botha FJ, van der Bijl P, Seifart HI, Parkin DP (1996) Fluctuation of the volume of distribution of amikacin and its effect on once-daily dosage and clearance in a seriously ill patient. Intensive Care Med 22: 443–446CrossRefPubMedGoogle Scholar
  23. 23.
    Ronchera-Oms CL, Tormo C, Ordovas JP, Abad J, Jimenez NV (1995) Expanded gentamicin volume of distribution in critically ill adult patients receiving total parenteral nutrition. J Clin Pharm Ther 20: 253–258CrossRefPubMedGoogle Scholar
  24. 24.
    Reaand RS, Capitano B (2007) Optimizing use of aminoglycosides in the critically ill. Semin Respir Crit Care Med 28: 596–603CrossRefGoogle Scholar
  25. 25.
    Mimoz O, Schaeffer V, Incagnoli P, et al (2001) Co-amoxiclav pharmacokinetics during posttraumatic hemorrhagic shock. Crit Care Med 29: 1350–1355CrossRefPubMedGoogle Scholar
  26. 26.
    Park GR (1996) Molecular mechanisms of drug metabolism in the critically ill. Br J Anaesth 77: 32–49PubMedGoogle Scholar
  27. 27.
    McKindley DS, Hanes S, Boucher BA (1998) Hepatic drug metabolism in critical illness. Pharmacotherapy 18: 759–778PubMedGoogle Scholar
  28. 28.
    Aninat C, Seguin P, Descheemaeker PN, Morel F, Malledant Y, Guillouzo A (2008) Catecholamines induce an inflammatory response in human hepatocytes. Crit Care Med 36: 848–854CrossRefPubMedGoogle Scholar
  29. 29.
    Boucher BA, Kuhl DA, Fabian TC, Robertson JT (1991) Effect of neurotrauma on hepatic drug clearance. Clin Pharmacol Ther 50: 487–497CrossRefPubMedGoogle Scholar
  30. 30.
    Meier-Hellmann A, Reinhart K, Bredle DL, Specht M, Spies CD, Hannemann L (1997) Epinephrine impairs splanchnic perfusion in septic shock. Crit Care Med 25: 399–404CrossRefPubMedGoogle Scholar
  31. 31.
    Obritsch MD, Bestul DJ, Jung R, Fish DN, MacLaren R (2004) The role of vasopressin in vasodilatory septic shock. Pharmacotherapy 24: 1050–1063CrossRefPubMedGoogle Scholar
  32. 32.
    De Backer D, Creteur J, Silva E, Vincent JL (2003) Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? Crit Care Med 31: 1659–1667CrossRefPubMedGoogle Scholar
  33. 33.
    Weinbren MJ (1999) Pharmacokinetics of antibiotics in burn patients. J Antimicrob Chemother 44: 319–327CrossRefPubMedGoogle Scholar
  34. 34.
    Kumar A, Roberts D, Wood KE, et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34: 1589–1596CrossRefPubMedGoogle Scholar
  35. 35.
    Lipman J, Wallis SC, Boots RJ (2003) Cefepime versus cefpirome: the importance of creatinine clearance. Anesth Analg 97: 1149–1154CrossRefPubMedGoogle Scholar
  36. 36.
    Han TH, Lee JH, Kwak IS, Kil HY, Han KW, Kim KM (2005) The relationship between bispectral index and targeted propofol concentration is biphasic in patients with major burns. Acta Anaesthesiol Scand 49: 85–91CrossRefPubMedGoogle Scholar
  37. 37.
    Tschida SJ, Hoey LL, Nahum A, Vance-Bryan K (1995) Atracurium resistance in a critically Ill patient. Pharmacotherapy 15: 533–539PubMedGoogle Scholar
  38. 38.
    Link E, Parish S, Bowman L, et al (2008) SLCOBI Variants and statin-induced myopathy — a genomewide study. N Engl J Med 359: 789–799CrossRefPubMedGoogle Scholar
  39. 39.
    Zeitlinger MA, Dehghanyar P, Mayer BX, et al (2003) Relevance of soft-tissue penetration by levofloxacin for target site bacterial killing in patients with sepsis. Antimicrob Agents Chemother 47: 3548–3553CrossRefPubMedGoogle Scholar
  40. 40.
    Denaroand CP, Ravenscroft PJ (1989) Comparison of Sawchuk-Zaske and Bayesian forecasting for aminoglycosides in seriously ill patients. Br J Clin Pharmacol 28: 37–44Google Scholar
  41. 41.
    Aarons L (1991) Population pharmacokinetics: theory and practice. Br J Clin Pharmacol 32: 669–670PubMedGoogle Scholar
  42. 42.
    U.S. Department of Health and Human Services, FDA, CDER, CBER (1999) Guidance for industry: population pharmacokinetics. Available at: pdf Accessed Nov 2008Google Scholar
  43. 43.
    Steimer JL, Mallet A, Golmard JL, Boisvieux JF (1984) Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model. Drug Metab Rev 15: 265–292CrossRefPubMedGoogle Scholar
  44. 44.
    Sheiner LB, Beal S, Rosenberg B, Marathe VV (1979) Forecasting individual pharmacokinetics. Clin Pharmacol Ther 26: 294–305PubMedGoogle Scholar
  45. 45.
    Roberts JA, Kruger P, Paterson DL, Lipman J (2008) Antibiotic resistance—what’s dosing got to do with it? Crit Care Med 36: 2433–2440CrossRefPubMedGoogle Scholar
  46. 46.
    del Mar Fernandez de Gatta Garcia M, Revilla N, Calvo MV, Dominguez-Gil A, Sanchez Navarro A (2007) Pharmacokinetic/pharmacodynamic analysis of vancomycin in ICU patients. Intensive Care Med 33: 279–285CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • X. Liu
    • 1
  • P. Kruger
    • 2
  • M. S. Roberts
    • 2
  1. 1.Therapeutics Research UnitPrincess Alexandra HospitalWoolloongabba, BrisbaneAustralia
  2. 2.Intensive Care UnitPrincess Alexandra HospitalWoolloongabba, BrisbaneAustralia

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