Pharmacodynamic drug-drug interactions in the intensive care unit – single-center experience and literature review
More details
Hide details
Katedra i Klinika Anestezjologii i Intensywnej Terapii, Wydział Lekarski w Katowicach, Śląski Uniwersytet Medyczny w Katowicach
Studenckie Koło Naukowe, Katedra i Klinika Anestezjologii i Intensywnej Terapii, Wydział Lekarski w Katowicach, Śląski Uniwersytet Medyczny w Katowicach
Corresponding author
Piotr Łój   

Katedra i Klinika Anestezjologii i Intensywnej Terapii, Wydział Lekarski w Katowicach, Śląski Uniwersytet Medyczny w Katowicach, ul. Medyków 14, 40-752 Katowice
Ann. Acad. Med. Siles. 2018;72:53-61
Drug-drug interactions (DDIs) constitute a serious health hazard in everyday clinical practice in the intensive care unit (ICU) setting. DDIs can be divided into pharmacokinetic and pharmacodynamic. We sought to investigate the quantity and quality of possible pharmacodynamic DDIs, and their possible side effects in ICU patients over a 12-month period.

Material and methods:
This retrospective study covered data on the pharmacological treatment of 43 consecutive patients (11 F, 32 M) aged 62 ± 15 years, hospitalized between 01.2015 and 02.2016 in a mixed ICU. Pharmacokinetic DDIs were identified and graded. Only severe and clinically important DDIs were subjected to further analysis.

The median baseline SAPS III was 53 (IQR 38–67) points. The median ICU stay was 12 (6–25) days. The subjects were treated with a median number of 22 (12–27) drugs. We identified 27 (16–41) possible DDIs per patient, including 3 (1–7) DDI of a severe grade. The total number of severe and clinically important pharmacodynamic pDDIs was 1189 and 320 of them were analyzed in details. Despite the gross number of those life-threatening conditions identified, no clinical sequelae of DDIs were recognized.

DDIs as well as their effects are challenging for precise evaluation, especially due to the need for multidrug treatment in ICU patients. Despite the gross number of pDDIs in the ICU setting, further investigations are needed to examine their clinical sequelae.

Kane-Gill S.L., Devlin J.W. Adverse drug event reporting in intensive care units: a survey of current practices. Ann. Pharmacother. 2006; 40(7–8): 1267–1273.
Joshua L., Devi P., Guido S. Adverse drug reactions in medical intensive care unit of a tertiary care hospital. Pharmacoepidemiol. Drug. Saf. 2009; 18(7): 639–645.
Kane-Gill S.L., Jacobi J., Rothschild J.M. Adverse drug events in intensive care units: risk factors, impact, and the role of team care. Crit. Care. Med. 2010; 38(6 Suppl.): S83–S89.
Kopp B.J., Mrsan M., Erstad B.L., Duby J.J. Cost implications of and potential adverse events prevented by interventions of a critical care pharmacist. Am. J. Health. Syst. Pharm. 2007; 64(23): 2483–2487.
Krähenbühl-Melcher A., Schlienger R., Lampert M., Haschke M., Drewe J., Krähenbühl S. Drug-related problems in hospitals: a review of the recent literature. Drug Saf. 2007; 30(5): 379–407.
Baxter K., Preston C.L. Stockley's Drug Interactions. [online] London: Pharmaceutical Press <http://www.medicinescomplete.c...> [dostęp: 01.03.2017].
Benoit S.R., Mendelsohn A.B., Nourjah P., Staffa J.A., Graham D.J. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur. J. Cardiovasc. Prev. Rehabil. 2005; 12(4): 363–368.
Baxter K., Preston C.L. Stockley's Drug Interactions. [online] London: Pharmaceutical Press <http://www.medicinescomplete.c...> [dostęp: 01.03.2017].
Yuan H.B., Yang M.W., Chan K.H., Lee T.Y. The interaction of diazepam with vecuronium: a clinical study. Zhonghua Yi Xue Za Zhi 1994; 54(4): 259–264.
Driessen J.J., Crul J.F., Vree T.B., van Egmond J., Booij L.H. Benzodiazepines and neuromuscular blocking drugs in patients. Acta Anaesthesiol. Scand. 1986; 30(8): 642–646.
Miller R.D., Sohn Y.J., Matteo R.S. Enhancement of d-tubocurarine neuromuscular blockade by diuretics in man. Anesthesiology 1976; 45(4): 442–445.
Azar I., Cottrell J., Gupta B., Turndorf H. Furosemide facilitates recovery of evoked twitch response after pancuronium. Anesth. Analg. 1980; 59(1): 55–57.
Scappaticci K.A., Ham J.A., Sohn Y.J., Miller R.D., Dretchen K.L. Effects of furosemide on the neuromuscular junction. Anesthesiology 1982; 57(5): 381–388.
Daller J.A., Erstad B., Rosado L., Otto C., Putnam C.W. Aminophylline antagonizes the neuromuscular blockade of pancuronium but not vecuronium. Crit. Care. Med. 1991; 19(7): 983–985.
Doll D.C., Rosenberg H. Antagonism of neuromuscular blockage by theophylline. Anesth. Analg. 1979; 58(2): 139–40.
Azar I., Kumar D., Betcher A.M. Resistance to pancuronium in an asthmatic patient treated with aminophylline and steroids. Can. Anaesth. Soc. J. 1982; 29(3): 280–282.
Belani K.G., Anderson W.W., Buckley J.J. Adverse drug interaction involving pancuronium and aminophylline. Anesth. Analg. 1982; 61(5): 473––474.
de Gouw N.E., Crul J.F., Vandermeersch E., Mulier J.P., van Egmond J., Van Aken H. Interaction of antibiotics on pipecuronium-induced neuromuscular blockade. J. Clin. Anesth. 1993; 5(3): 212–215.
Mackie K., Pavlin E.G. Recurrent paralysis following piperacillin administration. Anesthesiology 1990; 72(3): 561–563.
Albrecht R.F., Lanier W.L. Potentiation of succinylcholine-induced phase II block by vancomycin. Anesth. Analg. 1993; 77(6): 1300–1302.
LaPorte J., Mignault G., L’Allier R., Perron P. Un cas d’apnée à la néomycine. Union. Med. Can. 1959; 88(2): 149–152.
Pittinger C.B., Eryasa Y., Adamson R. Antibiotic-induced paralysis. Anesth. Analg. 1970; 49(3): 487–501.
Hasfurther D.L., Bailey P.L. Failure of neuromuscular blockade reversal after rocuronium in a patient who received oral neomycin. Can. J. Anaesth. 1996; 43(6): 617–620.
Bertino J.S., Booker L.A., Franck P.A., Jenkins P.L., Franck K.R., Nafziger A.N. Incidence of and significant risk factors for aminoglycoside-associated nephrotoxicity in patients dosed by using individualized pharmacokinetic monitoring. J. Infect. Dis. 1993; 167(1): 173–179.
Streetman D.S., Nafziger A.N., Destache C.J., Bertino J.S. Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs. Pharmacotherapy 2001; 21(4): 443–451.
Goetz M.B, Sayers J. Nephrotoxicity of vancomycin and aminoglycoside therapy separately and in combination. J. Antimicrob. Chemother. 1993; 32(2): 325–334.
Sumikawa K., Kawabata K., Aono Y., Kamibayashi T., Yoshiya I. Reduction in vecuronium infusion dose requirements by diltiazem in humans. Anesthesiology 1992; 77: A939.
Takasaki Y., Naruoka Y., Shimizu C., Ochi G., Nagaro T., Arai T. Diltiazem potentiates the neuromuscular blockade by vecuronium in humans. Masui 1995; 44(4): 503–507.
van Poorten J.F., Dhasmana K.M., Kuypers R.S., Erdmann W. Verapamil and reversal of vecuronium neuromuscular blockade. Anesth. Analg. 1984; 63(2): 155–157.
Lee T.H., Friedman P.L., Goldman L., Stone P.H., Antman E.M. Sinus arrest and hypotension with combined amiodarone-diltiazem therapy. Am. Heart. J .1985; 109(1): 163–164.
Marcus F.I. Drug interactions with amiodarone. Am. Heart. J. 1983; 106(4Pt 2): 924–930.
Cordarone X (Amiodarone hydrochloride). Zentiva. UK Summary of product characteristics, April 2014.
Cordarone (Amiodarone hydrochloride). Wyeth Pharmaceuticals Inc. US Prescribing information, December 2014.
Inoue K., El-Banayosy A., Stolarski L., Reichelt W. Vecuronium induced bradycardia following induction of anaesthesia with etomidate or thiopentone, with or without fentanyl. Br. J .Anaesth. 1988; 60(1): 10–17.
Werner D., Wuttke H., Fromm M.F., Schaefer S., Eschenhagen T., Brune K., Daniel W.G., Werner U. Effect of amiodarone on the plasma levels of metoprolol. Am. J. Cardiol. 2004; 94(10): 1319–1321.
Giri S., White C.M., Dunn A.B., Felton K., Freeman-Bosco L., Reddy P., Tsikouris J.P., Wilcox H.A., Kluger J. Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): a randomised placebo-controlled trial. Lancet 2001; 357(9259): 830–836.
Park-Wyllie L.Y., Mamdani M.M., Li P., Gill S.S., Laupacis A., Juurlink D.N. Cholinesterase inhibitors and hospitalisation for bradycardia: a population-based study. PLoS Med 2009; 6: e1000157.
Bartolone R.S., Rao T.L.K. Dysrhythmias following muscle relaxant administration in patients receiving digitalis. Anesthesiology 1983; 58(6): 567–569.
Ben-Shlomo I., Abd-El-Khalim H., Ezry J., Zohar S., Tverskoy M. Midazolam acts synergistically with fentanyl for induction of anaesthesia. Br. J. Anaesth. 1990; 64(1): 45–47.
Bailey P.L., Moll J.W.B., Pace N.L., East K.A., Stanley T.H. Respiratory effects of midazolam and fentanyl: potent interaction producing hypoxemia and apnea. Anesthesiology 1988; 69: 3A, A813.
Hase I., Oda Y., Tanaka K., Mizutani K., Nakamoto T., Asada A. I.v. fentanyl decreases the clearance of midazolam. Br. J. Anaesth. 1997; 79(6): 740–743.
Luger T.J., Hill H.F., Schlager A. Can midazolam diminish sufentanil analgesia in patients with major trauma? A retrospective study with 43 patients. Drug Metabol. Drug Interact. 1992; 10: 177–184.
Hamaoka N., Oda Y., Hase I., Mizutani K., Nakamoto T., Ishizaki T., Asada A. Propofol decreases the clearance of midazolam by inhibiting CYP3A4: an in vivo and in vitro study. Clin. Pharmacol. Ther. 1999; 66(2): 110–117.
Charkterystyka Produktu Leczniczego Amantix 200 mg/500 ml roztwór do infuzji. Merz Pharmaceuticals GmbH. Styczeń 2014.
Product Information. Symmetrel (amantadine). DuPont Pharmaceuticals, Wilmington, DE, January 2009.
Greiff J.M.C., Rowbotham D. Pharmacokinetic drug interactions with gastrointestinal motility modifying agents. Clin. Pharmacokinet. 1994; 27(6): 447–461.
Product Information. Reglan (metoclopramide). Wyeth-Ayerst Laboratories, Philadelphia, PA, August 2017.
Goulet J.P., Perusse R., Turcotte J.Y. Contraindications to vasoconstrictors in dentistry: Part III. Pharmacologic interactions. Oral Surg. Oral Med. Oral Pathol. 1992; 74(5): 692–697.
Lindenfeld J.A., Lowes B.D., Bristow M.R. Hypotension with dobutamine: B-adrenergic antagonist selectivity at low doses of carvedilol. Ann. Pharmacother. 1999; 33(12): 1266–1269.
Kotlyar E., Keogh A.M., Macdonald P.S., Arnold R.H., McCaffrey D.J., Glanville A.R. Tolerability of carvedilol in patients with heart failure and concomitant chronic obstructive pulmonary disease or asthma. J. Heart Lung Transplant. 2002; 21(12): 1290–1295.
Streetman D.S., Nafziger A.N., Destache C.J., Bertino J.S. Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs. Pharmacotherapy 2001; 21(4): 443–451.
Dowell J.A., Korth-Bradley J., Milisci M., Tantillo K., Amorusi P., Tse S. Evaluating possible pharmacokinetic interactions between tobramycin, piperacillin, and a combination of piperacillin and tazobactam in patients with various degrees of renal impairment. J. Clin. Pharmacol. 2001; 41(9): 979–986.
Ganzini L., Casey D.E., Hoffman W.F., McCall A.L. The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch. Intern. Med. 1993; 153(12): 1469–1475.
Kenney C., Hunter C., Davidson A., Jankovic J. Metoclopramide, an Increasingly Recognized Cause of Tardive Dyskinesia. J. Clin. Pharmacol. 2008; 48(3): 379–384.
Gardiner J.S., Blough D., Drinkard CR., Shatin D., Anderson G., Graham D., Alderfer R. Tramadol and seizures: a surveillance study in a managed care population. Pharmacotherapy 2000; 20(12): 1423–1431.
Rosenstein D.L., Nelson J.C., Jacobs S.C. Seizures associated with antidepressants: a review. J. Clin. Psychiatry 1993; 54(8): 289–299.
van der Linden P.D., Sturkenboom M.C., Herings R.M., Leufkens H.M., Rowlands S., Stricker B.H. Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids. Arch. Intern. Med. 2003; 163(15): 1801–1807.
Gillman P.K. A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol. Psychiatry. 2006; 59(11): 1046–1051.
Boyer E.W., Shannon M. The serotonin syndrome. N. Engl. J. Med. 2005; 352(11): 1112–1120.
Journals System - logo
Scroll to top