Skip to main content
SpringerLink
Log in

Modeling of Amiodarone Effect on Heart Rate Control in Critically Ill Patients with Atrial Tachyarrhythmias

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Aims

Amiodarone is the gold-standard medication to control heart rate in critically ill patients with atrial tachyarrhythmias (ATs); however, effective doses and covariates influencing its efficacy remain unknown. We therefore performed pharmacodynamic modeling of heart rate reduction induced by amiodarone in these patients.

Methods and Results

This observational study included 80 consecutive severely ill patients receiving amiodarone to treat ATs. A total of 1348 time–heart rate observations with 361 amiodarone dose administrations were analyzed during a period of up to 6 days after hospital treatment initiation using a nonlinear mixed-effect model. Pretreatment with amiodarone before intensive care administration, paroxysmal versus persistent AT, catecholamine infusion, and fluid and magnesium loading were among the covariates assessed in the model. In case of paroxysmal AT in a patient not pretreated with amiodarone, a 300 mg intravenous loading dose combined with an 800 mg oral dose on the first day, followed by 800 mg/day orally for 4 days was effective in achieving a heart rate between 80 and 115 bpm within the first day, and to maintain it during the next 4 days. Corresponding doses were twice as high in patients with persistent AT. Use of intravenous magnesium (p < 0.02) and fluid loading (p < 0.02) was associated with an earlier and greater heart rate decrease, while use of dobutamine had an opposite influence (p < 0.05).

Conclusions

In critically ill patients with AT, the dose of amiodarone required to control heart rate is influenced by the type of AT and by other easily measurable conditions which may allow better individualization of amiodarone dosing.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Artucio H, Pereira M. Cardiac arrhythmias in critically ill patients: epidemiologic study. Crit Care Med. 1990;18:1383–8.

    Article  CAS  PubMed  Google Scholar 

  2. Packer DL, Bardy GH, Worley SJ, et al. Tachycardia-induced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J Cardiol. 1986;57:563–70.

    Article  CAS  PubMed  Google Scholar 

  3. Nerheim P, Birger-Botkin S, Piracha L, Olshansky B. Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia. Circulation. 2004;110:247–52.

    Article  PubMed  Google Scholar 

  4. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369–429.

    Article  Google Scholar 

  5. January CT, Wann LS, Alpert JS, ACC/AHA Task Force Members, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published erratum appears in Circulation. 2014;130(23):e270–1. Circulation. 2014;130:2071–104.

    Article  PubMed  Google Scholar 

  6. Kumar A. Intravenous amiodarone for therapy of atrial fibrillation and flutter in critically ill patients with severely depressed left ventricular function. South Med J. 1996;89:779–85.

    Article  CAS  PubMed  Google Scholar 

  7. Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Intravenous amiodarone for acute heart rate control in the critically ill patient with atrial tachyarrhythmias. Am J Cardiol. 1998;81:594–8.

    Article  CAS  PubMed  Google Scholar 

  8. Mayr A, Knotzer H, Mutz N, Hasibeder W. Atrial tachyarrhythmia after cardiac surgery. Intensive Care Med. 1999;25:242–3.

    Article  CAS  PubMed  Google Scholar 

  9. Galve E, Rius T, Ballester R, et al. Intravenous amiodarone in treatment of recent-onset atrial fibrillation: results of a randomized, controlled study. J Am Coll Cardiol. 1996;27:1079–82.

    Article  CAS  PubMed  Google Scholar 

  10. Delle Karth G, Geppert A, Neunteufl T, et al. Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias. Crit Care Med. 2001;29:1149–53.

  11. Carlsson J, Miketic S, Windeler J, STAF Investigators, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol. 2003;41:1690–6.

    Article  PubMed  Google Scholar 

  12. Van Gelder IC, Hagens VE, Bosker HA, Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347:1834–40.

    Article  PubMed  Google Scholar 

  13. Donaldson L, Grant IS, Naysmith MR, Thomas JS. Acute amiodarone-induced lung toxicity. Intensive Care Med. 1998;24:626–30.

    Article  CAS  PubMed  Google Scholar 

  14. Rätz-Bravo AE, Drewe J, Schlienger RG, Krähenbühl S, Pargger H, Ummenhofer W. Hepatotoxicity during rapid intravenous loading with amiodarone: description of three cases and review of the literature. Crit Care Med. 2005;33:128–34 (discussion 245–6).

    Article  PubMed  Google Scholar 

  15. Papiris SA, Triantafillidou C, Kolilekas L, Markoulaki D, Manali ED. Amiodarone: review of pulmonary effects and toxicity. Drug Saf. 2010;33:539–58.

    Article  CAS  PubMed  Google Scholar 

  16. Lafont E, Urien S, Salem JE, Heming N, Faisy C. Modeling for critically ill patients: an introduction for beginners. J Crit Care. 2015;30:1287–94.

    Article  PubMed  Google Scholar 

  17. Tonet JL, Lechat P, Frank R, et al. Electrocardiographic effects and antiarrhythmic action of 1200 mg of oral amiodarone per day. Ann Cardiol Angeiol (Paris). 1984;33:309–15.

    CAS  PubMed  Google Scholar 

  18. Kochiadakis GE, Igoumenidis NE, Solomou MC, Kaleboubas MD, Chlouverakis GI, Vardas PE. Efficacy of amiodarone for the termination of persistent atrial fibrillation. Am J Cardiol. 1999;83:58–61.

    Article  CAS  PubMed  Google Scholar 

  19. Anastasiou-Nana M, Levis GM, Moulopoulos S. Pharmacokinetics of amiodarone after intravenous and oral administration. Int J Clin Pharmacol Ther Toxicol. 1982;20:524–9.

    CAS  PubMed  Google Scholar 

  20. Pourbaix S, Berger Y, Desager JP, Pacco M, Harvengt C. Absolute bioavailability of amiodarone in normal subjects. Clin Pharmacol Ther. 1985;37:118–23.

    Article  CAS  PubMed  Google Scholar 

  21. Daily Med. Current medication information: amiodarone. http://dailymed.nlm.nih.gov/dailymed/index.cfm. Accessed 1 Dec 2015.

  22. Vardas PE, Kochiadakis GE, Igoumenidis NE, et al. Amiodarone as a first-choice drug for restoring sinus rhythm in patients with atrial fibrillation: a randomized, controlled study. Chest. 2000;117:1538–45.

    Article  CAS  PubMed  Google Scholar 

  23. Lotto A, Satolli R, Baldini MR. Hemodynamic effects of amiodarone. Circulation. 1980;62:666.

    Article  CAS  PubMed  Google Scholar 

  24. Schwartz A, Shen E, Morady F, et al. Hemodynamic effects of intravenous amiodarone in patients with depressed left ventricular function and recurrent ventricular tachycardia. Am Heart J. 1983;106:848–56.

    Article  CAS  PubMed  Google Scholar 

  25. Remme WJ, Kruyssen HA, Look MP, et al. Hemodynamic effects and tolerability of intravenous amiodarone in patients with impaired left ventricular function. Am Heart J. 1991;122:96–103.

    Article  CAS  PubMed  Google Scholar 

  26. Jacqmin P, Snoeck E, van Schaick EA, et al. Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model. J Pharmacokinet Pharmacodyn. 2007;34:57–85.

    Article  CAS  PubMed  Google Scholar 

  27. Evans SJ, Myers M, Zaher C, et al. High dose oral amiodarone loading: electrophysiologic effects and clinical tolerance. J Am Coll Cardiol. 1992;19:169–73.

    Article  CAS  PubMed  Google Scholar 

  28. Hainsworth R. Reflexes from the heart. Physiol Rev. 1991;71:617–58.

    CAS  PubMed  Google Scholar 

  29. Fellahi J-L, Parienti J-J, Hanouz J-L, et al. Perioperative use of dobutamine in cardiac surgery and adverse cardiac outcome: propensity-adjusted analyses. Anesthesiology. 2008;108:979–87.

    Article  CAS  PubMed  Google Scholar 

  30. Butterworth J. Dobutamine: too dangerous for “routine” administration? Anesthesiology. 2008;108:973–4.

    Article  PubMed  Google Scholar 

  31. Miller S, Crystal E, Garfinkle M, et al. Effects of magnesium on atrial fibrillation after cardiac surgery: a meta-analysis. Heart. 2005;91:618–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mayr A, Ritsch N, Knotzer H, et al. Effectiveness of direct-current cardioversion for treatment of supraventricular tachyarrhythmias, in particular atrial fibrillation, in surgical intensive care patients. Crit Care Med. 2003;31:401–5.

    Article  PubMed  Google Scholar 

  33. Kanji S, Williamson DR, Yaghchi BM, et al. Epidemiology and management of atrial fibrillation in medical and noncardiac surgical adult intensive care unit patients. J Crit Care. 2012;27:326 (e1–8).

    Article  PubMed  Google Scholar 

  34. Singh BN, Singh SN, Reda DJ, Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) Investigators, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med. 2005;352:1861–72.

    Article  CAS  PubMed  Google Scholar 

  35. Sticherling C, Behrens S, Kamke W, Stahn A, Zabel M. Comparison of acute and long-term effects of single-dose amiodarone and verapamil for the treatment of immediate recurrences of atrial fibrillation after transthoracic cardioversion. Europace. 2005;7:546–53.

    Article  PubMed  Google Scholar 

  36. Harris L, Hind CR, McKenna WJ, et al. Renal elimination of amiodarone and its desethyl metabolite. Postgrad Med J. 1983;59:440–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vietti-Ramus G, Veglio F, Marchisio U, Burzio P, Latini R. Efficacy and safety of short intravenous amiodarone in supraventricular tachyarrhythmias. Int J Cardiol. 1992;35:77–85.

    Article  CAS  PubMed  Google Scholar 

  38. Brodsky MA, Allen BJ, Walker CJ, et al. Amiodarone for maintenance of sinus rhythm after conversion of atrial fibrillation in the setting of a dilated left atrium. Am J Cardiol. 1987;60:572–5.

    Article  CAS  PubMed  Google Scholar 

  39. Kochiadakis GE, Igoumenidis NE, Parthenakis FI, Chlouverakis GI, Vardas PE. Amiodarone versus propafenone for conversion of chronic atrial fibrillation: results of a randomized, controlled study. J Am Coll Cardiol. 1999;33:966–71.

    Article  CAS  PubMed  Google Scholar 

  40. Greenberg ML, Lerman BB, Shipe JR, Kaiser DL, DiMarco JP. Relation between amiodarone and desethylamiodarone plasma concentrations and electrophysiologic effects, efficacy and toxicity. J Am Coll Cardiol. 1987;9:1148–55.

    Article  CAS  PubMed  Google Scholar 

  41. Deharo JC, Durand A, Macaluso G, et al. Clinical electrophysiologic effects of a single high oral dose of amiodarone. Fundam Clin Pharmacol. 1997;11:275–80.

    Article  CAS  PubMed  Google Scholar 

  42. Patsilinakos S, Christou A, Kafkas N, et al. Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. Am J Cardiol. 2010;106:673–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacology and CIC-1421, AP-HP, Pitié-Salpêtrière Hospital, Paris, France

      Joe-Elie Salem, Jean-Sébastien Hulot & Christian Funck-Brentano

    2. Critical Care Unit, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité, Paris, France

      Maria El-Aissaoui & Nadia Aissaoui

    3. Faculty of Medicine, INSERM UMRS ICAN-1166, Sorbonne Universités, UPMC Univ Paris 06, Paris, France

      Joe-Elie Salem, Margaux Alazard, Jean-Sébastien Hulot & Christian Funck-Brentano

    4. Centre d’Investigation Clinique-1419 INSERM, EAU-08 Université Paris Descartes Sorbonne Paris Cité, Paris, France

      Christophe Faisy & Saik Urien

    5. Department of Cardiology-Rythmology Unit, AP-HP, Pitié-Salpêtrière Hospital, 75013, Paris, France

      Joe-Elie Salem & Margaux Alazard

    6. Cardiology-Rythmology Unit, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité, Paris, France

      Jean-Yves Le-Heuzey

    7. Centre d’Investigation Clinique Paris-Est, Hôpital La Pitié-Salpêtrière, Bâtiment Antonin Gosset, 47-83 Bld de l’hôpital, 75651, Paris Cedex 13, France

      Joe-Elie Salem

    Authors
    1. Joe-Elie Salem
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Maria El-Aissaoui
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Margaux Alazard
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Jean-Sébastien Hulot
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Nadia Aissaoui
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Jean-Yves Le-Heuzey
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Christian Funck-Brentano
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Christophe Faisy
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Saik Urien
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Joe-Elie Salem.

    Ethics declarations

    Funding

    No external funding was used in the preparation of this article.

    Disclosures

    Joe-Elie Salem, Maria El-Aissaoui, Margaux Alazard, Jean-Sébastien Hulot, Nadia Aissaoui, Jean-Yves Le-Heuzey, Christian Funck-Brentano, Christophe Faisy, and Saik Urien declare that they have no conflicts of interest.

    Additional information

    C. Faisy and S. Urien contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Salem, JE., El-Aissaoui, M., Alazard, M. et al. Modeling of Amiodarone Effect on Heart Rate Control in Critically Ill Patients with Atrial Tachyarrhythmias. Clin Pharmacokinet 55, 991–1002 (2016). https://doi.org/10.1007/s40262-016-0372-9

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s40262-016-0372-9

    Keywords

    Search

    Navigation