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In Response

Epker, Jelle L. MD; Kompanje, Erwin J. O. PhD

doi: 10.1213/ANE.0b013e3182330d9e
Letters to the Editor: Letters & Announcements

Department of Intensive Care Medicine ErasmusMC Rotterdam, The Netherlands (Epker, Kompanje)

Rady and Verheijde1 suggest that we made an incorrect or unreliable analysis with our data concerning the relationship between time of administration of opioids and sedatives and the time until death.2 This concern is surprising, however, because as mentioned in the Limitations section, we deliberately refrained from a statistical analysis. Because several other studies did show that in terminally ill patients the contribution of sedatives and opioids to the time until death is negative or cannot be proven, we used these results for our discussion.35 The study referred to was not published when our article was accepted and deals with a different population than that discussed in our article.6

Both Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation scores are high in comparison with those of other studies. This logically implies that the incidence of multiple organ failure is high in our population. Together with the fact that treatment is withdrawn simultaneously and not consecutively, it is inevitable that patients die within a very short time.

We did not show data of the level of discomfort; however, the dosage range of sedatives and opioids 4 hours before death was not very different from the maximum dosages in the last hour, suggesting that the standard sedation and pain medication regimen was continued and not automatically increased after the withdrawal of (life-sustaining) treatment. The articles referred to discuss medication use in neonatology departments, again a totally different patient population.

Pharmacodynamics are indeed different in critically ill patients with multiorgan failure than in “normal” patients. The question however is, should we take these alterations into account when we already titrate medication until the desired effect is reached? Furthermore, to our knowledge, there are no studies assessing pharmacodynamics of sedatives and opioids in terminally ill intensive care unit patients to get a better dose–effect relationship, and we therefore would not know how to implement the advice given.

Jelle L. Epker, MD

Erwin J. O. Kompanje, PhD

Department of Intensive Care Medicine


Rotterdam, The Netherlands

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1. Rady M, Verhijde J. The confounding effects of pharmacokinetics and pharmacodynamics of sedatives and opioids on time to death after terminal withdrawal of life-support in the intensive care unit. Anesth Analg 2011;113:1522–3
2. Epker JL, Bakker J, Kompanje EJ. The use of opioids and sedatives and time until death after withdrawing mechanical ventilation and vasoactive drugs in a Dutch intensive care unit. Anesth Analg 2011;112:628–34
3. Sykes N, Thorns A. Sedative use in the last week of life and the implications for end-of-life decision making. Arch Intern Med 2003;163:341–4
4. Chan JD, Treece PD, Englelberg RA, Crowley L, Rubenfeld GD, Steinberg KP, Curtis JR. Narcotic and benzodiazepine use after withdrawal of life support: association with time to death? Chest 2004;126:286–93
5. Edwards MJ. Opioids and benzodiazepines appear paradoxically to delay inevitable death after ventilator withdrawal. J Palliat Care 2005;21:299–302
6. Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA, Blow FC. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011;305:1315–21
© 2011 International Anesthesia Research Society