A Model of the Ventilatory Depressant Potency of Remifentanil in the Non–steady State

Abstract

Background The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil. Methods Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration. Results The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25. Conclusion Remifentanil is a potent ventilatory depressant. Simulations demonstrated that remifentanil concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration, confirming the acute risk of bolus administration of fast-acting opioids in spontaneously breathing patients.

Modeling Respiratory Depression Induced by Remifentanil and Propofol during Sedation and Analgesia Using a Continuous Noninvasive Measurement of pCO2

“…For both drugs, the presence of the effect compartment has been widely documented (Minto et al, 1997;Schnider et al, 1999;Babenco et al, 2000;Bouillon et al, 2003Bouillon et al, , 2004a). …”

“…Several models of respiratory effects have been reported for individual drugs commonly used during sedation (propofol and the opioids remifentanil and alfentanil) (Bouillon et al, 1999(Bouillon et al, , 2003(Bouillon et al, , 2004aCaruso et al, 2007). Few reports exist for models of combined effects of propofol with remifentanil on respiratory depression, despite the frequency with which agents are combined in anesthesia, and those that do are based on data derived from healthy volunteers (Nieuwenhuijs et al, 2003;Olofsen et al, 2010).…”

“…Feedback mechanisms regulate respiratory drive, which changes the alveolar minute ventilation. This makes it difficult to isolate and quantify key components of the system, and consequently, many of the current models have been developed in highly controlled conditions (Bouillon et al, 1999) and in healthy volunteers (Bouillon et al, 2003(Bouillon et al, , 2004aCaruso et al, 2007;Olofsen et al, 2010). This may limit their ability to predict respiratory depression in patient populations and the clinical environment.…”

Fatty Acid Amide Hydrolase–morphine Interaction Influences Ventilatory Response to Hypercapnia and Postoperative Opioid Outcomes in Children

“…The perioperative setting provides an ideal controlled clinical setting to evaluate this interaction as opioid-related RD is responsible for 50% of postoperative respiratory failure events [4][5][6]. A quantifiable objective indicator of sensitivity to opioidinduced RD is the hypercapnic ventilatory response (HCVR), measured by the rebreathing method [7,8]. This takes less time than the steady-state method and although less specific for opioid effects [9], it is the most suitable method realistically possible in a pre-and postsurgical clinical pediatric setting [7,10].…”

Population pharmacokinetics/pharmacodynamics of anesthetics

“…29 Respiratory depression is a side effect of opioid administration and may be life threatening, especially in the postoperative period. Population analysis of depression of ventilation and of the ventilatory response to hypoxia because of morphine, morphine-6-glucuronide, and remifentanil also revealed a relatively large interindividual variability, whereas no explanatory covariates were found, [30][31][32] but the studied populations were small and/or homogeneous.…”