Oxford Meeting - November 2002

Opioid-anesthestic interaction on ventilatory control

 Albert Dahan MD PhD

Deptartment of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands

Introduction. Most, if not all, agents, used to induce and maintain general anesthesia and to relieve pain and/or suppress somatic, autonomous and adrenergic responses to noxious stimulation change the control of breathing drastically. They do so by affecting chemical control of breathing, behavioral control, or, which happens most frequently, by affecting both. Chemical or metabolic control of breathing is coupled to the metabolism and depends on the chemical composition of arterial blood (pH, arterial PCO₂, arterial PO₂) and brainstem interstitial fluid (pH, brain tissue PCO₂). Chemical control occurs during non-rapid eye movement sleep and anesthesia. Behavioral control of breathing is control that allows for adjustment of breathing to specific situations such as speech, singing, exercising, pain, arousal and stress. An example of a group of agents that affects both control systems is the volatile halogenated anesthetics. For example, the inhalational anesthetics abolish the peripheral drive from the chemoreceptors at the carotid bodies, general depression of respiratory centers in the CNS, and the suppression of the function of motoneurons, intercostal muscles and diaphragm (all of which is chemical control of breathing) and by the loss of wakefulness drive (behavioral control). Opioids, on the other hand, affect ventilatory control predominantly via central sites through their interaction with mu-opioid-receptors (chemical control of breathing).

 Opioid-anesthetic interaction on ventilatory control. In order to analyze the interaction of drugs on ventilatory control we developed a response surface model of the form:

Effect (drug1,drug2) = Baseline Effect * [1 – 0.5 * (x₁ + x₂)^γ] * I(q)

where x₁ = C/C₅₀ of drug 1, x₂ C/C₅₀ of drug 2 and I(q) an interaction parameter (a simple spline) with I(q) = 1 additive interaction and, I(q) > 1 synergistic interaction. In contrast to the classical sigmoid Emax model, our function (that is the assymetric sigmoid or power function) is best suited to describe the drug-respiratory effect relationship and its particularities such as sudden apnea. This will be demonstrated in a series of simulations.

Drug interactions that we have studied so far include alfentanil—sevoflurane and remifentanil—propofol. The latter interaction will be discussed. In summary, all measured variables displayed a marked synergistic interaction (see figure for variable “Resting Ventilation”). We relate this to the different pathways through which the opioid and the anesthetic act on ventilatory control (remifentanil through chemical control pathways; propofol through behavioural control pathways) which interact through strong reinforcing mechanisms.