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October 22, 2008
9:00 AM - 11:00 AM
Room Hall E2-Area B,
Does the Pre-Botzinger Complex (Pbc) Mediate the Bradypnea Caused by Intravenous Opioids?
Sanda Mustapic, M.D., Eckehard A.E. Stuth, M.D., Tomislav Radocaj, M.D., Astrid G. Stucke, M.D., Edward J. Zuperku, Ph.D.
Anesthesia Research Service, Medical College of Wisconsin, Milwaukee, Wisconsin
Background: Remifentanil (Remi) is a short-acting potent Mu-opioid analgesic that can produce severe bradypnea. Mu-opioid receptors (MOR) on pBC neurons, the putative kernel of rhythmogenesis, are potential targets. Studies in brain slices that contain the pBC show that Mu-opioids markedly slow the burst rate of respiratory-related output (Gray et al. 1999). In addition perturbations of neuronal function within the pBC in adult animals severely disrupt breathing (Krolo et al. 2005). We hypothesized that in vivo MOR activation in the pBC causes the bradypnea produced by clinically relevant infusion rates of i.v. remifentanil.

Methods: The studies were approved by the Medical College of Wisconsin Animal Care Committee and conformed with the standards set forth by National Institutes of Health. Acute non-survival experiments were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated dogs during isocapnic hyperoxia. Multibarrel micropipettes were used to record pBC neuronal activity and picoeject naloxone (NAL, 0.5 mM) and the excitatory amino acid D,L-homocysteic acid (DLH, 20 mM). Inspiratory duration TI, expiratory duration TE, and peak phrenic nerve activity (PPA) were measured from the phrenic neurogram (PNG). The pBC within the ventral respiratory column was functionally located by its typical tachpneic response to microinjection of DLH. Remi was infused at an i.v. rate (0.2-0.5 mcg/kg/min) that resulted in a marked steady-state bradypnea. A series of bilateral injections of NAL (120 nl each), 3 on each side, centered in the pBC and 1 mm rostral and caudal, were used to locally block MORs while monitoring the PNG. Average values of TI, TE, and PPA were obtained before Remi infusion and from data 1 minute before and after each microinjection during Remi infusion. The same concentration of NAL was given iv following the microinjections to verify its effectiveness in reversing IV remifentanil. Effects were assessed with ANOVA.

Results: In 15 dogs, Remi (0.45±0.50 µg/kg/min) increased TE and TI by 143±128% (p<0.001) and 18±39% (p<0.001), respectively, and decreased PPA by 32±31% (p<0.001). NAL microinjections in the pBC region during steady state Remi infusion had no effect at any of the 6 sites and no cumulative effects were seen either. However, 14.7±13 µg/kg of NAL promptly and completely reversed all Remi-induced effects.[figure1]( ** p < 0.01, *** p < 0.001).

Conclusion: Remifentanil at clinically relevant plasma concentrations does not cause respiratory depression via direct Mu-opioid receptor activation in the pBC, the putative rhythm generating center.

Gray, P.A., Rekling, J.C., Bocchiaro, C.M., Feldman, J.L., 1999. Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBötzinger complex. Science 286, 1566-1568.

Krolo, M., Tonkovic-Capin, V., Stucke, A., Stuth, E., Hopp, F., Dean, C., Zuperku, E., 2005. Subtype composition and responses of respiratory neurons in the pre-Botzinger region to pulmonary afferent Inputs in dogs. J Neurophysiol 93, 2674-2687.

Anesthesiology 2008; 109 A1769
Figure 1