Coadministration of the AMPAKINE CX717 with Propofol Reduces Respiratory Depression and Fatal Apneas

Abstract

Background: Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea. Methods: The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem-spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heartbrainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats. Results:In vitro, respiratory depression caused by propofol (2 μM, n = 11, mean ± SEM, 41 ± 5% of control frequency, 63 ± 5% of control duration) was alleviated by CX717 (n = 4, 50-150 μM). In situ, a decrease in respiratory frequency (44 ± 9% of control), phrenic burst duration (66 ± 7% of control), and amplitude (78 ± 5% of control) caused by propofol (2 μM, n = 5) was alleviated by coadministration of CX717 (50 μM, n = 5). In vivo, pre-or coadministration of CX717 (20-25 mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20 mg/kg) and propofol-induced lethal apnea (n = 6; 30 mg/kg). Conclusions: Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death. P ROPOFOL (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's favorable attributes are its pharmacokinetic properties that result in a rapid, clear emergence. Its disadvantages include the induction of respiratory depression, apnea, and blood pressure reductions.1,2 Furthermore, there are increasing reports What We Already Know about This Topic• Propofol depresses respiration partly due to the activation of γ-aminobutyric acid receptors within brainstem respiratory center AMPAKINEs effectively alleviates opioid-induced respiratory depression without interfering with analgesia in rodentsWhat This Article Tells Us That Is New Address correspondence to Dr. Greer: University of Alberta, Department of Physiology, Centre for Neuroscience, Women and Children's Health Research Institute, 3-020M Katz Building, Edmonton, Alberta, Canada T6G 2S2. john.greer@ualberta.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology's articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.

AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain

“…20,21 By increasing excitatory inputs in neurons of the pre-Botzinger complex in the medulla, AMPAkines can stimulate the respiratory drive 26,27,71-73 to treat or prevent hypoventilation caused by sedatives often used intra- or postoperatively. 26,28,74,75 A previous study has shown the effect of AMPAkines in persistent or chronic pain. Our current study demonstrates that these drugs can also effectively relieve the incisional pain commonly associated with surgery.…”

AMPAkines Have Novel Analgesic Properties in Rat Models of Persistent Neuropathic and Inflammatory Pain

“…19,20 By increasing AMPA receptor-mediated currents in neurons of the pre-Botzinger complex in the medulla, AMPAkines directly stimulate the respiratory drive, 26,27,47–49 and they have been shown to treat or prevent hypoventilation caused by opioids and propofol. 26,28,50,51 The effect of AMPAkines in chronic pain, however, has not been previously studied. The analgesic dose for CX546 found in our study is comparable to the dose tested in rats to treat respiratory depression.…”

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

“…CX717 has been used in both animal models (15,17,20) and clinical trials to alleviate respiratory depression due to opioids (14). CX717 does not directly antagonize opioid receptors, because, in both rats and humans, CX717 counteracts respiratory depression without influencing analgesia (15)(16)(17)20). Animal studies have confirmed that CX717 stimulates breathing by potentiating AMPA currents in respiratory neurons, including both motor and premotor neurons (15,20).…”

“…These drugs successfully stimulated breathing after opiate-induced respiratory depression in clinical trials (13,14). Importantly, preclinical studies show that ampakines most effectively stimulate breathing when the neural input to respiratory muscles is blunted (13,(15)(16)(17). Ampakines may therefore be a therapeutic option for respiratory insufficiency, particularly when neuromotor impairment is suspected.…”