Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits.
BACKGROUND
It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e.g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic.


METHODS
PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 microgram.kg-1 i.v. or midazolam 0.05 mg.kg-1 i.v. on the effects of propofol and fentanyl respectively on PNA were studied.


RESULTS
Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg.kg-1 i.v. and 32 micrograms.kg-1 i.v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg.kg-1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg.kg-1. The mean ED50s, calculated from dose-response curves, were 5.4 mg.kg-1, 3.9 micrograms.kg-1 and 0.4 mg.kg-1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 microgram.kg-1 i.v. or midazolam 0.05 mg.kg-1 i.v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg.kg-1 and 8 micrograms.kg-1, respectively.


CONCLUSIONS
Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.
Ma
D
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Department of Anaesthetics and Intensive Care, Imperial College School of Medicine, Hammersmith Hospital London, UK.
Sapsed-Byrne
S M
SM
Chakrabarti
M K
MK
Whitwam
J G
JG
D000200:Action Potentials / Q000187:drug effects; D019162:Anesthetics, Combined / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology*; D010791:Phrenic Nerve / Q000187:drug effects* / Q000502:physiology; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits
D019162:Anesthetics, Combined; D018686:Anesthetics, Intravenous; D008874:Midazolam; D005283:Fentanyl; D015742:Propofol