Neural Mechanisms of Sevoflurane-induced Respiratory Depression in Newborn Rats

Abstract

Under the influence of sevoflurane, the region containing inspiratory neurons, i.e., the pre-Bötzinger complex, may determine the inspiratory rhythm, because reduced C4 bursts were still synchronized with the bursts of inspiratory neurons within the pre-Bötzinger complex. In contrast, the sevoflurane-induced decrease in C4 burst amplitude is mediated through the inhibition of phrenic motor neurons. gamma-Aminobutyric acid type A receptors may be involved in the sevoflurane-induced respiratory depression within the medulla, but not within the spinal cord.

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

“…The effects of sevoflurane on respiratory rate (slowing of C4 burst rate) are opposite to the speeding up of rate that is observed in vivo in humans and in decerebrate dogs (i.e., in pons-intact preparations). This opposite effect of sevoflurane on respiratory rate in the different preparations may be explained by the removal of the pons, which tends to result in a higher baseline respiratory rate in reduced brainstem-spinal cord preparations compared to pons-intact preparations (356). Thus in the pons-intact preparation, the increase in respiratory rate produced by sevoflurane and other volatile agents may be due to a suppression of functional pontine inhibition of the pBC by the anesthetic.…”

“…In vitro, Kuribayashi et al showed in a neonatal brainstemspinal cord preparation that superfusion with 0.8 to 3.6 MAC equivalent of sevoflurane decreased intraburst firing of expiratory and pre-I neurons but not of inspiratory neurons while phrenic motoneurons showed decreased intraburst firing and a decrease in membrane potential (356). The depression of phrenic burst rate, but not amplitude, could be reversed with the GABA-A antagonists bicuculline and picrotoxin.…”

“…However, one study suggested that rats may require significantly higher brain and plasma concentrations (15-40 μg/mL) for propofol anesthesia than humans (631), although estimates of brain propofol concentrations were based on brain homogenate levels, which may not reflect effect site concentrations. With propofol all observed effects appeared to be GABA-A receptor mediated and completely reversible with the GABA-A antagonist bicuculline and there was no effect on C4 amplitude (319), which was quite different from the mechanism of high-dose sevoflurane (356).…”

“…Studies using these preparations suggest that various types of respiratory neurons are not equally affected by anesthetics. For example pBC inspiratory neurons were found to be highly resistant to high, even supraclinical doses (3.57 MAC) of all volatile anesthetics (356,518), while parafacial pre-I neurons, BC expiratory neurons and phrenic motor neurons were depressed [for illustration see figure 5 in Kuribayashi et al 2008 (356), which shows the differential effects of a supraclinical dose of sevoflurane (3.57 MAC) on the membrane potential and discharge activity of various brainstem respiratory neurons]. Unfortunately, the authors in this study did not test the effects of lower, clinically relevant doses (< 2 MAC sevoflurane) on these respiratory neurons.…”

“…The distinct advantages of reduced preparations are (1) no need for background anesthesia, (2) feasibility to record from neurons intracellularly with high reliability, and (3) ease of manipulation of the extracellular milieu without loss of stable intracellular neuron recordings. However, these preparations are completely or severely deafferented and the brainstem spinal cord preparation lacks respiratory-modulating pontine inputs (356). Studies using these preparations suggest that various types of respiratory neurons are not equally affected by anesthetics.…”