Temporal summation governs part of the minimum alveolar concentration of isoflurane anesthesia.

Background: General anesthesia may delay the onset of movement in response to noxious stimulation. The authors hypothesized that the production of immobility could involve depression of time-related processes involved in the generation of movement. Methods: The delays (latencies) between onset of tail clamp (n 16) or 50-Hz continuous electrical stimulation (n 8) and movement were measured in rats equilibrated at 0.1– 0.2% increasing steps of isoflurane. In other rats (n 8), the isoflurane concentrations just permitting and preventing movement (crossover concentrations) in response to trains of 0.5-ms 50-V square-wave pulses of interstimulus intervals of 10, 3, 1, 0.3, or 0.1 s during the step increases were measured. These measures were again made during administration of intravenous MK801, an N-methyl-D-aspartate receptor antagonist that can block temporal summation (n 6). Temporal summation refers to the cumulative effect of repeated stimuli. Crossover concentrations to 10- and 0.1-s interstimulus interval pulses ranging in voltage from 0.25–50 V were also measured (n 4). Results: The increase in concentrations from 0.6 to nearly 1.0 minimum alveolar concentration progressively increased latency from less tha n1st o 58 s.Shortening the interstimulus interval (50 V) pulses from 10 to 0.1 s progressively increased crossover concentrations from 0.6 to 1.0 minimum alveolar concentration. In contrast, during MK801 administration shortening interstimulus intervals did not change crossover concentrations, producing a flat response to change in the interstimulus interval. Increasing the voltage of interstimulus interval pulses increased the crossover concentrations but did not change the response to change in interstimulus intervals for pulses greater than 1 V. Conclusions: Increasing the duration or frequency (interstimulus interval) of stimulation increases the concentration of isoflurane required to suppress movement by a 0.4 minimum alveolar concentration MK801 blocks this effect, a finding consistent with temporal summation (which requires intact N-methyl-D-aspartate receptor activity) at concentrations of up to 1 minimum alveolar concentration isoflurane. THE mechanical or electrical stimulation used to determine MAC (the minimum alveolar concentration producing immobility in 50% of subjects receiving noxious stimulation) is applied continuously for up to 1 min. 1–5 This period allows for a delay between the onset of stimulation and the beginning of movement. The delay seems to increase as the anesthetic concentration approaches MAC, suggesting that time-related processes underlie the generation of the movement and that increasing anesthetic concentrations are required to suppress the response to increasing durations of stimulation. Such processes may be assessed by application of temporally graded electrical stimuli of the type used to create neuronal windup. 6 –10 Typically, these stimuli are trains of brief (0.5 ms) high-intensity square-wave pulses with relatively large interstimulus intervals (ISI), often up to 3 s. Such stimuli delivered to spinal cord afferents of spinal cord-transected rats can produce a cumulative depolarization of dorsal and ventral horn neurons. After several seconds, this progressive depolarization can reach a threshold, triggering a sustained burst of action potentials, giving rise to the term “windup.” N-methyl-Daspartate (NMDA) receptor activity underlies at least part of the cumulative depolarization and subsequent windup. 11,12 We hypothesized that temporal summation, the cumulative effect of repeated stimulation, might govern part of the MAC for isoflurane anesthesia. Although electrophysiologic and electromyographic effects of temporal summation have been investigated during isoflurane and halothane anesthesia in humans and rodents, 13–16 the involvement of temporal summation in the generation of movement during anesthesia has not been investigated. To document the time-related dose-dependent effect of isoflurane on the generation of movement responses, we measured the latency to movement after tail clamp and 50-Hz continuous stimulation. To test for temporal summation, we measured the effect of the ISI on the latency to movement responses, on the concentrations required to achieve immobility, and on the observed buildup of muscle tone and hindlimb electromyogram. To determine if disruption of temporal summation impaired the generation of movement, we measured the effect of the NMDA antagonist, MK801, on isoflurane concentrations required to achieve immobility during the ISI pulses. To study the dose-dependent effect of isoflurane on temporal summation, we studied the effect of ISIs of increasing voltage and the corresponding increasing concentrations required to achieve immobility.