Caffeine accelerates recovery from general anesthesia

Abstract

General anesthetics inhibit neurotransmitter release from both neurons and secretory cells. If inhibition of neurotransmitter release is part of an anesthetic mechanism of action, then drugs that facilitate neurotransmitter release may aid in reversing general anesthesia. Drugs that elevate intracellular cAMP levels are known to facilitate neurotransmitter release. Three cAMP elevating drugs (forskolin, theophylline, and caffeine) were tested; all three drugs reversed the inhibition of neurotransmitter release produced by isoflurane in PC12 cells in vitro. The drugs were tested in isoflurane-anesthetized rats. Animals were injected with either saline or saline containing drug. All three drugs dramatically accelerated recovery from isoflurane anesthesia, but caffeine was most effective. None of the drugs, at the concentrations tested, had significant effects on breathing rates, O2 saturation, heart rate, or blood pressure in anesthetized animals. Caffeine alone was tested on propofol-anesthetized rats where it dramatically accelerated recovery from anesthesia. The ability of caffeine to accelerate recovery from anesthesia for different chemical classes of anesthetics, isoflurane and propofol, opens the possibility that it will do so for all commonly used general anesthetics, although additional studies will be required to determine whether this is in fact the case. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in human patients.

Keywords: cAMP elevating drugs; caffeine; emergence from anesthesia; isoflurane; propofol.

Fig. 1.

Forskolin, theophylline, and caffeine reversed the inhibition of neurotransmitter release produced by isoflurane (Iso). PC12 cells were permeabilized with digitonin (20 μM) and then stimulated by exposing cells to a solution containing 100 μM Ca²⁺. Neurotransmitter release was monitored with an amperometric electrode that gently touched the cell. Under these conditions, isoflurane (0.5 mM) significantly inhibited neurotransmitter release by ∼36% (P < 0.05, relative to control and all other conditions). The number of events recorded from control PC12 cells were about the same as those from PC12 cells exposed to isoflurane + forskolin (5 μM) or isoflurane and theophylline (50 μM) or isoflurane and caffeine [50 μM; control 81.28 ± 5.1 (n = 36), isoflurane 52.29 ± 6.31 (n = 17), isoflurane + forskolin 83.4 ± 6.1 (n = 17), isoflurane + theophylline 79.75 ± 7.07 (n = 12), and isoflurane + caffeine 79.43 ± 12.12 (n = 7) events per stimulation]. *Neurotransmitter release significantly different from control.

Fig. 2.

Methylphenidate reversed the inhibition of neurotransmitter release produced by isoflurane. Isoflurane (0.5 mM) normally inhibits neurotransmitter release by ∼40%. Control PC12 cells produced about the same number of events when stimulated as did PC12 cells exposed to isoflurane + 5 μM methyphenidate (control 86.6 ± 9.6, iso + meth 91.6 ± 6.1 events per stimulation, n = 17).

Fig. 3.

Variability in recovery times from isoflurane anesthesia. Rats were exposed to isoflurane and then exposed to isoflurane again a week later. Animals, 420–510 g, were placed in an airtight anesthesia box and exposed to 3% isoflurane (in 3 l/min O₂) for 8 min. The rats were then kept in the same chamber while isoflurane was reduced to 2% (2 l/min O₂) for another 45 min. The animals were removed from the chamber and allowed to recover on a table top breathing room air. They were placed on their backs and the time to recover from isoflurane anesthesia was the time from terminating the 2% anesthetic exposure until the animals had all four paws on the table. A: recovery time from a single group of 10 rats exposed twice to isoflurane. The first exposure is plotted as ■ and the second exposure as (○). Lines connect the 2 exposures from the same rat. Although there was some variability in recovery times, even in the same animal, the average recovery time was remarkably constant. B: plot data obtained from 3 different groups of rats. Each group was exposed to isoflurane twice. Note that the average recovery time for each group stayed relatively constant between exposures. C: distribution of all recovery times for all 30 rats tested in this study.

Fig. 4.

Forskolin accelerated recovery from isoflurane anesthesia. A: adult rats were anesthetized with 3% isoflurane (3 l/min O₂) for 8 min and were then exposed to 2% isoflurane (2 l/min O₂) for 45 min. During the anesthesia an intravenous line was inserted into a tail vein, while anesthesia was maintained with a nose cone. Five minutes before discontinuing the anesthetic the animals received an intravenous injection of either saline (control, ■) or saline with 0.1 mg/kg forskolin (○). The anesthetic was then terminated and the animals were allowed to wake up. Every symbol represents a single trial. The same animals were used as controls and to test forskolin. B: average waking time normalized to the control value, set to 100%, at different forskolin concentrations. *Waking times that were significantly different than control. (n = 14; control, n = 16; 0.02 mg/kg, n = 16; 0.1 mg/kg, n = 20; 0.5 mg/kg, n = 9; 1 mg/kg). Inset: percent reduction in waking time as a function of the forskolin concentration. The data are fit with a standard dose-response function, with a midpoint at 0.021 mg/kg forskolin and a maximal reduction of waking time of ∼41.2%.

Fig. 5.

Theophylline accelerated recovery from isoflurane anesthesia. A: adult rats were anesthetized as described in Fig. 3. Thirty minutes before discontinuing the anesthetic the animals received an intravenous injection of either saline (control, ■) or saline with 10 mg/kg theophylline (○). The anesthetic was then terminated and the animals were allowed to recover. Each symbol represents a single trial of 1 rat. B: average waking time normalized to control value, set to 100%, at different theophylline concentrations. (n = 12; control, n = 21; 0.1 mg/kg, n = 11; 1 mg/kg, n = 15; 10 mg/kg, n = 12; 100 mg/kg). Inset: plots of percent reduction in waking time as a function of the theophylline concentration. The midpoint was ∼0.28 mg/kg forskolin, max reduction in recovery time ∼41%. *Waking times significantly different from control.

Fig. 6.

Caffeine accelerated recovery from isoflurane anesthesia. A: adult rats were anesthetized as described in Fig. 3. Five minutes before discontinuing the isoflurane the animals received an intravenous injection of either saline (control, ■) or saline with 25 mg/kg caffeine (○). The isoflurane was terminated and the animals were allowed to recover. B: average waking time normalized to the control value, set to 100%, at different caffeine concentrations (n = 13; control, n = 8; 0.1 mg/kg, n = 13; 1 mg/kg, n = 12; 5 mg/kg, n = 12; 25 mg/kg). Inset: plot of percent reduction in waking time as a function of the caffeine concentration. The midpoint was at ∼0.9 mg/kg caffeine and the maximal reduction of waking time was ∼60.5%. *Waking times significantly different from control.

Fig. 7.

There was no significant change in blood pressure, heart rate or respiratory rate in rats exposed to forskolin, theophylline, or caffeine. Rats were anesthetized as described in Fig. 3. A: forskolin (0.1 mg/kg) was injected into each animal. Just before forskolin injection blood pressure, heart rate and respiratory rate was measured. Ten minutes after forskolin, the parameters were remeasured. B: theophylline (10 mg/kg) was injected into each animal. Just before theophylline injection blood pressure, heart rate and respiratory rate were measured. Ten minutes after theophylline, the parameters were remeasured. C: caffeine (25 mg/kg) was injected into each animal. Just before caffeine injection blood pressure, heart rate and respiratory rate was measured. 10 min after caffeine, the parameters were remeasured. h, Heart rate; BR, breathing rate; pre, predrug application; post, 10 min after drug application.

Fig. 8.

Caffeine accelerated recovery from propofol anesthesia. Adult rats were anesthetized with 3% isoflurane for 8 min at which time an intravenous line was inserted. The animals were allowed to wake and then a bolus of propofol (4 mg/kg) was injected along with either saline (control, ■) or with 25 mg/kg caffeine in saline (○). All rats became unconscious again within 5 s of propofol injection. The animals were allowed to wake. The same animals were used as controls and to test caffeine (n = 16 per group).