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Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

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Abstract

This article provides a comprehensive, up to date summary of the effects of volatile, gaseous, and intravenous anesthetics and opioid agonists on ventilatory control. Emphasis is placed on data from human studies. Further mechanistic insights are provided by in vivo and in vitro data from other mammalian species. The focus is on the effects of clinically relevant agonist concentrations and studies using pharmacological, that is, supraclinical agonist concentrations are de‐emphasized or excluded. © 2012 American Physiological Society. Compr Physiol 2:2281‐2367, 2012.

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Figure 1. Figure 1.

Dose‐dependent effects of volatile anesthesia on cardiorespiratory and clinical parameters in humans. By convention, 1 minimum alveolar concentration (MAC) refers to 1 MACsurgical, which is the anesthetic concentration at which 50% of humans will not show purposeful movement to skin incision; MAC awake: 50% will not recall information; MAC bar: 50% will not have increase in blood pressure and heart rate with skin incision [reproduced with permission of Taylor and Francis Group, Boca Raton, FL from Central Effects of General Anesthesia by Stuth et al. in Pharmacology and Pathophysiology of the Control of Breathing, Volume 202, 2005; permission conveyed through Copyright Clearance Center, Inc. ].

Figure 2. Figure 2.

Anesthetic effects on the different components of the respiratory center; excitatory receptors are marked red, inhibitory receptors are marked blue. If studies have shown the presence of the receptor but have not investigated the effects of anesthetics the receptor is colored in light colors; if studies have shown that the receptor is affected by anesthetics the receptor is colored with dark colors. Receptors for which conflicting results are published are marked with #. Tandem‐pore acid‐sensitive K+ (TASK) channels serve as modulators of membrane potential and excitability of the cell; they are here marked as “inhibitory” since activation of TASK channels by volatile anesthetics leads to hyperpolarization of the neuron (upward triangle: potentiation of receptor function; downward triangle: inhibition of receptor function; #: conflicting results; *: presynaptic glutamatergic and GABA‐Aergic input reduced by anesthetic; Kat: unidentified kation channel).

Figure 3. Figure 3.

The depression of the hypoxic ventilatory response (HVR) by volatile anesthetics in different, nonprimate mammalian species. Data for this figure were derived from the studies in Table and were analyzed for anesthetic concentration in minimum alveolar concentration (MAC) (top) and Vol% (bottom). Shown are only data for the ratios between control and the lowest FiO2 used in each study. Overall, the depression of the HVR is concentration dependent with less than 50% depression below 1 MAC or below 1 Vol%. A clear difference between species cannot be identified. Differences listed in the literature may be the result of differences in the recording parameters; filled: phrenic nerve recording; hollow: sinus nerve recording; circled in black: MV. Please note that the baseline (control value) for the canine data is 0.5 MAC.

Figure 4. Figure 4.

Depression of the hypoxic ventilatory response (HVR) by isoflurane and enflurane (as indicated) and halothane (all other data points), presented in minimum alveolar concentration (MAC) (top) and Vol% (bottom). Data are derived from studies by Davies et al. , Van Dissel et al. , and Ponte et al. . Please note that these studies used different levels of hypoxia (FiO2); dark blue: FiO2 0.08, light blue: FiO2 0.11 to 0.13, hollow: FiO2 0.16.

Figure 5. Figure 5.

Effects of different anesthetics and different FiO2 on the hypoxic ventilatory response in rabbits. Data are shown for isoflurane and enflurane (as indicated) and halothane (all others) and presented in minimum alveolar concentration (MAC) (top) or Vol% (bottom). Data are derived from studies by Joensen et al. and Ponte et al. . The stimulation of the carotid body by lower FiO2, that is, stronger hypoxic stimuli, seems to offset the depression of carotid body function by volatile anesthetics. Overall, halothane up to 1 MAC causes only slight depression of the hypoxic ventilatory response (HVR); dark green: FiO2 0.08, light green: FiO2 0.11 to 0.13, hollow: FiO2 0.16.

Figure 6. Figure 6.

Effects of volatile anesthetics on the CO2 response in cats, rabbits, dogs, and goats. The data are derived, with permission, from studies in Table . The study by Biscoe et al. describes only one animal (n = 1). Overall, there is a dose‐dependent depression of the CO2 response by volatile anesthetics; however, this only becomes unequivocally apparent at concentrations greater than 0.5 to 1 minimum alveolar concentration (MAC). Halothane seems to have a greater depressant effect; however, this may be confounded by the fact that the other anesthetics were only tested at lower concentrations. No clear difference seems to exist between species. Red: halothane, purple: isoflurane, orange: enflurane.

Figure 7. Figure 7.

Effects of volatile anesthetics on the hypoxic ventilatory response (HVR) and the carotid body‐mediated CO2 response in rabbits and cats. All data are taken from the publication by Ponte et al. , which used a uniform preparation, so that blood pressure and thus carotid body discharge were likely changed to a similar degree in all substudies. The results suggest that in both species all volatile anesthetics depress the peripheral CO2 response less than the HVR. Circles: rabbit, triangle: cat; hollow symbols: HVR, filled symbols: CO2 response, red: halothane, purple: isoflurane, orange: enflurane.

Figure 8. Figure 8.

Effects of the volatile anesthetics halothane (H), isoflurane (I), enflurane (E), and sevoflurane (S) on the neuronal discharge activity of respiratory neurons in animals without the use of background anesthesia. (A) shows data from inspiratory (solid line) and expiratory (dashed line) premotor neurons in the caudal ventral respiratory group in neuraxis‐intact (a‐c) and decerebrate dogs (d‐j). (a) refers to reference , (b) to reference , (c) to reference , (d) to reference , (e) to reference , (f) to reference , (g) to reference , (h) to reference , (i) to reference , and (j) to reference . The data are normalized to the neuronal discharge frequency at 0 minimum alveolar concentration (MAC) (decerebrate animals) or 1 MAC anesthesia (intact animals). (B) shows data from inspiratory neurons in the region of the nucleus ambiguus of the ventral respiratory group in cats. In two studies, the authors compared the effects of halothane and sevoflurane (k = 134) and halothane and enflurane (l = 317) with crossover administration of the two agents while recording from the same neuron. The neuronal discharge activity was normalized to the frequency at 1 MAC halothane for each study. (C) compares the effects of halothane (m = 686) and enflurane (n = 685) on inspiratory neurons in the dorsal respiratory group in decerebrate cats. The data are normalized to the neuronal discharge activity at 0 MAC for both studies. Figure 8A‐C is reproduced with permission of Taylor and Francis Group, Boca Raton, FL from Central Effects of General Anesthesia by Stuth et.al in Pharmacology and Pathophysiology of the Control of Breathing, Volume 202, 2005; permission conveyed through Copyright Clearance Center, Inc. .

Figure 9. Figure 9.

(Top) Depression of the hypoxic ventilatory response (HVR) by volatile anesthetics in human subjects; data originate from different studies and were compiled by . Data are presented as the ratio between the HVR under anesthesia vs. preanesthesia control. The data indicate that despite considerable variability amongst anesthetics and between studies the HVR is already significantly depressed by subanesthetic concentrations of some volatile anesthetics. (Bottom) The hypercapnic ventilatory response in human subjects; data originate from different studies and were compiled by . Data are presented as the ratio between the hypercapnic responses under anesthesia versus preanesthesia control. Compared to the HVR the peripheral hypercapnic response is much less depressed at subanesthetic levels of volatile anesthetics. Red: halothane, purple: isoflurane, orange: enflurane, green: sevoflurane, hollow diamond: desflurane, hollow circle: nitrous oxide.

Figure 10. Figure 10.

Physiologically relevant synaptic inputs during the active phase of canine respiratory bulbospinal neurons (BSNs). Inspiratory BSNs receive phasic and tonic excitatory drive (Fe) through AMPA and NMDA receptors while expiratory BSNs receive only tonic excitatory drive via NMDA receptors. The total excitatory drive is attenuated via gain modulation by tonic inhibition (α), which is mediated by GABA‐A receptors and can be blocked with bicuculline. Neuronal control discharge frequency (Fcon, green output) is thus the product of overall excitation (red inputs) and inhibition (blue inputs). Fn: neuronal discharge frequency; Fcon: gain modulated baseline Fn under control conditions; Fe: Fcon observed during complete block of GABA‐A receptor‐mediated gain modulation (α = 0) that reflects the unmodulated, that is, not attenuated transmission of glutamatergic excitatory drive to BSNs [modified, with permission, from figure 1 in Respiratory Physiology and Neurobiology, Volume 164 (2008), 151‐159, Stuth et al. Anesthetic effects on synaptic neurotransmission and gain control in respiratory control, with permission from Elsevier B.V. ].

Figure 11. Figure 11.

Analysis of the response of an inspiratory bulbospinal respiratory neuron to the GABA‐A antagonist bicuculline (BIC) at 0 and 1 minimum alveolar concentration (MAC) sevoflurane to estimate anesthetic effects on overall synaptic neurotransmission: Rate‐meter recordings of neuronal discharge frequency Fn (in hertz) are shown during picoejection at increasing dose rates of BIC until no further increase in Fn is observed, that is, until all BIC‐sensitive GABA‐A receptors are blocked. At the point of complete GABAergic block, Fn reflects the overall excitatory input to the neuron, Fe. The factor by which neuronal frequency under control conditions (Fcon) is attenuated from Fe is the overall inhibition (α). This method thus allows estimation of the anesthetic effect on overall excitation and overall inhibition (α). Subscripts indicate 0 = 0 MAC, 1 = 1 MAC. Bars on right are mean peak discharge frequencies. In this neuron overall inhibition was enhanced by 31% (Δα = 100(α1‐α0)/α0,) while overall excitation was decreased by 9% (ΔFe = 100(Fe1‐Fe0)/Fe0) [reprinted, with permission, from Respiratory Physiology and Neurobiology, Volume 164 (2008), 151‐159, Stuth et al. Anesthetic effects on synaptic neurotransmission and gain control in respiratory control, with permission from Elsevier B.V. ].

Figure 12. Figure 12.

Summary data of the effects of 1 minimum alveolar concentration (MAC) halothane and 1 MAC sevoflurane on inspiratory (IBSN) and expiratory (EBSN) bulbospinal neurons in dogs: the anesthetic effects on control frequency (Fcon) are divided into effects on overall glutamatergic excitation (Fe) (in red) and overall GABAergic inhibition (α) (in blue) and these effects are further separated into their presynaptic and postsynaptic components. Significant anesthesia‐induced changes are shown as increases or decreases compared to control. Ø: no significant change. For presynaptic changes, which cannot be directly measured but only estimated, assuming cascaded effects, the trend is indicated. + = excitatory glutamatergic inputs (red); − = inhibitory GABAergic inputs (blue). Anesthetic effects on neurotransmission in this decerebrate canine paradigm are only assessed for the active phase of each neuron type when extracellular discharge activity is present and can be recorded [reprinted, with permission, from Respiratory Physiology and Neurobiology, Volume 164 (2008), 151‐159, Stuth et al. Anesthetic effects on synaptic neurotransmission and gain control in respiratory control, with permission from Elsevier B.V. ].

Figure 13. Figure 13.

Summary of the clinical effects of opioids on brainstem respiratory neurons. The scheme is based on data from references , and . The effects on membrane potential and discharge activity of the neurons as well as central inspiratory activity are linked hypothetically to observed clinical effects in animals and humans. Red frame: presence of functional opioid receptors was demonstrated on these neurons/structures; arrow: projecting to downstream neuron group; BSNs: bulbospinal neurons; MNs: motoneurons.

Figure 14. Figure 14.

Effect of halothane and 5‐HT on a hypoglossal motoneuron in an in vitro, neonatal rodent brainstem slice. A hypoglossal motoneuron was induced to discharge action potentials by direct, depolarizing current injection under current clamp conditions. Exposure to a 1.3 minimum alveolar concentration (MAC) dose (0.35 mM, equivalent to a clinical ED95) of halothane in the bath solution caused neuronal membrane hyperpolarization, which resulted in suppression of action potential discharges. Despite the continued presence of halothane the anesthetic‐induced hyperpolarization could be reversed by serotonin with resumption of neuronal firing, suggesting that halothane acted in opposite direction to a serotonin‐responsive mechanisms such as tandem‐pore acid‐sensitive K+ (TASK) channels. [reproduced with permission of Journal of Physiology from Volume 541: 717‐729, 2002 : Convergent and reciprocal modulation of a leak K+ current and Ih by an inhalational anesthetic and neurotransmitters in rat brainstem motoneurons by Sirois et al.; permission conveyed through Copyright Clearance Center, Inc. ].

Figure 15. Figure 15.

Increase in motoneuronal excitability by serotonin (5‐HT) in a neonatal rodent slice preparation. Serotonin‐inhibited acid sensitive K+ channels [tandem‐pore acid‐sensitive K+ (TASK)] as shown by the inward shift in the neuronal membrane holding current. Halothane caused opposite effects in the membrane current and the serotonin‐induced inward shift in current was enhanced in the presence of halothane. This suggests that serotonin prevails over halothane concerning their reciprocal effects on TASK channels. A confounding hyperpolarization‐activated cationic current (Ih) that is also present in these neurons and also modulated by halothane was removed by pharmacological block in this protocol. [reproduced with permission of Journal of Physiology from Volume 541: 717‐729, 2002 : Convergent and reciprocal modulation of a leak K+ current and Ih by an inhalational anesthetic and neurotransmitters in rat brainstem motoneurons by Sirois et al.; permission conveyed through Copyright Clearance Center, Inc. ].

Figure 16. Figure 16.

Scheme of the expected and observed effects of isoflurane and serotonin on the discharge frequency pattern (Fn) of canine inspiratory hypoglossal motoneurons in vivo. The observed effect on the discharge pattern for each condition was averaged from the response of 19 neurons in an in vivo canine preparation. Neuronal discharge under control conditions (control, thick solid line) was decreased by 0.3 minimum alveolar concentration (MAC) isoflurane (iso, thick interrupted line). Ejection of near maximal doses of serotonin onto the neurons increased neuronal discharge frequency (5‐HT, thick solid line). The study investigated whether neuronal K+‐leak (TASK) channels were responsible for the anesthetic depression of Fn. In vitro studies have shown that isoflurane opens TASK channels leading to membrane hyperpolarization while serotonin completely antagonizes TASK channel activation (adapted, with permission, from reference ). It was thus expected (upper panel) that the depression of Fn by isoflurane (downward arrow) would be completely reversed and Fn would increase (upward arrow) to Fn during maximal serotonin ejection (5‐HT and 5‐HT+iso). Indeed it was observed (lower panel) that isoflurane depressed Fn (iso); however, ejection of serotonin raised Fn far less (5‐HT+iso) than it had without isoflurane (5‐HT). This would indicate that TASK channel blockade with serotonin could not reverse the anesthetic depression of Fn suggesting that TASK channels do not play a significant role in this depression. Data adapted from reference ).

Figure 17. Figure 17.

Effects of volatile anesthesia on clinical respiratory parameters in humans. The data are compiled, with permission, from studies in references , and ) and the figure is modified, with permission, from reference [reproduced with permission of Taylor and Francis Group, Boca Raton, FL from Central Effects of General Anesthesia by Stuth et al. in Pharmacology and Pathophysiology of the Control of Breathing, Volume 202, 2005; permission conveyed through Copyright Clearance Center, Inc. .



Figure 1.

Dose‐dependent effects of volatile anesthesia on cardiorespiratory and clinical parameters in humans. By convention, 1 minimum alveolar concentration (MAC) refers to 1 MACsurgical, which is the anesthetic concentration at which 50% of humans will not show purposeful movement to skin incision; MAC awake: 50% will not recall information; MAC bar: 50% will not have increase in blood pressure and heart rate with skin incision [reproduced with permission of Taylor and Francis Group, Boca Raton, FL from Central Effects of General Anesthesia by Stuth et al. in Pharmacology and Pathophysiology of the Control of Breathing, Volume 202, 2005; permission conveyed through Copyright Clearance Center, Inc. ].



Figure 2.

Anesthetic effects on the different components of the respiratory center; excitatory receptors are marked red, inhibitory receptors are marked blue. If studies have shown the presence of the receptor but have not investigated the effects of anesthetics the receptor is colored in light colors; if studies have shown that the receptor is affected by anesthetics the receptor is colored with dark colors. Receptors for which conflicting results are published are marked with #. Tandem‐pore acid‐sensitive K+ (TASK) channels serve as modulators of membrane potential and excitability of the cell; they are here marked as “inhibitory” since activation of TASK channels by volatile anesthetics leads to hyperpolarization of the neuron (upward triangle: potentiation of receptor function; downward triangle: inhibition of receptor function; #: conflicting results; *: presynaptic glutamatergic and GABA‐Aergic input reduced by anesthetic; Kat: unidentified kation channel).



Figure 3.

The depression of the hypoxic ventilatory response (HVR) by volatile anesthetics in different, nonprimate mammalian species. Data for this figure were derived from the studies in Table and were analyzed for anesthetic concentration in minimum alveolar concentration (MAC) (top) and Vol% (bottom). Shown are only data for the ratios between control and the lowest FiO2 used in each study. Overall, the depression of the HVR is concentration dependent with less than 50% depression below 1 MAC or below 1 Vol%. A clear difference between species cannot be identified. Differences listed in the literature may be the result of differences in the recording parameters; filled: phrenic nerve recording; hollow: sinus nerve recording; circled in black: MV. Please note that the baseline (control value) for the canine data is 0.5 MAC.



Figure 4.

Depression of the hypoxic ventilatory response (HVR) by isoflurane and enflurane (as indicated) and halothane (all other data points), presented in minimum alveolar concentration (MAC) (top) and Vol% (bottom). Data are derived from studies by Davies et al. , Van Dissel et al. , and Ponte et al. . Please note that these studies used different levels of hypoxia (FiO2); dark blue: FiO2 0.08, light blue: FiO2 0.11 to 0.13, hollow: FiO2 0.16.



Figure 5.

Effects of different anesthetics and different FiO2 on the hypoxic ventilatory response in rabbits. Data are shown for isoflurane and enflurane (as indicated) and halothane (all others) and presented in minimum alveolar concentration (MAC) (top) or Vol% (bottom). Data are derived from studies by Joensen et al. and Ponte et al. . The stimulation of the carotid body by lower FiO2, that is, stronger hypoxic stimuli, seems to offset the depression of carotid body function by volatile anesthetics. Overall, halothane up to 1 MAC causes only slight depression of the hypoxic ventilatory response (HVR); dark green: FiO2 0.08, light green: FiO2 0.11 to 0.13, hollow: FiO2 0.16.



Figure 6.

Effects of volatile anesthetics on the CO2 response in cats, rabbits, dogs, and goats. The data are derived, with permission, from studies in Table . The study by Biscoe et al. describes only one animal (n = 1). Overall, there is a dose‐dependent depression of the CO2 response by volatile anesthetics; however, this only becomes unequivocally apparent at concentrations greater than 0.5 to 1 minimum alveolar concentration (MAC). Halothane seems to have a greater depressant effect; however, this may be confounded by the fact that the other anesthetics were only tested at lower concentrations. No clear difference seems to exist between species. Red: halothane, purple: isoflurane, orange: enflurane.



Figure 7.

Effects of volatile anesthetics on the hypoxic ventilatory response (HVR) and the carotid body‐mediated CO2 response in rabbits and cats. All data are taken from the publication by Ponte et al. , which used a uniform preparation, so that blood pressure and thus carotid body discharge were likely changed to a similar degree in all substudies. The results suggest that in both species all volatile anesthetics depress the peripheral CO2 response less than the HVR. Circles: rabbit, triangle: cat; hollow symbols: HVR, filled symbols: CO2 response, red: halothane, purple: isoflurane, orange: enflurane.



Figure 8.

Effects of the volatile anesthetics halothane (H), isoflurane (I), enflurane (E), and sevoflurane (S) on the neuronal discharge activity of respiratory neurons in animals without the use of background anesthesia. (A) shows data from inspiratory (solid line) and expiratory (dashed line) premotor neurons in the caudal ventral respiratory group in neuraxis‐intact (a‐c) and decerebrate dogs (d‐j). (a) refers to reference , (b) to reference , (c) to reference , (d) to reference , (e) to reference , (f) to reference , (g) to reference , (h) to reference , (i) to reference , and (j) to reference . The data are normalized to the neuronal discharge frequency at 0 minimum alveolar concentration (MAC) (decerebrate animals) or 1 MAC anesthesia (intact animals). (B) shows data from inspiratory neurons in the region of the nucleus ambiguus of the ventral respiratory group in cats. In two studies, the authors compared the effects of halothane and sevoflurane (k = 134) and halothane and enflurane (l = 317) with crossover administration of the two agents while recording from the same neuron. The neuronal discharge activity was normalized to the frequency at 1 MAC halothane for each study. (C) compares the effects of halothane (m = 686) and enflurane (n = 685) on inspiratory neurons in the dorsal respiratory group in decerebrate cats. The data are normalized to the neuronal discharge activity at 0 MAC for both studies. Figure 8A‐C is reproduced with permission of Taylor and Francis Group, Boca Raton, FL from Central Effects of General Anesthesia by Stuth et.al in Pharmacology and Pathophysiology of the Control of Breathing, Volume 202, 2005; permission conveyed through Copyright Clearance Center, Inc. .



Figure 9.

(Top) Depression of the hypoxic ventilatory response (HVR) by volatile anesthetics in human subjects; data originate from different studies and were compiled by . Data are presented as the ratio between the HVR under anesthesia vs. preanesthesia control. The data indicate that despite considerable variability amongst anesthetics and between studies the HVR is already significantly depressed by subanesthetic concentrations of some volatile anesthetics. (Bottom) The hypercapnic ventilatory response in human subjects; data originate from different studies and were compiled by . Data are presented as the ratio between the hypercapnic responses under anesthesia versus preanesthesia control. Compared to the HVR the peripheral hypercapnic response is much less depressed at subanesthetic levels of volatile anesthetics. Red: halothane, purple: isoflurane, orange: enflurane, green: sevoflurane, hollow diamond: desflurane, hollow circle: nitrous oxide.



Figure 10.

Physiologically relevant synaptic inputs during the active phase of canine respiratory bulbospinal neurons (BSNs). Inspiratory BSNs receive phasic and tonic excitatory drive (Fe) through AMPA and NMDA receptors while expiratory BSNs receive only tonic excitatory drive via NMDA receptors. The total excitatory drive is attenuated via gain modulation by tonic inhibition (α), which is mediated by GABA‐A receptors and can be blocked with bicuculline. Neuronal control discharge frequency (Fcon, green output) is thus the product of overall excitation (red inputs) and inhibition (blue inputs). Fn: neuronal discharge frequency; Fcon: gain modulated baseline Fn under control conditions; Fe: Fcon observed during complete block of GABA‐A receptor‐mediated gain modulation (α = 0) that reflects the unmodulated, that is, not attenuated transmission of glutamatergic excitatory drive to BSNs [modified, with permission, from figure 1 in Respiratory Physiology and Neurobiology, Volume 164 (2008), 151‐159, Stuth et al. Anesthetic effects on synaptic neurotransmission and gain control in respiratory control, with permission from Elsevier B.V. ].



Figure 11.

Analysis of the response of an inspiratory bulbospinal respiratory neuron to the GABA‐A antagonist bicuculline (BIC) at 0 and 1 minimum alveolar concentration (MAC) sevoflurane to estimate anesthetic effects on overall synaptic neurotransmission: Rate‐meter recordings of neuronal discharge frequency Fn (in hertz) are shown during picoejection at increasing dose rates of BIC until no further increase in Fn is observed, that is, until all BIC‐sensitive GABA‐A receptors are blocked. At the point of complete GABAergic block, Fn reflects the overall excitatory input to the neuron, Fe. The factor by which neuronal frequency under control conditions (Fcon) is attenuated from Fe is the overall inhibition (α). This method thus allows estimation of the anesthetic effect on overall excitation and overall inhibition (α). Subscripts indicate 0 = 0 MAC, 1 = 1 MAC. Bars on right are mean peak discharge frequencies. In this neuron overall inhibition was enhanced by 31% (Δα = 100(α1‐α0)/α0,) while overall excitation was decreased by 9% (ΔFe = 100(Fe1‐Fe0)/Fe0) [reprinted, with permission, from Respiratory Physiology and Neurobiology, Volume 164 (2008), 151‐159, Stuth et al. Anesthetic effects on synaptic neurotransmission and gain control in respiratory control, with permission from Elsevier B.V. ].



Figure 12.

Summary data of the effects of 1 minimum alveolar concentration (MAC) halothane and 1 MAC sevoflurane on inspiratory (IBSN) and expiratory (EBSN) bulbospinal neurons in dogs: the anesthetic effects on control frequency (Fcon) are divided into effects on overall glutamatergic excitation (Fe) (in red) and overall GABAergic inhibition (α) (in blue) and these effects are further separated into their presynaptic and postsynaptic components. Significant anesthesia‐induced changes are shown as increases or decreases compared to control. Ø: no significant change. For presynaptic changes, which cannot be directly measured but only estimated, assuming cascaded effects, the trend is indicated. + = excitatory glutamatergic inputs (red); − = inhibitory GABAergic inputs (blue). Anesthetic effects on neurotransmission in this decerebrate canine paradigm are only assessed for the active phase of each neuron type when extracellular discharge activity is present and can be recorded [reprinted, with permission, from Respiratory Physiology and Neurobiology, Volume 164 (2008), 151‐159, Stuth et al. Anesthetic effects on synaptic neurotransmission and gain control in respiratory control, with permission from Elsevier B.V. ].



Figure 13.

Summary of the clinical effects of opioids on brainstem respiratory neurons. The scheme is based on data from references , and . The effects on membrane potential and discharge activity of the neurons as well as central inspiratory activity are linked hypothetically to observed clinical effects in animals and humans. Red frame: presence of functional opioid receptors was demonstrated on these neurons/structures; arrow: projecting to downstream neuron group; BSNs: bulbospinal neurons; MNs: motoneurons.



Figure 14.

Effect of halothane and 5‐HT on a hypoglossal motoneuron in an in vitro, neonatal rodent brainstem slice. A hypoglossal motoneuron was induced to discharge action potentials by direct, depolarizing current injection under current clamp conditions. Exposure to a 1.3 minimum alveolar concentration (MAC) dose (0.35 mM, equivalent to a clinical ED95) of halothane in the bath solution caused neuronal membrane hyperpolarization, which resulted in suppression of action potential discharges. Despite the continued presence of halothane the anesthetic‐induced hyperpolarization could be reversed by serotonin with resumption of neuronal firing, suggesting that halothane acted in opposite direction to a serotonin‐responsive mechanisms such as tandem‐pore acid‐sensitive K+ (TASK) channels. [reproduced with permission of Journal of Physiology from Volume 541: 717‐729, 2002 : Convergent and reciprocal modulation of a leak K+ current and Ih by an inhalational anesthetic and neurotransmitters in rat brainstem motoneurons by Sirois et al.; permission conveyed through Copyright Clearance Center, Inc. ].



Figure 15.

Increase in motoneuronal excitability by serotonin (5‐HT) in a neonatal rodent slice preparation. Serotonin‐inhibited acid sensitive K+ channels [tandem‐pore acid‐sensitive K+ (TASK)] as shown by the inward shift in the neuronal membrane holding current. Halothane caused opposite effects in the membrane current and the serotonin‐induced inward shift in current was enhanced in the presence of halothane. This suggests that serotonin prevails over halothane concerning their reciprocal effects on TASK channels. A confounding hyperpolarization‐activated cationic current (Ih) that is also present in these neurons and also modulated by halothane was removed by pharmacological block in this protocol. [reproduced with permission of Journal of Physiology from Volume 541: 717‐729, 2002 : Convergent and reciprocal modulation of a leak K+ current and Ih by an inhalational anesthetic and neurotransmitters in rat brainstem motoneurons by Sirois et al.; permission conveyed through Copyright Clearance Center, Inc. ].



Figure 16.

Scheme of the expected and observed effects of isoflurane and serotonin on the discharge frequency pattern (Fn) of canine inspiratory hypoglossal motoneurons in vivo. The observed effect on the discharge pattern for each condition was averaged from the response of 19 neurons in an in vivo canine preparation. Neuronal discharge under control conditions (control, thick solid line) was decreased by 0.3 minimum alveolar concentration (MAC) isoflurane (iso, thick interrupted line). Ejection of near maximal doses of serotonin onto the neurons increased neuronal discharge frequency (5‐HT, thick solid line). The study investigated whether neuronal K+‐leak (TASK) channels were responsible for the anesthetic depression of Fn. In vitro studies have shown that isoflurane opens TASK channels leading to membrane hyperpolarization while serotonin completely antagonizes TASK channel activation (adapted, with permission, from reference ). It was thus expected (upper panel) that the depression of Fn by isoflurane (downward arrow) would be completely reversed and Fn would increase (upward arrow) to Fn during maximal serotonin ejection (5‐HT and 5‐HT+iso). Indeed it was observed (lower panel) that isoflurane depressed Fn (iso); however, ejection of serotonin raised Fn far less (5‐HT+iso) than it had without isoflurane (5‐HT). This would indicate that TASK channel blockade with serotonin could not reverse the anesthetic depression of Fn suggesting that TASK channels do not play a significant role in this depression. Data adapted from reference ).



Figure 17.

Effects of volatile anesthesia on clinical respiratory parameters in humans. The data are compiled, with permission, from studies in references , and ) and the figure is modified, with permission, from reference [reproduced with permission of Taylor and Francis Group, Boca Raton, FL from Central Effects of General Anesthesia by Stuth et al. in Pharmacology and Pathophysiology of the Control of Breathing, Volume 202, 2005; permission conveyed through Copyright Clearance Center, Inc. .

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Eckehard A.E. Stuth, Astrid G. Stucke, Edward J. Zuperku. Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control. Compr Physiol 2012, 2: 2281-2367. doi: 10.1002/cphy.c100061