Astrid G. Stucke

Effects of Sevoflurane on excitatory neurotransmission to medullary expiratory neurons and on phrenic nerve activity in a decerebrate dog model

Background Sevoflurane is a new volatile anesthetic with a pronounced respiratory depressant effect. Synaptic neurotransmission in canine expiratory bulbospinal neurons is mainly mediated by excitatory N-methyl-d-aspartatic acid (NMDA) receptor input and modulated by inhibitory &ggr;-aminobutyric acid type A (GABAA) receptors. The authors investigated the effect of sevoflurane on these mechanisms in decerebrate dogs. Methods Studies were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC; 2.4%) sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the glutamate agonist NMDA and the GABAA receptor blocker bicuculline in a two-part protocol. First, complete blockade of the GABAAergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABAAergic inhibition and on overall glutamatergic excitation. In a second step, the neuronal response to exogenous NMDA was used to estimate sevoflurane’s effect on postsynaptic glutamatergic neurotransmission. Results One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 16 expiratory neurons by 36.7 ± 22.4% (mean ± SD). Overall glutamatergic excitation was depressed 19.5 ± 16.2%, and GABAAergic inhibition was enhanced 18.7 ± 20.6%. However, the postsynaptic response to exogenous NMDA was not significantly altered. In addition, 1 MAC sevoflurane depressed peak phrenic nerve activity by 61.8 ± 17.7%. Conclusions In the authors’in vivo expiratory neuronal model, the depressive effect of sevoflurane on synaptic neurotransmission was caused by a reduction of presynaptic glutamatergic excitation and an enhancement of GABAAergic inhibition. The effects on expiratory neuronal activity were similar to halothane, but sevoflurane caused a stronger depression of phrenic nerve activity than halothane.

Clinically Relevant Infusion Rates of μ-Opioid Agonist Remifentanil Cause Bradypnea in Decerebrate Dogs but not Via Direct Effects in the pre-Bötzinger Complex Region

Systemic administration of mu-opioids at clinical doses for analgesia typically slows respiratory rate. Mu-opioid receptors (MORs) on pre-Bötzinger Complex (pre-BötC) respiratory neurons, the putative kernel of respiratory rhythmogenesis, are potential targets. The purpose of this study was to determine the contribution of pre-BötC MORs to the bradypnea produced in vivo by intravenous administration of clinically relevant infusion rates of remifentanil (remi), a short-acting, potent mu-opioid analgesic. In decerebrate dogs, multibarrel micropipettes were used to record pre-BötC neuronal activity and to eject the opioid antagonist naloxone (NAL, 0.5 mM), the glutamate agonist D-homocysteic acid (DLH, 20 mM), or the MOR agonist [D-Ala(2), N-Me-Phe(4), gly-ol(5)]-enkephalin (DAMGO, 100 microM). Inspiratory and expiratory durations (T(I) and T(E)) and peak phrenic nerve activity (PPA) were measured from the phrenic neurogram. The pre-BötC was functionally identified by its rate altering response (typically tachypnea) to DLH microinjection. During intravenous remi-induced bradypnea (approximately 60% decrease in central breathing frequency, f(B)), bilateral injections of NAL in the pre-BötC did not change T(I), T(E), f(B), and PPA. Also, NAL picoejected onto single pre-BötC neurons depressed by intravenous remi had no effect on their discharge. In contrast, approximately 60 microg/kg of intravenous NAL rapidly reversed all remi-induced effects. In a separate group of dogs, microinjections of DAMGO in the pre-BötC increased f(B) by 44%, while subsequent intravenous remi infusion more than offset this DAMGO induced tachypnea. These results indicate that mu-opioids at plasma concentrations that cause profound analgesia produce their bradypneic effect via MORs located outside the pre-BötC region.

Pontine μ-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs

Life-threatening side effects such as profound bradypnea or apnea and variable upper airway obstruction limit the use of opioids for analgesia. It is yet unclear which sites containing μ-opioid receptors (μORs) within the intact in vivo mammalian respiratory control network are responsible. The purpose of this study was 1) to define the pontine region in which μOR agonists produce bradypnea and 2) to determine whether antagonism of those μORs reverses bradypnea produced by intravenous remifentanil (remi; 0.1-1.0 μg·kg(-1)·min(-1)). The effects of microinjections of agonist [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO; 100 μM) and antagonist naloxone (NAL; 100 μM) into the dorsal rostral pons on the phrenic neurogram were studied in a decerebrate, vagotomized, ventilated, paralyzed canine preparation during hyperoxia. A 1-mm grid pattern of microinjections was used. The DAMGO-sensitive region extended from 5 to 7 mm lateral of midline and from 0 to 2 mm caudal of the inferior colliculus at a depth of 3-4 mm. During remi-induced bradypnea (~72% reduction in fictive breathing rate) NAL microinjections (~500 nl each) within the region defined by the DAMGO protocol were able to reverse bradypnea by 47% (SD 48.0%) per microinjection, with 13 of 84 microinjections producing complete reversal. Histological examination of fluorescent microsphere injections shows that the sensitive region corresponds to the parabrachial/Kölliker-Fuse complex.

Negative-pressure pulmonary edema in a child with hiccups during induction

An 8-yr-old, 20-kg girl was scheduled to undergo dental restorations and extractions as an outpatient. The patient had a history of seizures and multiple ischemic strokes secondary to Moyamoya disease. She had undergone three previous operations during general anesthesia, without anesthesia-related difficulties. At the preoperative visit, she was aphasic and drooling. Significant left lower extremity weakness and diffuse fine motor deficits were also present, but the patient was ambulatory. The patient received 10 mg midazolam via G-tube as premedication. After application of electrocardiogram leads and pulse oximetry, inhalational induction with 70% nitrous oxide in oxygen and halothane was begun. Within seconds after the start of induction, vigorous hiccups, which were accompanied by tracheal tugging, developed in the patient. Pulse oximetry showed a stable arterial saturation of 99-10076 throughout induction, and capnography did not show impairment of gas exchange. Therefore, inhalational induction was continued, with the child breathing spontaneously. The strong hiccups never ceased during approximately 10 min of induction. Finally, intravenous access was obtained and 20 mg rocuronium was administered intravenously. As neuromuscular blockade occurred, spontaneous ventilation and the hiccups stopped, and positive pres-

Effects of halothane on excitatory neurotransmission to medullary expiratory neurons in a decerebrate dog model.

BackgroundThe activity of canine expiratory (E) neurons in the caudal ventral respiratory group is primarily dependent on N-methyl-d-aspartic acid (NMDA) receptor–mediated excitatory chemodrive inputs and modulated by an inhibitory mechanism mediated via &ggr;-aminobutyric acidA (GABAA) receptors. In an intact canine preparation, halothane depressed the activity of these neurons mainly by reduction in overall glutamatergic excitation. A new decerebrate preparation allows comparison of the effects of halothane on these synaptic mechanisms with an anesthetic-free baseline state. MethodsTwo separate studies were performed in decerebrate, vagotomized, paralyzed, mechanically ventilated dogs during hypercapnic hyperoxia. In study 1, the effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded E neuronal activity was studied before and during complete GABAA receptor blockade by localized pressure ejection of bicuculline. Complete blockade of the inhibitory mechanism allowed differentiation between the effects of halothane on overall GABAA-mediated inhibition and on overall NMDA receptor–mediated excitation. In study 2, the effect of 1 MAC halothane on the dose response of neurons to localized picoejection of the glutamate agonist NMDA was used to estimate halothane effect on postsynaptic glutamatergic excitatory neurotransmission. ResultsIn study 1, the spontaneous activity of 14 E neurons was depressed 38.6 ± 20.6% (mean ± SD) by 1 MAC halothane. Overall excitation was depressed 31.5 ± 15.5%. The GABAergic inhibition showed a 11.7 ± 18.3% enhancement during halothane. In study 2, the spontaneous activity of 13 E neurons was again significantly depressed by 1 MAC halothane (27.9 ± 10.6%), but the postsynaptic response of the neurons to exogenous NMDA was not significantly depressed by halothane (3.3 ± 38.4%). ConclusionsTogether these results suggest that in our E neuron paradigm, halothane exerted its depressive effect mainly via reduction of glutamatergic presynaptic mechanisms.

Opioid Receptors on Bulbospinal Respiratory Neurons Are Not Activated During Neuronal Depression by Clinically Relevant Opioid Concentrations

Opioids depress the activity of brain stem respiratory-related neurons, but it is not resolved whether the mechanism at clinical concentrations consists of direct neuronal effects or network effects. We performed extracellular recordings of discharge activity of single respiratory neurons in the caudal ventral respiratory group of decerebrate dogs, which were premotor neurons with a likelihood of 90%. We used multibarrel glass microelectrodes, which allowed concomitant highly localized picoejection of opioid receptor agonists or antagonists onto the neuron. Picoejection of the mu receptor agonist [d-Ala(2), N-Me-phe(4), gly-ol(5)]-enkephalin (DAMGO, 1 mM) decreased the peak discharge frequency (mean +/- SD) of expiratory neurons to 68 +/- 22% (n = 12), the delta(1) agonist d-Pen(2,5)-enkephalin (DPDPE, 1 mM) to 95 +/- 11% (n = 15), and delta(2) receptor agonist [d-Ala(2)] deltorphin-II to 86 +/- 17% (1 mM, n = 15). The corresponding values for inspiratory neurons were: 64 +/- 12% (n = 11), 48 +/- 30% (n = 12), and 75 +/- 15% (n = 11), respectively. Naloxone fully reversed these effects. Picoejection of morphine (0.01-1 mM) depressed most neurons in a concentration dependent fashion to maximally 63% (n = 27). Picoejection of remifentanil (240-480 nM) did not cause any significant depression of inspiratory (n = 11) or expiratory neurons (n = 9). 4. Intravenous remifentanil (0.2-0.6 microg.kg(-1).min(-1)) decreased neuronal peak discharge frequency to 60 +/- 12% (inspiratory, n = 7) and 58 +/- 11% (expiratory, n = 11). However, local picoejection of naloxone did not reverse the neuronal depression. Our data suggest that mu, delta(1), and delta(2) receptors are present on canine respiratory premotor neurons. Clinical concentrations of morphine and remifentanil caused no local depression. This lack of effect and the inability of local naloxone to reverse the neuronal depression by intravenous remifentanil suggest that clinical concentrations of opioids produce their depressive effects on mechanisms upstream from respiratory bulbospinal premotor neurons.

Sevoflurane Enhances γ-Aminobutyric Acid Type A Receptor Function and Overall Inhibition of Inspiratory Premotor Neurons in a Decerebrate Dog Model

Background:Inspiratory premotor neurons in the caudal ventral medulla relay excitatory drive to phrenic and inspiratory intercostal motoneurons in the spinal cord. These neurons are subject to tonic &ggr;-aminobutyric acid type A (GABAA)ergic inhibition. In a previous study, 1 minimum alveolar concentration (MAC) sevoflurane depressed overall glutamatergic excitatory drive and enhanced overall GABAAergic inhibitory drive to the neurons. This study investigated in further detail the effects of sevoflurane on GABAAergic inhibition by examining postsynaptic GABAA receptor activity in these neurons. Methods:Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor antagonist bicuculline and the GABAA agonist muscimol. Complete blockade of GABAAergic inhibition by bicuculline allowed estimation of the prevailing overall inhibition of the neuron. The neuronal response to muscimol was used to assess the anesthetic effect on the postsynaptic GABAA receptor function. Results:One MAC sevoflurane depressed the spontaneous activity of 21 inspiratory premotor neurons by (mean ± SD) 32.6 ± 20.5% (P < 0.001). Overall excitatory drive was depressed 17.9 ± 19.8% (P < 0.01). Overall GABAAergic inhibition was enhanced by 18.5 ± 18.2% (P < 0.001), and the postsynaptic GABAA receptor function was increased by 184.4 ± 121.8% (n = 20; P < 0.001). Conclusion:One MAC sevoflurane greatly enhanced GABAA receptor function on inspiratory premotor neurons and increased overall synaptic inhibition but to a smaller extent, indicating that the presynaptic inhibitory input was also reduced. Therefore, the anesthetic depression of spontaneous inspiratory premotor neuronal activity by 1 MAC sevoflurane in vivo is due to a combined effect on the two major ionotropic synaptic neurotransmitter systems with a decrease in overall glutamatergic excitation and a strong enhancement of postsynaptic GABAA receptor function.

Effects of halothane and sevoflurane on inhibitory neurotransmission to medullary expiratory neurons in a decerebrate dog model.

Background In canine expiratory bulbospinal neurons, 1 minimum alveolar concentration (MAC) halothane and sevoflurane reduced the glutamatergic excitatory drive at a presynaptic site and enhanced the overall &ggr;-aminobutyric acid (GABA)-mediated inhibitory input. The authors investigated if this inhibitory enhancement was mainly caused by postsynaptic effects. Methods Two separate anesthetic studies were performed in two sets of decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC halothane or sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline. Complete blockade of GABAA-mediated inhibition with bicuculline was used to assess the prevailing overall inhibitory input to the neuron. The neuronal response to muscimol was used to estimate the anesthetic effect on postsynaptic GABAA receptor function. Results Halothane at 1 MAC depressed the spontaneous activity of 12 expiratory neurons 22.2 ± 14.8% (mean ± SD) and overall glutamatergic excitation 14.5 ± 17.9%. Overall GABA-mediated inhibition was enhanced 14.1 ± 17.9% and postsynaptic GABAA receptor function 74.2 ± 69.2%. Sevoflurane at 1 MAC depressed the spontaneous activity of 23 neurons 20.6 ± 19.3% and overall excitation 10.6 ± 21.7%. Overall inhibition was enhanced 15.4 ± 34.0% and postsynaptic GABAA receptor function 65.0 ± 70.9%. The effects of halothane and sevoflurane were not statistically different. Conclusion Halothane and sevoflurane at 1 MAC produced a small increase in overall inhibition of expiratory premotor neuronal activity. The increase in inhibition results from a marked enhancement of postsynaptic GABAA receptor function that is partially offset by a reduction in presynaptic inhibitory input by the anesthetics.

Droperidol for perioperative sedation causes a transient prolongation of the QTc time in children under volatile anesthesia1

Background : Droperidol is useful for postoperative sedation in infants and children after cardiac surgery because it provides sedation and akinesia with minimal respiratory depression. However, droperidol has been associated with QT prolongation and ventricular arrhythmias. We investigated, if neuroleptanalgesic doses of droperidol led to QT prolongation and cardiac arrhythmias in children undergoing cardiac surgery.

Sevoflurane Depresses Glutamatergic Neurotransmission to Brainstem Inspiratory Premotor Neurons but Not Postsynaptic Receptor Function in a Decerebrate Dog Model

Background:Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive motoneurons, which innervate pump muscles such as the diaphragm and external intercostals. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and &agr;-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and is modulated by an inhibitory &ggr;-aminobutyric acid type A (GABAA)ergic input. The authors investigated the effect of sevoflurane on these synaptic mechanisms in decerebrate dogs. Methods:Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration sevoflurane on extracellularly recorded activity of single neurons was measured during localized picoejection of the GABAA receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABAAergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABAAergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission. Results:One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 23 inspiratory premotor neurons by (mean ± SD) 30.0 ± 21.0% (P < 0.001). Overall glutamatergic excitation was depressed 19.2 ± 18.5% (P < 0.001), whereas overall GABAAergic inhibition was enhanced by 11.9 ± 25.1% (P < 0.05). The postsynaptic responses to exogenous AMPA and NMDA did not change. Conclusion:One minimum alveolar concentration depressed the activity of inspiratory premotor neurons by a reduction of glutamatergic excitation and an increase in overall inhibition. The postsynaptic AMPA and NMDA receptor response was unchanged. These findings contrast with studies in inspiratory premotor neurons where halothane did not change overall inhibition but significantly reduced the postsynaptic glutamate receptor response.