[Anesthetic management of a neonate with congenital cystic adenomatoid malformation].

We report the anesthetic management of a female neonate with congenital cyst adenoid malformation (CCAM) type III of the lung who underwent the lower right lobe resection 22 days after birth. General anesthesia was induced with propofol and rocuronium. The trachea was intubated with a 3.0 standard tube. Anesthesia was maintained with sevoflurane in an air/oxygen mixture and fentanyl. Intraoperative anesthetic course was uneventful except transient desaturation during lung compression. Immediately, the saturation was restored by interruption of lung compression. One lung ventilation was not necessary in this operation. Postoperative course was uneventful. Patient was discharged home on the 28th postoperative day.

[Anesthetic management of a patient with moyamoya disease undergoing mitral valve repair].

Moyamoya disease is the result of progressive steno-occlusive changes in the internal carotid arteries followed by formation of bilateral abnormal vascular networks. The disease may present with cerebral ischemia causing cerebral hemorrhage in the perioperative period. There are few reports of cardiac surgeries in patients with moyamoya disease, and the management during cardiopulmonary bypass for moyamoya disease has not been established. We gave general anesthesia for mitral valve plasty in patient with the moyamoya disease. A 52-year-old woman underwent mitral valve plasty. She had been diagnosed with moyamoya disease and during the cardiopulmonary bypass, we used alpha-stat blood gas management with mild hypothermia, and maintained PaCO2 around 40 mmHg. We maintained the perfusion flow of CPB above 3.0 l x min(-1) x m(-2) and the mean perfusion pressure above 70 mmHg. In addition, we used the pulsatile perfusion assist with intraaortic balloon pumping to maintain cerebral circulation. Postoperative course was uneventful without apparent neurologic deficit, and she was discharged from hospital on 10th postoperative day.

[Perioperative anticoagulant therapy in a patient with congenital antithrombin III deficiency undergoing posterior spinal fusion].

A 22-year-old female was scheduled to undergo posterior thoracolumbar spinal fusion. She had been diagnosed with congenital antithrombin III (AT-III) deficiency by the onset of pulmonary embolism and deep vein thrombosis after the first operation at the age of 18. Thereafter she had taken warfarin, 5 mg daily, until 4 days before the surgery. Preoperatively, we administered AT-III products to regulate AT-III activity. The posterior spinal fusion was performed successfully without surgical complications. Postoperatively, we continued administration of AT-III products to maintain AT-III activity above 75%. We also used low dose unfractionated heparin with AT-III by continuous intravenous infusion. Heparin was administered with dose adjustment to achieve a target activated partial thromboplastin time of 45 to 60 seconds. After the activated partial thromboplastin time was stabilized in the target range, we started warfarin therapy (target international normalized ratio, 1.5 to 2.5) on postoperative day 16 and stopped administration of heparin on postoperative day 19. There was no thrombosis complications during the perioperative period. Good anticoagulant management was achieved in a patient with congenital AT-III deficiency undergoing posterior spinal fusion.

Effect of JM-1232(-), a new sedative on central respiratory activity in newborn rats.

JM-1232(-), a newly manufactured isoindole derivative, shows sedative effect at a lower concentration compared with propofol. In the present study, we analyzed the response of the central respiratory activity to JM-1232(-). The brainstem-spinal cord of a newborn rat was isolated and was continuously superfused with oxygenated artificial cerebrospinal fluid (ACSF). Rhythmic inspiratory burst activity was recorded from C4 spinal ventral root using a glass suction electrode. We measured C4 burst rate and amplitude of integrated C4 activity. After obtaining a control recording, the preparation was superfused with ACSF containing JM-1232(-) at 10, 100 or 500 microM for 10 min. The application of both 10 and 100 microM JM-1232(-) did not decrease C4 burst rate significantly. However, 500 microM JM-1232(-) reduced C4 burst rate. On the contrary, C4 burst amplitude was not affected by the application of JM-1232(-) for 10 min at any concentrations. In conclusion, JM-1232(-) at a low concentration (but presumably higher than hypnotic dose), did not depress the central respiratory activity, whereas at a high concentration depression was seen.

Neural mechanisms of sevoflurane-induced respiratory depression in newborn rats.

BACKGROUND: Sevoflurane-induced respiratory depression has been reported to be due to the action on medullary respiratory and phrenic motor neurons. These results were obtained from extracellular recordings of the neurons. Here, the authors made intracellular recordings of respiratory neurons and analyzed their membrane properties during sevoflurane application. Furthermore, they clarified the role of gamma-aminobutyric acid type A receptors in sevoflurane-induced respiratory depression. METHODS: In the isolated brainstem-spinal cord of newborn rat, the authors recorded the C4 nerve burst as an index of inspiratory activity. The preparation was superfused with a solution containing sevoflurane alone or sevoflurane plus the gamma-aminobutyric acid type A receptor antagonist picrotoxin or bicuculline. Neuronal activities were also recorded using patch clamp techniques. RESULTS: Sevoflurane decreased C4 burst rate and amplitude. Separate perfusion of sevoflurane to the medulla and to the spinal cord decreased C4 burst rate and amplitude, respectively. Both picrotoxin and bicuculline attenuated the reduction of C4 burst rate. Sevoflurane reduced both intraburst firing frequency and membrane resistance of respiratory neurons except for inspiratory neurons. CONCLUSION: 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.

CO2-sensitivity of GABAergic neurons in the ventral medullary surface of GAD67-GFP knock-in neonatal mice.

We investigated the CO2 responsiveness of GABAergic neurons in the ventral medullary surface (VMS), a putative chemoreceptive area using a 67-kDa isoform of GABA-synthesizing enzyme (GAD67)-green fluorescence protein (GFP) knock-in neonatal mouse, in which GFP is specifically expressed in GABAergic neurons. The slice was prepared by transversely sectioning at the level of the rostral rootlet of the XII nerve and the rostral end of the inferior olive in mock cerebrospinal fluid (CSF). Each medullary slice was continuously superfused with hypocapnic CSF. GFP-positive neurons in the VMS were selected by using fluorescent optics and their membrane potentials and firing activities were analyzed with a perforated patch recording technique. Thereafter, superfusion was changed from hypocapnic to hypercapnic CSF. In 4 out of 8 GABAergic neurons in the VMS, perfusion with hypercapnic CSF induced more than a 20% decrease in the discharge frequency and hyperpolarized the neurons. The remaining 4 GFP-positive neurons were CO2-insensitive. GABAergic neurons in the VMS have chemosensitivity. Inhibition of chemosensitive GABAergic neural activity in the VMS may induce increases in respiratory output in response to hypercapnia.

Anesthetic management of a patient with Hermansky-Pudlak syndrome undergoing video-assisted bullectomy.

The Hermansky-Pudlak syndrome (HPS) is a rare set of disorders characterized by oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, with the latter 2 conditions presenting major challenges in anesthetic management. We report a 53-year-old woman with pulmonary fibrosis secondary to HPS who underwent video-assisted bullectomy to treat recurrent pneumothorax. Preoperative bleeding time and platelet count were within normal limits, but the surgeons had difficulty with continuous oozing from the incision site; the surgical blood loss was 270 mL, which was a relatively large amount for this surgery. Because of her restrictive lung disease, the patient's tidal volume was only 250 mL under pressure-controlled ventilation, with a peak inspiratory pressure of 30 cm H2O and a positive end-expiratory pressure of 5 cm H2O. She also had postoperative respiratory insufficiency, with a partial pressure of arterial CO2 of 112 mm Hg and a pH of 7.08 on arterial blood gas analysis. Then, the patient needed mechanical ventilation for 4 days. In conclusion, patients with HPS require strict respiratory management to support their restrictive pulmonary dysfunction, and, also, we should consider preventive management for hemostasis and adequate analgesia to reduce the patient's work of breathing.

Effects of neuromuscular blocking agents on central respiratory control in the isolated brainstem-spinal cord of neonatal rat.

Although neuromuscular blocking agents (NMBAs) function as muscular nicotinic acetylcholine receptor (nAChR) antagonists, several studies have shown that they block neuronal nAChRs as well, which led us to hypothesize that these agents can affect neuronal nAChRs expressed in respiratory centers. To test this hypothesis, we studied the effects of two NMBAs on respiratory activity and respiratory neurons in brainstem-spinal cord preparations from neonatal rats. The application of either D-tubocurarine or vecuronium resulted in dose-dependent reductions in C4 respiratory rate. These reductions were concomitant with reductions in the depolarizing cycle rate of inspiratory (Insp) neurons; the depolarizing cycle rate of preinspiratory (Pre-I) neurons, however, was not affected. We also detected C4 burst activity during the depolarizing phase in Pre-I neurons, even during NMBA-induced respiratory depression. Both NMBAs inhibited drive potential amplitude and intraburst firing frequency in Insp and Pre-I neurons. These agents also induced a hyperpolarization and an increase in membrane resistance in Pre-I neurons, however they had no effect on these membrane properties in Insp neurons. Our findings indicate that these agents suppress central respiratory activity mainly through their inhibitory effects on Pre-I neurons and the Pre-I to Insp neuron synaptic drive, and that nAChRs are involved in central respiratory control.

Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit.

Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.

Association of nicotinic acetylcholine receptors with central respiratory control in isolated brainstem-spinal cord preparation of neonatal rats.

Nicotine exposure is a risk factor in several breathing disorders Nicotinic acetylcholine receptors (nAChRs) exist in the ventrolateral medulla, an important site for respiratory control. We examined the effects of nicotinic acetylcholine neurotransmission on central respiratory control by addition of a nAChR agonist or one of various antagonists into superfusion medium in the isolated brainstem-spinal cord from neonatal rats. Ventral C4 neuronal activity was monitored as central respiratory output, and activities of respiratory neurons in the ventrolateral medulla were recorded in whole-cell configuration. RJR-2403 (0.1-10 mM), alpha4beta2 nAChR agonist induced dose-dependent increases in respiratory frequency. Non-selective nAChR antagonist mecamylamine (0.1-100 mM), alpha4beta2 antagonist dihydro-beta-erythroidine (0.1-100 mM), alpha7 antagonist methyllycaconitine (0.1-100 mM), and a-bungarotoxin (0.01-10 mM) all induced dose-dependent reductions in C4 respiratory rate. We next examined effects of 20 mM dihydro-beta-erythroidine and 20mM methyllycaconitine on respiratory neurons. Dihydro-beta-erythroidine induces hyperpolarization and decreases intraburst firing frequency of inspiratory and preinspiratory neurons. In contrast, methyllycaconitine has no effect on the membrane potential of inspiratory neurons, but does decrease their intraburst firing frequency while inducing hyperpolarization and decreasing intraburst firing frequency in preinspiratory neurons. These findings indicate that alpha4beta2 nAChR is involved in both inspiratory and preinspiratory neurons, whereas alpha7 nAChR functions only in preinspiratory neurons to modulate C4 respiratory rate.

Effects of neuromuscular blocking agents on central respiratory chemosensitivity in newborn rats.

Neuromuscular blocking agents suppress central respiratory activity through their inhibitory effects on preinspiratory neurons and the synaptic drive from preinspiratory neurons to inspiratory neurons. Central CO2-chemosensitive areas, which partly consist of CO2-excited neurons, in the rostral ventrolateral medulla are thought to provide tonic drive to the central respiratory network and involve cholinergic mechanisms, which led us to hypothesize that neuromuscular blocking agents can inhibit CO2-excited neurons and attenuate respiratory CO2 responsiveness. To test this hypothesis, we used isolated brainstem-spinal cord preparations from newborn rats. The increase of C4 burst frequency induced by a hypercapnic superfusate, i.e. respiratory CO2 responsiveness, was suppressed by the application of neuromuscular blocking agents, either d-tubocurarine (10, 100 microM) or vecuronium (100 microM). These agents (40 microM) also induced hyperpolarization and decreases in firing frequency of CO2-excited neurons in the rostral ventrolateral medulla. Our results demonstrate that neuromuscular blocking agents inhibit CO2-excited tonic firing neurons and attenuate respiratory CO2 responsiveness.

Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit

Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C0(2). In the other experiment, apneic threshold PaC0(2) was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.

Association of nicotinic acetylcholine receptors with central respiratory control in isolated brainstem-spinal cord preparation of neonatal rats

Nicotine exposure is a risk factor in several breathing disorders Nicotinic acetylcholine receptors (nAChRs) exist in the ventrolateral medulla, an important site for respiratory control. We examined the effects of nicotinic acetylcholine neurotransmission on central respiratory control by addition of a nAChR agonist or one of various antagonists into superfusion medium in the isolated brainstem-spinal cord from neonatal rats. Ventral C4 neuronal activity was monitored as central respiratory output, and activities of respiratory neurons in the ventrolateral medulla were recorded in whole-cell configuration. RJR-2403 (0.1-10mM), a4b2 nAChR agonist induced dose-dependent increases in respiratory frequency. Non-selective nAChR antagonist mecamylamine (0.1-100mM), a4b2 antagonist dihydro-b-erythroidine (0.1-100mM), a7 antagonist methyllycaconitine (0.1-100mM), and a-bungarotoxin (0.01-10mM) all induced dose-dependent reductions in C4 respiratory rate. We next examined effects of 20mM dihydro-b-erythroidine and 20mM methyllycaconitine on respiratory neurons. Dihydro-b-erythroidine induces hyperpolarization and decreases intraburst firing frequency of inspiratory and preinspiratory neurons. In contrast, methyllycaconitine has no effect on the membrane potential of inspiratory neurons, but does decrease their intraburst firing frequency while inducing hyperpolarization and decreasing intraburst firing frequency in preinspiratory neurons. These findings indicate that a4b2 nAChR is involved in both inspiratory and preinspiratory neurons, whereas a7 nAChR functions only in preinspiratory neurons to modulate C4 respiratory rate.

Effects of neuromuscular blocking agents on central respiratory chemosensitivity in newborn rats

Neuromuscular blocking agents suppress central respiratory activity through their inhibitory effects on preinspiratory neurons and the synaptic drive from preinspiratory neurons to inspiratory neurons. Central CO2-chemosensitive areas, which partly consist of CO2-excited neurons, in the rostral ventrolateral medulla are thought to provide tonic drive to the central respiratory network and involve cholinergic mechanisms, which led us to hypothesize that neuromuscular blocking agents can inhibit CO2-excited neurons and attenuate respiratory CO2 responsiveness. To test this hypothesis, we used isolated brainstem-spinal cord preparations from newborn rats. The increase of C4 burst frequency induced by a hypercapnic superfusate, i.e. respiratory CO2 responsiveness, was suppressed by the application of neuromuscular blocking agents, either d-tubocurarine (10, 100M) or vecuronium (100M). These agents (40M) also induced hyperpolarization and decreases in firing frequency of CO2-excited neurons in the rostral ventrolateral medulla. Our results demonstrate that neuromuscular blocking agents inhibit CO2-excited tonic firing neurons and attenuate respiratory CO2 responsiveness.