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Background: We investigated the associations between postoperative delirium (POD) and both the relative ratio of the alpha (α)-power of electroencephalography (EEG) and inflammatory markers in a prospective, single-center observational study., Methods: We enrolled 84 patients who underwent radical cancer surgeries with reconstruction for esophageal cancer, oral floor cancer, or pharyngeal cancer under total intravenous anesthesia. We collected the perioperative EEG data and the perioperative data of the inflammatory markers, including neutrophil gelatinase-associated lipocalin, presepsin, procalcitonin, C-reactive protein, and the neutrophil-lymphocyte ratio (NLR). The existence of POD was evaluated based on the Intensive Care Delirium Screening Checklist. We compared the time-dependent changes in the relative ratio of the EEG α-power and inflammatory markers between the patients with and without POD., Results: Four of the 84 patients were excluded from the analysis. Of the remaining 80 patients, 25 developed POD and the other 55 did not. The relative ratio of the α-power at baseline was significantly lower in the POD group than the non-POD group (0.18 ± 0.08 vs 0.28 ± 0.11, P < .001). A time-dependent decline in the relative ratio of α-power in the EEG during surgery was observed in both groups. There were significant differences between the POD and non-POD groups in the baseline, 3-h, 6-h, and 9-h values of the relative ratio of α-power. The preoperative NLR of the POD group was significantly higher than that of the non-POD group (2.88 ± 1.04 vs 2.22 ± 1.00, P < .001), but other intraoperative inflammatory markers were comparable between the groups. Two multivariable logistic regression models demonstrated that the relative ratio of the α-power at baseline was significantly associated with POD., Conclusions: Intraoperative frontal relative ratios of the α-power of EEG were associated with POD in patients who underwent radical cancer surgery. Intraoperative EEG monitoring could be a simple and more useful tool for predicting the development of postoperative delirium than measuring perioperative acute inflammatory markers. A lower relative ratio of α-power might be an effective marker for vulnerability of brain and ultimately for the development of POD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

A rectus sheath block can provide postoperative analgesia for midline incisions. However, information regarding the pharmacokinetics of local anesthetics used in this block is lacking. In this study, we detail the time course of ropivacaine concentrations after this block. Thirty-nine patients undergoing elective lower abdominal surgery were assigned to 3 groups receiving rectus sheath block with 20 mL of different concentrations of ropivacaine. Peak plasma concentrations were dose dependent, and there were no significant differences in the times to peak plasma concentrations. The present data also suggested a slower absorption kinetics profile for ropivacaine after rectus sheath block than other compartment blocks.

Background: Neuropeptide S (NPS) and its receptor (NPSR) is a novel neuropeptide system that regulates arousal and anxiety. A link between natural sleep and general anesthesia has been suggested. Therefore, we hypothesized that the NPS neuronal system may also modulate general anesthesia., Methods: The effects of intracerebroventricular NPS and [D-Cys(tBu)(5)]NPS, a peptide NPSR antagonist, on ketamine and thiopental anesthesia time were measured in rats. Anesthesia time was defined as the interval between the loss of righting reflex and its recovery., Results: Intracerebroventricular NPS 1 to 30 nmol significantly reduced ketamine anesthesia time, showing a bell-shaped dose-response curve. [D-Cys(tBu)(5)]NPS 20 nmol antagonized NPS 1 nmol effects and was per se able to increase ketamine anesthesia time. Similar results were obtained investigating thiopental anesthesia time that was significantly reduced by NPS and prolonged by [D-Cys(tBu)(5)]NPS., Conclusion: NPS via selective NPSR activation stimulates the wakefulness-promoting pathway, thus reducing anesthesia duration. The endogenous NPS/NPSR system seems to tonically control these pathways.

Background: In clinical anesthesia, robust surgical stress occasionally causes unintended light anesthesia during operation. To test the hypothesis that neural input condition could modify actions of general anesthetics as a result of presynaptic alteration in the central nervous system, we investigated the mechanisms by which the stimulus frequency modifies synaptic transmission of the rat hippocampus in the presence of general anesthetics., Methods: Field population spikes (PSs) of CA1 pyramidal neurons were elicited using orthodromic stimulation of Schaffer collateral-commissural fibers (test-pulse). A second stimulating electrode was placed in the region of the alveus hippocampi to activate recurrent inhibition of area CA1 (pre-pulse). The pre-pulses were applied as train stimuli (100-200 Hz) to activate release and then deplete the neurotransmitter (gamma-aminobutyric acid [GABA]) at presynaptic terminals of inhibitory interneurons., Results: After the activation of inhibitory interneurons with pre-pulses, both IV (thiopental and pentobarbital) and volatile (sevoflurane and isoflurane) anesthetics attenuated the PS amplitudes elicited with test-pulses (test-PS). The IV anesthetics, but not the volatile drugs, produced stimulus frequency- and use-dependent recurrent inhibition of test-PSs. Neither a GABA type A agonist nor a GABA uptake inhibitor produced frequency-dependent modification. The pre-pulse train protocol revealed that IV anesthetics, but not volatile drugs, can enhance GABA release from presynaptic terminals., Conclusions: IV anesthetics, but not volatile drugs, enhance the discharge of a readily releasable pool of GABA vesicles from presynaptic terminals. Depletion of an active pool of GABA after high-frequency stimuli would produce frequency- and use-dependent recurrent inhibition in the presence of IV anesthetics. The stimulus frequency-dependent modification of synaptic transmission might be responsible for the unsuccessful immobilization or hypnosis during general anesthesia after IV anesthetic administration.

Background: Urotensin II (UII) and its receptor (UT) are implicated in mood disorders, such as stress and anxiety, and this may result, at least in part, from increased norepinephrine release from the cerebral cortex. Benzodiazepines have been widely used as hypnotics and anxiolytics, producing a decrease in cerebrocortical norepinephrine release. We hypothesized that there was some interaction between benzodiazepines and the UII system in the cerebral cortex., Methods: In the present study, we have examined the effects of benzodiazepines on UII-increased norepinephrine release from rat cerebrocortical slices and intracellular Ca(2+) concentrations ([Ca(2+)]i) in HEK293 cells expressing rat UT receptor (HEK293-rUT cells)., Results: Midazolam, diazepam and flunitrazepam concentration-dependently inhibited UII-evoked norepinephrine release but did not affect [Ca(2+)]i. The IC(50) of midazolam for inhibition of UII-evoked norepinephrine release (0.32 microM, P < 0.01) was significantly lower than that of diazepam (187 microM) or flunitrazepam (40 microM). The inhibitory effects of midazolam on UII-evoked norepinephrine release were significantly attenuated by flumazenil, a benzodiazepine site antagonist., Conclusion: The present study suggests that midazolam, at clinically relevant concentration, significantly inhibited UII-evoked norepinephrine release. This inhibitory effect may be partially mediated via central benzodiazepine receptors.

Background: Orexins (OXs) regulate wakefulness, and a lack of OX Type-I receptors cause narcolepsy. OX selectively increases norepinephrine (NE) release from rat cerebral cortical slices, and brain noradrenergic neurons are involved in the sleep-wakefulness cycle. Ketamine increases NE release from the rat cerebral cortex. We hypothesized that OX would affect ketamine anesthesia's interactions with brain noradrenergic neuronal activity., Methods: We used Sprague Dawley rats. We studied 1) in vivo effects of orexin A (OXA) and SB-334867-A (Orexin-1 receptor antagonist) on ketamine-induced anesthesia time, 2) in vivo effects of OXA on ketamine-induced increase in NE release from the frontal cortex assessed using microdialysis, and 3) in vitro effects of ketamine on OXA-evoked NE release from rat cerebrocortical slices., Results: 1) Intracerebroventricular OXA 1 nmol significantly decreased ketamine anesthesia time by 20%-30% at 50, 100, and 125 mg/kg intraperitoneal (IP) ketamine. SB-334867-A fully reversed the decrease produced by OXA. 2) OXA also decreased the release of NE induced by ketamine even though OXA increased the release of NE in rat prefrontal cortex. Maximum NE release in Group OX + K (intracerebroventricular OXA 1 nmol + IP ketamine 100 mg/kg) was 271% and was significantly smaller than that in Group K (ketamine 100 mg/kg IP, 390% of baseline, P = 0.029). 3) Ketamine inhibited OX-evoked NE release with clinically relevant IC(50) values., Conclusion: Orexinergic neurons may be an important target for ketamine. OXA antagonized ketamine anesthesia via Orexin-1 receptor with noradrenergic neurons.

Background: We report a novel method to estimate regional blood flow in the atelectatic lung using transesophageal echocardiography in an experimental dog model. To verify the efficacy of the method, we investigated the ability of this experimental model to detect changes in regional pulmonary blood flow., Methods: Fourteen anesthetized and ventilated mongrel dogs were randomized into an isoproterenol group (n = 7) or a dopamine group (n = 7). To produce an atelectatic lesion, 60 mL/kg of saline was infused into the left pleural space. The velocity time integral (VTI) derived from pulse Doppler was evaluated as an index of blood flow in the atelectatic lesion. To investigate the response of the method to changes in blood flow, the VTI and the shunt fraction (Qs/Qt) were measured during systemic administration of isoproterenol 0.05 microg x kg(-1) x min(-1) (as a pulmonary vasodilator) and dopamine 10 microg x kg(-1) x min(-1) (as a pulmonary vasoconstrictor)., Results: Both VTI and Qs/Qt were increased significantly by isoproterenol administration. There was a significant correlation between the percentage changes of VTI and Qs/Qt with isoproterenol administration (r2 = 0.50, P < 0.001). Both VTI and Qs/Qt were unchanged during administration of dopamine., Conclusions: Transesophageal echocardiography may be useful in detecting changes in regional pulmonary blood flow in an atelectatic lesion.

Hypercapnia during laparoscopy with CO2 is predicted in the following situations: compromised pulmonary function, retroperitoneal insufflation, and subcutaneous emphysema. We present a case of sudden electroencephalogram (EEG) depression in response to severe hypercapnia during laparoscopic ureteronephrectomy in a 77-yr-old patient with chronic pulmonary emphysema. During intraperitoneal and retroperitoneal insufflation, subcutaneous emphysema and difficult ventilation occurred. Severe hypercapnia ensued, with pH = 6.94, and Paco2 = 137 mm Hg. Subsequent EEG activity was markedly depressed with a minimum Bispectral Index of 4, accompanied by an increase in arterial blood pressure and heart rate. Termination of the laparoscopic procedure improved ventilation, EEG, and hemodynamics. These EEG changes may result from the narcotic properties of CO2 or hypercapnia-induced neurological abnormalities.

Background: Heme oxygenase produces carbon monoxide (CO) during the breakdown of heme molecules. A variety of stressors upregulate this enzymatic activity and can increase exhaled CO levels. Recently, exhaled CO levels have been reported to increase in critically ill patients and after anesthesia and surgery. To use this measurement during mechanical ventilation, it is important to clarify the effects of factors which interfere with exhaled CO levels. The fraction of inspired oxygen (Fio2) is often changed during artificial ventilation. To investigate the effect of changes of Fio2 on exhaled CO, we measured exhaled CO levels during general anesthesia., Methods: Thirty patients who underwent elective operations were enrolled in this study. Anesthesia was maintained with sevoflurane and fentanyl. All patients were tracheally intubated and ventilated with a non-rebreathing ventilator. Exhaled CO levels were measured in gas sampled from the expired limb of the respiration circuit using a CO monitor. The effects of sequential changes of Fio2 on exhaled CO levels, and the effects of long-term inhalation of Fio2 0.75 and Fio2 0.35 on exhaled CO levels and arterial carboxyhemoglobin concentrations were investigated., Results: Exhaled CO levels changed rapidly in response to changes of Fio2. Long-term inhalation of Fio2 0.75 initially increased and then gradually decreased exhaled CO to basal levels, concomitant with a decrease of arterial carboxyhemoglobin. Long-term inhalation of Fio2 0.35 did not elicit any significant change in the observed variables., Conclusion: When monitoring exhaled CO levels during mechanical ventilation, it is important to consider the effects of Fio2.

Background: As orexinergic (OXergic) neurons have been reported to mediate emotional changes, benzodiazepines might interact with OXergic neurons., Methods: We examined the interactions between OXergic neurons and benzodiazepine receptors in orexin-A (100 nM) and K+ (25 mM)-evoked norepinephrine release from rat cerebrocortical slices., Results: Midazolam, diazepam, and flunitrazepam concentration-dependently inhibited both OX-A- and K+-evoked norepinephrine release. The IC50 of midazolam for orexin-A-evoked release (0.87 microM, P < 0.01), which was insensitive to flumazenil, was significantly lower than that of diazepam and flunitrazepam (around 60 microM), whereas the IC50s for K+-evoked release were not different among the benzodiazepines., Conclusion: There may be no interaction between OXergic neurons and central benzodiazepine receptors.

In this study, we have examined the effects of both volatile and IV general anesthetics on excitatory synaptic transmission, with and without recurrent inhibition, to clarify whether excitatory or inhibitory synapses are the major targets of action. Field population spike amplitudes (fPSs) of CA1 pyramidal neurons were recorded in rat hippocampal slices. Schaffer-collateral-commissural fibers (Sch) were stimulated orthodromically, and the evoked fPSs (PS[Sch]) in CA1 area were measured. In addition, the fPSs (PS[Alv+Sch]) elicited by stimulation of the Sch after antidromic stimulation of the alveus hippocampi (Alv) to produce recurrent inhibition were determined. It was observed that sevoflurane (0.5%-5%) and isoflurane (0.5%-5%) primarily inhibited PS[Sch] and also produced additive inhibition on the PS[Alv+Sch] in a concentration-dependent manner. The calculated 50% effective concentration (EC50) values for PS[Sch] and PS[Alv+Sch] were 5.3 vol% and 3.9 vol% (sevoflurane) and 1.7 vol% and 1.1 vol% (isoflurane), respectively. In comparison, thiopental (2.0 x 10(-5)-5.0 x 10(-4) mol/L) reduced both the PS[Sch] and PS[Alv+Sch] in a concentration-dependent manner. The calculated EC50 values for thiopental on PS[Sch] and PS[Alv+Sch] were 3.4 x 10(-4) and 5.7 x 10(-5) mol/L, respectively. Propofol (2.0 x 10(-5)-3.5 x 10(-4) mol/L) had little effect on the PS[Sch] but reduced PS[Alv+Sch] with a calculated EC(50) value of 5.1 x 10(-4) mol/L. The effects of the IV anesthetics with recurrent inhibition were antagonized in the presence of the gamma-aminobutyric acid-A-receptor antagonist bicuculline methiodide. In addition, all anesthetics prolonged recurrent inhibition from 100 ms (sevoflurane and isoflurane) to 400 ms (propofol). The results suggest that sevoflurane and isoflurane inhibit mainly on glutamate-mediated orthodromic pathways, whereas thiopental and propofol enhance gamma-aminobutyric acid-A-mediated recurrent inhibitory pathways in CA1 neurons, thus providing further evidence that the mechanisms of general anesthetics are drug- and pathway-specific.

Measurement of stress hormones is a common objective method for assessment of mental stress. However, the stress of blood sampling alone may also increase stress hormone levels. In the present study, we sampled salivary biomarkers from healthy volunteers under noninvasive conditions and determined their efficacy to assess mental stress. Specifically, we examined the relationship between State Anxiety Inventory score (STAI-s) in subjects exposed to arithmetic stress and salivary chromogranin-A, alpha-amylase, or cortisol. The STAI-s was significantly correlated to salivary alpha-amylase (r = 0.589; P < 0.01) but not to salivary chromogranin-A or cortisol. Therefore, salivary alpha-amylase is a useful indicator of psychosocial stress.

Unlabelled: We previously reported that H2-antagonist medication given for longer than 4 wk may produce complete tolerance to preanesthetic H2 antagonist therapy. In this study, we evaluated the efficacy of preanesthetic proton pump inhibitor (PPI; oral rabeprazol) use in patients receiving regular H2-antagonist (oral famotidine) therapy for more than 4 wk. Forty-eight patients with assumed complete tolerance to H2 antagonists undergoing elective surgery were recruited and randomly assigned to receive either a preanesthetic PPI (rabeprazol 20 mg; n = 24) or H2-antagonist (H2 group; roxatidine 75 mg; n = 24) at 9:00 pm on the day before surgery and 2 h before the induction of anesthesia. Volume of gastric contents and pH values were measured after the induction of anesthesia. Gastric pH value in the PPI group (5.38 +/- 2.42) was significantly higher than in the H2 group (3.27 +/- 1.98; P < 0.01). Gastric volume in the PPI group (8.6 +/- 1.5 mL) was significantly smaller than in the H2 group (15.4 +/- 2.8 mL; P < 0.05; cf. PPI). Fourteen patients in the H2 group were at risk of acid aspiration pneumonia (gastric pH <2.5 or volume >25 mL), whereas only four patients in the PPI group (P < 0.05) were at risk. These data suggest that in patients receiving H2-antagonist therapy for longer than 4 wk, prophylaxis for acid aspiration pneumonia should include preanesthetic PPI medication., Implications: We previously reported that more than 4 wk of administration of H2-antagonists may produce a full tolerance to preanesthetic H2-antagonists. The present study suggests that a proton pump inhibitor may be effective for prophylaxis of acid aspiration pneumonia in patients showing the full tolerance to H2 antagonists.

Unlabelled: Capsaicin, acting at the vanilloid 1 receptor (VR1), may potentiate local anesthetic activity, and as a ligand-gated ion channel of the transient receptor potential family, may also be a target for IV general anesthetics. We have examined whether local (lidocaine, prilocaine, and procaine 0.1-10 mM; 10 mM represents 0.25%-0.27% wt/vol) or IV anesthetics (propofol 10 micro M, thiopental 100 micro M, and ketamine 100 micro M) interact with recombinant rat VR1 expressed in human embryonic kidney (HEK293) cells (VR1-HEK293). We have assessed receptor interaction functionally by monitoring intracellular Ca(2+) ([Ca(2+)](i)) in Fura2-loaded cells at 37 degrees C. The addition of capsaicin (60 nM) produced a time-dependent biphasic increase in [Ca(2+)](i) amounting to 50-100 nM above than basal, which was inhibited by capsazepine 10 micro M and was absent in wild type HEK293 cells. Lidocaine and prilocaine alone (e.g., at 10 mM) significantly increased [Ca(2+)](i) by 67 +/- 6 nM and 33 +/- 7 nM, respectively, and concentration-dependently inhibited the capsaicin response. The effects of procaine were obscured by anesthetic-induced quenching of Fura2. In wild type HEK293 cells, lidocaine (10 mM) alone produced a small increase in [Ca(2+)](i). All IV anesthetics failed to modify capsaicin-increased [Ca(2+)](i). In conclusion, the present data suggest that local but not IV general anesthetics interact with recombinant rat VR1 receptors with the former anesthetics having antagonistic activity., Implications: Vanilloid receptors (VR1) are activated by capsaicin, the pain-producing component of hot chili peppers. We suggest that local (but not IV general) anesthetics may have inhibitory actions on this receptor.

Unlabelled: Previous reports suggest that the effects of propofol, ketamine, and thiopental on airway tone may be because of modulation of parasympathetic activity. We examined if these anesthetics interact with recombinant human M1-M3 muscarinic receptors expressed in Chinese hamster ovary cells (CHO-M1, M2, and M3) using the displacement of 0.4 nM of l-[N-methyl-(3)H]scopolamine methyl chloride([(3)H]NMS). In addition, functional studies were performed by fluorometrically monitoring methacholine (1 mM) stimulated intracellular Ca(2+) ([Ca(2+)](i)) responses. Ketamine concentration dependently displaced [(3)H]NMS binding to CHO-M1, M2, and M3 cells with affinity, pK(i) (mean K(i)) values of 4.34 +/- 0.14 (45 micro M), 3.53 +/- 0.10 (294 micro M), and 3.61 +/- 0.02 (246 micro M), respectively. The effects at M1 were in the clinical range. Ketamine did not affect either basal or methacholine stimulated increase in [Ca(2+)](i) in CHO-M1 cells. Thiopental significantly displaced [(3)H]NMS binding to M3 (pKi [mean Ki] = 4.12 +/- 0.06 [75 micro M]) but not M1 or M2 receptors. Thiopental (10(-5)-10(-3) M) concentration dependently inhibited methacholine stimulated increase in [Ca(2+)](i) in CHO-M3 cells. Propofol and barbituric acid did not interact with any muscarinic receptor subtype. We suggest that at the level of [Ca(2+)](I), thiopental may possess M3 antagonist activity, whereas there are no functional consequences of the interaction of ketamine with the M1 receptor., Implications: In this study using recombinant human M1-M3 muscarinic receptors, we show that for agonist-stimulated increases in intracellular Ca(2+) thiopental acts as a M3 antagonist.

Unlabelled: The amount of emboli formed (percentage of total emboli area to the right atrial area [%Ae]) after tourniquet release in invasive procedures of the medullary cavity is empirically much larger than that in noninvasive procedures, even if the tourniquet duration is similar. Thus, we compared %Ae between arthroscopic reconstruction of the anterior cruciate ligament (ACL, n = 20) and total knee arthroplasty (TKA, n = 20). The right atrium was continuously monitored by transesophageal echocardiography to assess %Ae. Peak %Ae +/- SD (ACL, 4.1% +/- 3.4%; TKA, 20.7% +/- 16.7%) appeared 30-40 s after tourniquet release in both groups. However, %Ae in the TKA group was always larger than the peak %Ae in the ACL group. In addition, although the ET(CO(2)) significantly increased after tourniquet release in both groups, increase of ET(CO(2)) (1.1% +/- 0.3%) in the ACL group was significantly larger than that in the TKA group (0.5% +/- 0.2%). An increase in ET(CO(2)) was inversely proportional to peak %Ae (P < 0.01; r = 0.703). Therefore, the present data suggest that the risk of acute pulmonary embolism after tourniquet release may be more frequent during TKA than ACL., Implications: We compared emboli formation after tourniquet release in patients undergoing arthroscopic reconstruction of the anterior cruciate ligament (ACL, n = 20) and total knee arthroplasty (TKA, n = 20) using transesophageal echocardiography. The present data suggest that the risk of acute pulmonary embolism after tourniquet release could be more frequent during TKA than ACL.

Unlabelled: alpha(2) Adrenoceptor activity is involved in the mechanism of anesthesia. Clonidine, a alpha(2) adrenoceptor agonist, and yohimbine, a alpha(2) adrenoceptor antagonist, increase and decrease barbiturate-induced sleep times. In this study, we examined the effects of these drugs on propofol-induced sleep time. One-hundred-eighteen male Wistar rats weighing 320-400 g were used. Rats received saline, yohimbine (1, 0.1, or 0 mg/kg), or clonidine (300, 30, 3, or 0 microg/kg) intraperitoneally followed by 60 mg/kg of propofol in various combinations. In two series of experiments, either sleep time or prefrontal cortex norepinephrine release (microdialysis) was measured. One milligram/kilogram of yohimbine decreased propofol-induced sleep time to approximately 70% of control, and this was accompanied by an increase in perfusate norepinephrine of approximately 240% of control. Clonidine increased sleep time approximately 260% (300 microg/kg) and approximately 170% (30 microg/kg), and this was accompanied by a decrease (approximately 60% in both doses) in perfusate norepinephrine. In the present study, we show that the alpha(2) antagonist, yohimbine, decreased and the alpha(2) agonist, clonidine, increased propofol-induced sleep times. These changes were essentially mirrored in both groups by changes in norepinephrine release in the prefrontal cortex., Implications: Central alpha(2) adrenoceptor is thought to be involved in several IV anesthetics-induced sleep. In this study, activation of the receptor increased the propofol-induced sleep time, whereas its inhibition decreased the sleep time. The results provide further evidence that the alpha(2) receptor is a good tool to elucidate the mechanism of anesthetics-induced sleep.

Near-fatal pulmonary embolism can occur immediately after tourniquet release after orthopedic surgeries. In this study, we determined the relationship between tourniquet time and the occurrence of pulmonary emboli in 30 patients undergoing arthroscopic knee surgeries, by using transesophageal echocardiography. The right atrium (RA) was continuously monitored by transesophageal echocardiography, and the number of emboli present was assessed with the following formula: Amount of emboli = 100 x [(total embolic area in the RA after tourniquet release) - (total area of emboli or artifact in the RA before tourniquet release)]/(RA area). The area was assessed 0-300 s after tourniquet release by using image-analysis software. The peak amount of emboli appeared approximately 50 s after tourniquet release. In addition, there was a significant correlation between amount of emboli (Ae [%]) and tourniquet time (Ttq [min]): (Ae = 0.1 x Ttq - 1.0, r = 0.795, P < 0.01). This study suggests that acute pulmonary embolism may occur within 1 min of tourniquet release and that the number of emboli is dependent on Ttq.

Unlabelled: IV aminophylline, a nonselective phosphodiesterase (PDE) inhibitor, is often used to treat an asthma attack during anesthesia. However, in some instances, aminophylline-resistant attacks are observed. Selective PDE3 inhibitors are now clinically available and have been reported to produce bronchodilation. Thus, we compared the relaxant effects of olprinone, a novel PDE3 inhibitor, and aminophylline on methacholine-induced bronchoconstriction. Dogs were anesthetized with pentobarbital. Bronchoconstriction was elicited with methacholine (0.5 microg/kg + 5.0 microg. kg(-1). min(-1)) and assessed as percentage of changes in the bronchial cross-sectional area (BCA; basal = 100%) monitored by bronchoscope. Initially, the relaxant effects of olprinone (n = 8; 0-1000 microg/kg) and aminophylline (n = 8; 0-50 mg/kg) were compared. The bronchial cross-sectional areas were assessed before and 30 min after methacholine infusion began and 5 min after each dose of olprinone or aminophylline. We then determined whether propranolol (0.4 mg/kg) reversed the relaxation induced by olprinone (1000 microg/kg) and aminophylline (50 mg/kg). Olprinone and aminophylline dose-dependently antagonized bronchoconstriction by 56.2% +/- 21.3% (SD) and 68.0% +/- 30.3% with -log 50% effective dose (mean) of 4.80 +/- 0.38 (15.8) microg/kg and 1.96 +/- 0.42 (10.9) mg/kg, respectively. Aminophylline 50 mg/kg significantly increased plasma epinephrine, whereas olprinone did not. In addition, propranolol significantly reduced aminophylline-induced relaxation, but not olprinone-induced relaxation. Therefore, the relaxant effects of olprinone are independent of plasma epinephrine, whereas aminophylline effects may partially result from increased circulating concentrations of epinephrine., Implications: We compared the relaxant effects of olprinone and aminophylline on methacholine-induced bronchoconstriction in dogs. The relaxant effects of olprinone are independent of plasma epinephrine, whereas the aminophylline effects may be partly caused by an increase in plasma epinephrine.

In the present study in dogs, we compared with aminophylline the spasmolytic effects of olprinone, a novel phosphodiesterase 3 inhibitor, on serotonin-induced pulmonary hypertension (PH) and bronchoconstriction. Mongrel dogs were anesthetized with pentobarbital. PH and bronchoconstriction were induced with serotonin: 10 microg/kg + 1 mg x kg(-1) x h(-1), and assessed as % changes in pulmonary vascular resistance and bronchial cross-sectional area (basal = 100%). Initially, the relaxant effects of olprinone (n = 8: 0-1000 microg/kg) and aminophylline (n = 8: 0-100 mg/kg) were compared. Pulmonary vascular resistance and bronchial cross-sectional area were assessed before and 30 min after serotonin infusion began and 5 min after each dose of olprinone or aminophylline. We then determined whether propranolol (0.4 mg/kg) reversed the relaxation induced by olprinone (1000 microg/kg, n = 6) or aminophylline (100 mg/kg, n = 6) compared with saline (n = 6 each). Olprinone and aminophylline dose-dependently attenuated both PH and bronchoconstriction (olprinone > aminophylline: -logED(50)[mean] for PH and bronchoconstriction 5.37+/- 0.35[4.24 microg/kg] vs. 1.60+/-0.23[25.4 mg/kg] and 4.06+/-0.12[87.8 microg/kg] vs. 1.51+/-0.21[30.6 mg/kg], respectively). In addition, olprinone produced more potent pulmonary vasodilation than bronchodilation while aminophylline was equipotent. In addition, there was a significant increase in plasma catecholamines after olprinone (> or =100 microg/kg) and aminophylline (> or =10 mg/kg). With the exception of aminophylline-induced bronchodilation, propranolol did not reverse any of the other effects measured. Therefore, the spasmolytic effects of olprinone are independent of plasma catecholamines, while the bronchodilating effect of aminophylline may partially involve increased levels of circulating catecholamines.

Unlabelled: We determined whether milrinone, a phosphodiesterase III inhibitor, attenuates serotonin-induced (5-hydroxytryptamine [5HT]) pulmonary hypertension (PH) and bronchoconstriction. Dogs were anesthetized with pentobarbital (30 mg/kg + 2 mg. kg(-1). h(-1)). Bronchoconstriction and PH were elicited by 5HT (10 microg/kg + 1.0 mg. kg(-1). h(-1)). Pulmonary vascular resistance was used to assess PH. Bronchoconstriction was also assessed by changes in bronchial cross-sectional area obtained from our bronchoscopic method. At 30 min after 5HT infusion started, seven dogs were given milrinone: 0 (saline), 5, 50, 500, and 5000 microg/kg at 10-min intervals. The other 12 dogs were given milrinone 5000 microg/kg 30 min after 5HT infusion, and 5 min later were given propranolol 0.2 mg/kg (n = 6) or saline (n = 6) IV. The 5HT significantly increased percentage of pulmonary vascular resistance to 208% +/- 27% and decreased percentage of bronchial cross-sectional area to 52% +/- 5% of the basal. Milrinone significantly attenuated both PH and bronchoconstriction in a dose-dependent manner. However, -log 50% effective concentration (mean ED(50) in microg/kg) of milrinone for bronchoconstriction: 4.32 +/- 0.13 (47.6) was significantly smaller than that for PH: 3.84 +/- 0.29 (144.9) (P < 0.01). In addition, the spasmolytic effects of milrinone (5000 microg/kg) were not antagonized by propranolol, although this dose significantly increased plasma catecholamines. In conclusion, milrinone attenuates 5HT-induced PH and bronchoconstriction; however, this drug may be more sensitive to phosphodiesterase III in the airway smooth muscle than in pulmonary vascular smooth muscle. In addition, the relaxant effects could not be caused by beta-adrenoceptor activation because beta-blocker did not antagonize., Implications: We studied the effects of milrinone on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs. Milrinone produces pulmonary vasodilation and bronchodilation, whose effects may not be caused by beta-adrenoceptor activation. In addition, this drug may be more sensitive to phosphodiesterase III in the airway smooth muscle than that in pulmonary vascular smooth muscle.

Unlabelled: Although the autonomic nervous system regulates cardiac function, the cellular mechanism(s) of general anesthetics on the activities of parasympathetic neurons have not been directly assessed. We therefore studied the volatile anesthetic actions on the Ca2+ current of parasympathetic neurons isolated from bullfrog hearts. Neurons were enzymatically isolated from the interatrial septum of bullfrog heart and maintained in a short-term tissue culture. The Ca2+ current was recorded with a whole-cell voltage-clamp method under a Na+, K+ -free condition. Isoflurane (2.5 vol%) and sevoflurane (5.0 vol%) reduced the peak amplitude of the Ca2+ current (to 79% and 72% of control, respectively) without changing the reversal potential. The curve-fit analysis of the inactivation kinetics revealed that isoflurane and sevoflurane accelerated the inactivation of the current and that isoflurane shifted the midpoint of the steady-state inactivation curve of the Ca2+ current toward negative by 13.6 mV. The results indicate that volatile anesthetics reduce the Ca2+ current of parasympathetic neurons and modify the inactivation kinetics., Implications: The anesthetic reduction of the Ca2+ current of parasympathetic neurons can induce a decrease of acetylcholine release from the post-ganglionic endings. These findings, in part, account for the anesthetic attenuation of the vagal efferent activities observed in humans and experimental animals.

Unlabelled: Airway epithelium and vascular endothelium modulate the tension of the underlying smooth muscle by releasing relaxing factors such as prostanoids and nitric oxide (NO). We investigated whether the relaxant effect of propofol on airway smooth muscle is dependent on airway epithelial function. Tracheal spirals of female guinea pigs were mounted in water-jacketed organ baths filled with Krebs-bicarbonate buffer aerated with 95% O2 and 5% CO2 at 37 degrees C. Changes in isometric tension of the specimens were measured with a force-displacement transducer and recorded with a polygraph. Propofol (10(-4) to 10(-3) M) inhibited carbachol (CCh)-, histamine (HA)-, or endothelin-1-induced contractions of the muscles in a dose-dependent manner. Neither mechanical removal of the epithelial layer, chemical inhibition of epithelial synthesis of prostanoids, nor NO affected the relaxant effect of propofol on CCh- or HA-induced tracheal contraction. Furthermore, the blockade of beta-adrenoceptors did not change the relaxant effect of propofol. These results indicate that the relaxant effect of propofol on the airway smooth muscle is independent of the epithelial function or beta-adrenoceptor activity. Propofol is an excellent anesthetic for patients with hyperreactive airways in which the epithelial layer is damaged., Implications: Airway epithelium, as well as vascular endothelium, plays an important role in modulating the baseline tone and reactivity of underlying smooth muscle. We investigated, in vitro, whether the relaxant effect of propofol on airway smooth muscle is dependent on airway epithelial function. We suggest that propofol relaxes airway smooth muscle independently of the epithelial function.

Unlabelled: It is unclear whether general anesthetics induce enhancement of neural inhibition and/or attenuation of neural excitation. We studied the effects of pentobarbital (5 x 10(-4) mol/L), propofol (5 x 10(-4) mol/L), ketamine (10(-3) mol/L), halothane (1.5 vol%), and isoflurane (2.0 vol%) on both excitatory and inhibitory synaptic transmission in rat hippocampal slices. Excitatory or inhibitory synaptic pathways were isolated using pharmacological antagonists. Extracellular microelectrodes were used to record electrically evoked CA1 neural population spikes (PSs). In the presence of the gamma-aminobutyric acid type A (GABA(A)) receptor antagonist (bicuculline), the inhibitory actions of pentobarbital and propofol were completely antagonized, whereas those of ketamine, halothane, and isoflurane were only partially blocked. To induce the N-methyl-D-aspartate (NMDA) receptor-mediated PS (NMDA PS), the non-NMDA and GABA(A) receptors were blocked in the absence of Mg2+. Ketamine, halothane, and isoflurane decreased the NMDA PS, and pentobarbital and propofol had no effect on the NMDA PS. The non-NMDA receptor-mediated PS (non-NMDA PS) was examined using the antagonists for the NMDA and GABA(A) receptors. Volatile, but not i.v., anesthetics reduced the non-NMDA PS. These findings indicate that pentobarbital and propofol produce inhibitory actions due to enhancement in the GABA(A) receptor; that ketamine reduces NMDA receptor-mediated responses and enhances GABA(A) receptor-mediated responses; and that halothane and isoflurane modulate GABA(A), NMDA, and non-NMDA receptor-mediated synaptic transmission., Implications: Volatile anesthetics modulate both excitatory and inhibitory synaptic transmission of in vitro rat hippocampal pathways, whereas i.v. anesthetics produce more specific actions on inhibitory synaptic events. These results provide further support the idea that general anesthetics produce drug-specific and distinctive effects on different pathways in the central nervous system.

Unlabelled: Ketamine and magnesium (Mg2+), well known bronchodilators, have been used to treat patients with status asthmaticus. Both can block the N-methyl-D-aspartic acid (NMDA) receptor. NMDA receptors exist in the airway, and their activation seems to be linked to the release actions of sensory neuropeptides resulting in increased airway tone. We sought to determine whether ketamine relaxes the guinea pig trachea contracted by histamine by blocking the NMDA receptor. Female guinea pigs (250-400 g) were killed with an overdose of pentobarbital. The trachea was removed and cut spirally into strips 3 mm wide and 15 mm long. The strips were mounted in a 10-mL organ bath filled with Tyrode's solution bubbled through with 95% O2/5% CO2 at 37 degrees C. Strip contractions were measured isometrically with a force displacement transducer. We then studied the effect of NMDA receptor antagonists on histamine-induced tracheal contraction. In this protocol, we examined the effect of ketamine, Mg2+, zinc (Zn2+), or MK-801 (a noncompetitive NMDA receptor blocker) on strips contracted by 10(-5) M histamine. After full contraction was attained, ketamine (0.5-1.5 mM), MgSO4 (2-8 mM), ZnCl2(0.2-0.8 mM), or MK-801 (1.5-6 x 10(-5) M) was added, and the strip tension was measured again. We also studied the effect of NMDA on the relaxation by ketamine. After full contraction by 10(-5) M histamine, 0.5-1.5 mM KET was added alone or in combination with 0.1 mM NMDA, and the strip tension was measured again. Finally, we measured the effect of MK-801 on the relaxant effect of ketamine. After full contraction by 10(-5) M histamine, 0.5-2 mM ketamine was added alone or in combination with 0.75 or 1.5 x 10(-5) M MK-801, and the strip tension was measured again. All NMDA receptor antagonists tested reversed the tracheal contraction induced by histamine in a dose-dependent manner. However, neither the agonist NMDA nor the noncompetitive receptor blocker MK-801 affected tracheal relaxation induced by ketamine. We conclude that ketamine relaxes the tracheal smooth muscle contracted by histamine through a mechanism independent of NMDA receptors. The decreased bronchomotor tone induced by ketamine is probably due to interference with a Ca2+-requiring step necessary to maintain the contraction caused by histamine., Implications: Stimulation of the N-methyl-D-aspartic acid (NMDA) receptor in the airway results in airway constriction. The bronchodilator ketamine blocks the NMDA receptor. However, ketamine relaxes the guinea pig trachea contracted by histamine through a mechanism independent of the NMDA receptor.

Unlabelled: We studied the effects of sevoflurane on population spikes (PSs) in two synaptic pathways in rat hippocampal slices. Stimulating electrodes were placed on Schaffer collateral fibers or perforant path to activate inputs to CA1 pyramidal neurons or dentate gyrus (DG) neurons, respectively. Extracellular glass microelectrodes were used to record PSs. The paired-pulse stimulus was used to induce the paired-pulse facilitation (PPF). Sevoflurane (0.4-5.0 vol%) significantly decreased the amplitudes of PSs of CA1 and DG in a dose-dependent and reversible manner (25% effective dose values were 4.1 and 0.9 vol%, respectively). The stimulus-response relationships for PS amplitudes revealed that sevoflurane increased the threshold for PS generation in CA1 and DG. Sevoflurane (2.0 vol%) significantly enhanced PPF from 127% and 263% to 153% and 494% in CA1 and DG, respectively. The results imply that the effects of sevoflurane on PSs are greater in DG than in CA1 neurons, that sevoflurane enhances the PPF in both CA1 and DG, and that the actions of sevoflurane are not similar to those of other volatile or intravenous anesthetics previously reported in hippocampal preparations., Implications: The volatile anesthetic sevoflurane alters neural excitability of individual pathways in the hippocampus in a manner different from other general anesthetics. The results are consistent with a site-specific mechanism of action for general anesthesia.

We compared the effect of propofol with that of sevoflurane anesthesia on uric acid (UA) excretion in ASA physical status I and II patients with normal renal function. A propofol group (n = 11) received propofol-nitrous oxide-fentanyl after induction of anesthesia by propofol, while a sevoflurane group (n = 12) received sevoflurane-nitrous oxide-fentanyl after induction of anesthesia by thiamylal. UA, creatinine (Cr), and urea nitrogen concentrations in serum and urine were measured before induction of anesthesia, 1, 2, and 3 h after induction, and on Postoperative Day 1. N-acetyl-beta-D-glucosaminidase, beta2-microglobulin concentrations, and pH in urine were also examined. Plasma clearance of UA (CUA) and Cr (CCr) were calculated. The hourly concentration and excretion of urine UA were significantly higher than those of the sevoflurane group (P < 0.01). Significant correlations were noted between the hourly urine volume and UA concentration (r = 0.58, P < 0.01 for the propofol group; r = 0.51, P < 0.01 for the sevoflurane group). The CUA of the propofol group was significantly higher than that of the sevoflurane group (22.9 +/- 10.6 vs 5.9 +/- 3.4 mL/min, mean +/- SD, P < 0.05). There were no significant differences in other renal variables between the two groups. The present study demonstrated that the UA excretion increased during propofol anesthesia, while it remained stable during sevoflurane anesthesia.

Airway epithelial cells and vascular endothelial cells modulate the tone of the underlying smooth muscle by releasing relaxing factors such as prostanoids and nitric oxide (NO). In the present study, we investigated whether the relaxant effect of ketamine depends on any of the epithelium-derived relaxing factors. Tracheae of female guinea pigs were cut spirally into strips (15 x 3 mm) and mounted in water-jacketed organ baths filled with Krebs-bicarbonate buffer aerated with a mixture of 95% O2 and 5% CO2 at 37 degrees C. Changes in the tension of the strips were measured isometrically with a force displacement transducer and recorded with a polygraph. In the first set of experiments, we examined the effect of ketamine on the concentration-response curves for histamine and carbachol in strips in which the epithelium was kept intact and in strips with denuded epithelium. In the second and third set of experiments, we studied the effect of indomethacin, a cyclooxygenase inhibitor, and N-omega-nitro-L-arginine methylester(L-NAME), a NO synthase inhibitor, on the relaxant activity of ketamine on tracheal strips contracted by histamine or carbachol. The following results were obtained: 1. Mechanical denudation of the tracheal epithelium shifted the concentration-response curve for histamine to the left (the 50% effective concentration [EC50] value of histamine decreased from 3.5 +/- 0.02 x 10(-6) M in the intact strips to 0.98 +/- 0.01 x 10(-6) M in denuded strips, P < 0.001). However, removal of the tracheal epithelium did not change the response to carbachol (the EC50 for carbachol was 1.1 +/- 0.02 x 10(-7) M in intact strips versus 0.88 +/- 0.01 x 10(-7) M after epithelial removal, P > 0.05). 2. Ketamine shifted to the right the concentration-response curves for histamine and carbachol in both intact and denuded tracheae. 3. Indomethacin did not alter the relaxant effect of ketamine on the tracheae contracted by either histamine (the concentration that inhibits 50% [IC50] of ketamine = 1.5 +/- 0.01 x 10(-3) M in control strips and 1.3 +/- 0.04 x 10(-3) M in strips pretreated with indomethacin, P > 0.05) or carbachol (the IC50 of ketamine was 2.5 +/- 0.02 x 10(-4) M in control strips and 2.4 +/- 0.01 x 10(-4) M in strips pretreated with indomethacin, P > 0.05). 4. L-NAME did not influence the relaxant effect of ketamine on tracheae contracted by either histamine (the IC50 of ketamine = 1.6 +/- 0.05 x 10(-3) M in control strips and 1.6 +/- 0.05 x 10(-3) M in strips pretreated with L-NAME, P > 0.05) or carbachol (the IC50 of ketamine = 2.6 +/- 0.04 x 10(-4) M in control strips and 2.3 +/- 0.01 x 10(-4) M in trips pretreated with L-NAME, P > 0.05). These results indicate that neither the mechanical removal of the tracheal epithelium nor the blockade of the release of potent mediators from tracheal epithelial cells influence the relaxant effect of ketamine on guinea pig tracheal strips contracted by histamine or carbachol. We conclude that ketamine relaxes the airway smooth muscle by an epithelium-independent mechanism.

In a prospective study, we determined the anesthetic induction dose of thiopental and the clinical variables influencing the appropriate induction dose of thiopental in 20 patients with the hypertrophic variety of Charcot-Marie-Tooth syndrome (CMT). As controls we chose 50 patients without CMT. Motor disturbance was evaluated in terms of muscle weakness of the distal lower and upper extremities. We examined sensory disturbance by evaluating loss of sensation in the index finger and great toe. The preinduction cardiac output was measured by echocardiography. Anesthesia was induced with repeated injections of 50 mg thiopental. The minimum induction dose of thiopental (MID) was confirmed when the eyelash reflex ceased. We maintained anesthesia with enflurane and nitrous oxide. The 95% confidence interval of the MID in patients used as the controls was 2.5-4.9 mg/kg. The MID in 11 patients with CMT was less than 2.5 mg/kg. MIDs in the patients with CMT were significantly smaller than those of the control patients (P < 0.0001). Also we found a strong relationship between the MID and the severity of both motor and sensory disturbances (P = 0.003 and 0.002, respectively). There was no relationship between the MID and other clinical variables, such as age, gender, inherited type, body weight, and preinduction cardiac output. Because delay in the recovery from anesthesia can be caused by an inappropriate dose of thiopental in CMT patients in whom motor and sensory function is seriously impaired, the dose of thiopental probably should be reduced and based on the individual patient's response.

Lactated Ringer's solution is frequently used to avoid metabolic acidosis during fluid resuscitation. The standard lactated Ringer's solution contains racemic lactate, an equal mixture of the D- and L-stereoisomers. We investigated whether sodium L-lactate or sodium racemic lactate (DL-lactate) is more effective for increasing buffering capacity in body fluids. For the purpose of this comparison, Ringer's solutions containing no lactate, sodium L-lactate, or racemic lactate at a concentration of 84 mEq/L (three times more than the ordinary level) were infused in patients under general anesthesia during tympanoplasty. Although differences occurred among the three groups in blood concentrations of L-lactate, D-lactate, and the L-lactate/pyruvate ratio, no differences occurred between the two lactate groups in either bicarbonate ion concentration or base excess. The amount of buffering capacity increased significantly in both lactate groups, compared with preinfusion levels, and was more than the values in the nonlactated Ringer's solution group. We conclude that sodium racemic lactate is metabolized at nearly the same rate as that of sodium L-lactate.

We studied the effects of halothane on the electrophysiologic and biochemical properties of both Langendorff perfused hearts and single ventricular myocytes isolated from guinea pigs. Isometric contractions of left ventricles in perfused hearts, elicited by atrial pacing, decreased to 14% of control after exposure to 2% halothane-equilibrated perfusate. Subsequently the slow inward Ca2+ current (ICa) was recorded in isolated myocytes with a whole cell voltage clamp technique. ICa, recorded in response to 100-ms depolarizations from -40 mV to 0 mV, was decreased by 2% halothane to 28.4% of control. Halothane-induced ICa depression did not exhibit use dependency. To define a possible site at which halothane acts, we measured the cyclic adenosine 3',5'-monophosphate (cAMP) content of single ventricular myocytes using a radioimmunoassay. Two percent halothane decreased myocardial cAMP content to 68.9% of control. Further addition of dibutyryl cAMP (10(-3) mol/L) partially reversed the depressed contractility during 2% halothane administration in perfused hearts. In conclusion, the present study demonstrated that the decrease of myocardial cAMP by halothane was due to a direct action, at least partly, and not to other factors such as catecholamines, and suggested that the decreases in contractility and ICa were induced possibly through the decrease in cellular cAMP.