Kiyoshi Nagase

The differential effects of stereoisomers of ropivacaine and bupivacaine on cerebral pial arterioles in dogs

We investigated whether the stereoisomers of ropivacaine and bupivacaine exert differential effects on the cerebral microcirculation. Pentobarbital-anesthetized dogs (n = 16) were prepared for measurement of cerebral pial vessel diameters by using a closed cranial window preparation. We administered three different concentrations (10−7, 10−5, and 10−3 M) of each of three drug solutions [R(+), racemic, and S(−) forms of ropivacaine (n = 8) or bupivacaine (n = 8)] under the window in a randomized manner and measured cerebral pial arteriolar diameters. Various physiologic data were obtained before and after topical application of each test solution. All three forms of ropivacaine constricted cerebral pial arterioles, each in a concentration-dependent manner. The rank order for degree of vasocon- striction was S(−) ropivacaine > racemic ropivacaine > R(+) ropivacaine. In contrast, R(+) and racemic bupivacaine dilated, but S(−) bupivacaine constricted, cerebral pial arterioles, each in a concentration-dependent manner. We could find no difference in vascular reactivity to these drugs between large (≥100 &mgr;m) and small (<100 &mgr;m) arterioles. Topical application of these drugs induced no changes in mean blood pressure or heart rate. The observed differences in the microvascular alterations induced by the stereoisomers of ropivacaine and bupivacaine suggest that the vasoactive effects of these drugs on cerebral arterioles could, at least in part, depend on their chirality.

The effects of topical and intravenous ketamine on cerebral arterioles in dogs receiving pentobarbital or isoflurane anesthesia.

To evaluate the effects of ketamine on cerebral arterioles, we used a closed cranial window technique in mechanically ventilated, anesthetized dogs. Fourteen dogs were assigned to one of the following two basal-anesthesia groups: pentobarbital 2 mg · kg−1 · h−1 or isoflurane 0.5 MAC (n = 7 each). We administered three different concentrations of ketamine (10−7, 10−5, and 10−3 M) under the window and measured arteriolar diameters. For comparison, in another 14 dogs we examined the effect of systemic (IV) ketamine (1 mg/kg and 5 mg/kg) using the same two basal anesthetics. We measured diameters before and after ketamine administration, and we evaluated the effect of ketamine on CO2 reactivity of the cerebral arterioles. Neither topical nor systemic ketamine dilated pial arterioles in either basal-anesthesia group. CO2 reactivity of pial arterioles was reduced under systemic ketamine in both basal-anesthesia groups. The results indicate that although ketamine does not dilate pial arteriolar diameters when topically or IV administered, IV ketamine does attenuate hypercapnic vasodilation in dogs under basal pentobarbital or isoflurane anesthesia. These results provide some insight that ketamine is suitable for supplementary neurosurgical anesthesia.

The Anxiolytic Effects of the 5-Hydroxytryptamine-1A Agonist Tandospirone Before Otolaryngologic Surgery

We studied 160 ASA I or II patients undergoing elective otolaryngologic surgery in order to compare the anxiolytic effects of a novel 5-hydroxytryptamine-1A agonist, tandospirone, with diazepam. To monitor preoperative anxiety, the following variables were used: systolic and diastolic arterial pressure, heart rate, and the state anxiety score yielded by the Spielberger State-Trait Anxiety Inventory. We performed pretreatment evaluation on the day before surgery and posttreatment examination immediately after entry into the operating room. In a double-blinded, randomized design, four groups of 40 patients each received one of the following oral medications 90 min before entry into the operating room: 1) tandospirone 10 mg (T10 group); 2) tandospirone 30 mg (T30 group); 3) diazepam 10 mg (D group); or 4) placebo (P group). After premedication, the State-Trait Anxiety Inventory state anxiety decreased in the T10 (P < 0.02), T30 (P < 0.02), and D groups (P < 0.001), but it increased in the P group (P < 0.001). Tandospirone, 10 and 30 mg, safely reduced preoperative anxiety to a similar extent as oral diazepam 10 mg in patients undergoing elective otolaryngologic surgery.

Effects of ketamine on isoflurane- and sevoflurane-induced cerebral vasodilation in rabbits.

Although ketamine has been reported to have little effect on the cerebral circulation when used with other anesthetics, its effect on the cerebral vascular response to volatile anesthetics, which increase cerebral blood flow in a concentration-dependent manner, remains obscure. A closed cranial window was prepared in 15 pentobarbital-anesthetized adult rabbits. The cerebral pial arteriolar alteration induced by either isoflurane (n = 8) or sevoflurane (n = 7) at 0 (before volatile anesthetic), 0.33, 0.67, and 1.0 minimum alveolar concentration (MAC) was measured under three consecutive conditions: intravenous infusion with saline, with ketamine, and with ketamine plus l-arginine. Ketamine reduced the vasodilation induced by 0.67 (120 ± 9% versus 113 ± 9%;P < .05) and 1.0 MAC isoflurane (136 ± 11% versus 118 ± 10%;P < .05), but l-arginine did not restore the isoflurane-induced cerebral vasodilation. In rabbits inhaling sevoflurane, the degree of cerebral vasodilator response was smaller than that by isoflurane, and the cerebral vasodilation was comparable whether in the presence or absence of ketamine (with or without l-arginine). In conclusion, ketamine reduces isoflurane-induced cerebral vasodilation, apparently independently of nitric oxide formation, while sevoflurane-induced cerebral vasodilation is not significantly affected by ketamine.

Ketamine, Not Propofol, Attenuates Cerebrovascular Response to Carbon Dioxide in Humans With Isoflurane Anesthesia

STUDY OBJECTIVES To investigate the effects of ketamine and propofol on the cerebrovascular response to carbon dioxide (CO(2)) in humans during isoflurane anesthesia. DESIGN Randomized clinical investigation. SETTINGS University hospital of a medical school. PATIENTS 30 ASA physical status I and II adult, elective surgical patients. INTERVENTIONS AND MEASUREMENTS With each patient given air/oxygen/isoflurane anesthesia, the flow velocity in the middle cerebral artery (Vmca) and pulsatility index were measured using the transcranial Doppler method under hypocapnic [arterial CO(2)tension (PaCO(2)) 28-32 mmHg], normocapnic (PaCO(2) 38-42 mmHg), and hypercapnic conditions (PaCO(2) 48-52 mmHg). PaCO(2) was altered by supplementing the inspired gas with CO(2) without changing the respiratory conditions. Patients were then randomly assigned to receive either ketamine 1 mg. kg(-1) or propofol (2 mg. kg(-1)followed by an infusion of 6-10 mg. kg(-1). hr(-1)) (n = 15 for each drug), and the measurements were repeated. MAIN RESULTS Ketamine reduced both absolute and relative cerebrovascular reactivity to CO(2) significantly [2.9 +/- 0.8 (control) vs. 2.6 +/- 1.0 (ketamine) cm. sec(-1). mmHg(-1): p < 0.05; and 3.5 +/- 0.7 (control) vs. 2.8 +/- 0.9 (ketamine) %. mmHg(-1): p < 0.01, respectively]. However, ketamine did not reduce Vmca during hypercapnic conditions (117 +/- 29 cm. sec(-1)) compared with controls (120 +/- 28 cm. sec(-1)). Although propofol decreased Vmca during all conditions, it did not cause any change in either absolute or relative CO(2) reactivity [2.5 +/- 0.8 (control) vs. 2.5 +/- 1.0 (propofol) cm. sec(-1). mmHg(-1), and 3.3 +/- 1.3 (control) vs. 4.1 +/- 1.0 (propofol) %. mmHg(-1), respectively]. CONCLUSIONS In humans given isoflurane anesthesia, a) ketamine reduced cerebrovascular response to CO(2), but cerebral blood flow (CBF) during hypercapnic conditions was comparable with controls, and b) although propofol decreases CBF, it maintains the cerebrovascular response to CO(2).

The Association Between the Initial End-Tidal Carbon Dioxide Difference and the Lowest Arterial Oxygen Tension Value Obtained During One-Lung Anesthesia With Propofol or Sevoflurane

OBJECTIVE The purpose of this study was to examine the correlation between the lowest PaO(2) value recorded during the first 45 minutes of one-lung ventilation (OLV) and the end-tidal CO(2) (ETCO(2)) difference between two-lung ventilation (TLV) and the early phase of OLV. DESIGN A prospective, randomized study. SETTING A university hospital. PARTICIPANTS Thirty-six patients scheduled for elective thoracic surgery. INTERVENTIONS Thoracic surgery patients were randomly assigned to 1 of 2 groups (group P [n = 18], maintained with propofol; group S [n = 18], maintained with sevoflurane). After setting up, the authors measured arterial blood gases at F(I)O(2) = 1.0 as follows: during TLV and at 5 minutes, 15 minutes, 30 minutes, and 45 minutes after the start of OLV. ETCO(2) was recorded just before and at 3 minutes after the start of OLV. The authors examined the relationship between the initial ETCO(2) difference and the lowest PaO(2) value recorded during the first 45 minutes of OLV. MEASUREMENTS AND MAIN RESULTS There was a significant negative correlation between the lowest PaO(2) (x) value and the initial ETCO(2) difference (y) during OLV in each group (group P: y = -0.0203x + 7.2571, r(2) = 0.5351; group S: y = -0.0257x + 7.3158, r(2) = 0.6129). This correlation was not significantly different between the groups. CONCLUSION The present study indicates that the ETCO(2) difference between TLV and early OLV has an association with impaired oxygenation later during OLV. This would be a simple and clinically convenient predictor of the lowest PaO(2) value likely to be reached during one-lung anesthesia with either propofol or sevoflurane.

L-arginine and nitroglycerin restore hypercapnia-induced cerebral vasodilation in rabbits after its attenuation by ketamine

Although it has been reported that ketamine attenuates hypercapnia-induced cerebral vasodilation, the mechanism remains unknown. Because nitric oxide is involved in cerebral CO2 reactivity, we studied the effects of l-arginine and nitroglycerin on ketamine-mediated attenuation of vascular responses to hypercapnia. Under pentobarbital anesthesia, 16 rabbits underwent closed cranial window preparation. Hypercapnic challenges were repeated after IV saline, ketamine (10 mg/kg, followed by 20 mg · kg−1 · h−1), or ketamine plus either l-arginine (150 mg/kg, followed by 100 mg · kg−1 · h−1;n = 8) or nitroglycerin (5 &mgr;g · kg−1 · min−1 infusion;n = 8). Ketamine reduced hypercapnia-induced cerebral vasodilation (1.27%/mm Hg ± 0.45%/mm Hg [saline] versus 0.82%/mm Hg ± 0.53%/mm Hg [ketamine]:P < 0.05), but l-arginine restored reactivity (1.28%/mm Hg ± 0.73%/mm Hg:P < 0.05 versus ketamine), as did nitroglycerin (1.14%/mm Hg ± 0.73%/mm Hg [saline] versus 0.56%/mm Hg ± 0.63%/mm Hg [ketamine]:P < 0.05, and 1.15%/mm Hg ± 0.74%/mm Hg [ketamine plus nitroglycerin]:P < 0.05 versus ketamine). This indicates that ketamine attenuates cerebral CO2 reactivity, at least in part, via suppression of nitric oxide-cyclic guanosine monophosphate mechanisms in the cerebral vasculature.

Attenuated additional hypocapnic constriction, but not hypercapnic dilation, of spinal pial arterioles during spinal ropivacaine.

UNLABELLED Ropivacaine constricts spinal vessels. Because the CO2 response of spinal vessels is similar to that of cerebral vessels, we tested to see if hypocapnia would cause further spinal vasoconstriction during ropivacaine administration. In 12 pentobarbital-anesthetized dogs, spinal pial arteriolar diameter was measured using a closed spinal window preparation. Either ropivacaine solution (0.1%; n = 6) or artificial cerebrospinal fluid (n = 6) was infused continuously into the spinal window. After a period of hypocapnia (Paco2, 20-25 mm Hg) had been induced, inspired CO2 levels were adjusted to produce normocapnia (35-40 mm Hg) followed by hypercapnia (55-60 mm Hg). When the desired Paco2 was reached, measurements were made of the arteriolar diameter and physiological variables. During normocapnia, ropivacaine infusion produced a significant constriction of pial arterioles, whereas artificial cerebrospinal fluid caused no change. Hypocapnia induced a much smaller (almost nonexistent) additional vasoconstriction in the ropivacaine group than in the control group (P < 0.01). The final hypercapnic vasodilation was somewhat greater during ropivacaine (P < 0.05 versus control group). Topical ropivacaine induced no change in hemodynamic variables. We conclude that hypocapnia of the magnitude tested did not cause further constriction in spinal vessels during spinal ropivacaine. IMPLICATIONS During topical application of the local anesthetic ropivacaine in dogs, hypocapnia (Paco2, 20-25 mm Hg) induced almost no additional constriction of spinal arterioles, and the hypercapnic vasodilation was maintained. These data suggest that an additional constriction in spinal vessels is unlikely when hypocapnia occurs during spinal ropivacaine.

Sphingosine 1-phosphate (S1P) suppresses the collagen-induced activation of human platelets via S1P4 receptor

Sphingosine 1-phosphate (S1P) is as an extracellular factor that acts as a potent lipid mediator by binding to specific receptors, S1P receptors (S1PRs). However, the precise role of S1P in human platelets that express S1PRs has not yet been fully clarified. We previously reported that heat shock protein 27 (HSP27) is released from human platelets accompanied by its phosphorylation stimulated by collagen. In the present study, we investigated the effect of S1P on the collagen-induced platelet activation. S1P pretreatment markedly attenuated the collagen-induced aggregation. Co-stimulation with S1P and collagen suppressed collagen-induced platelet activation, but the effect was weaker than that of S1P-pretreatment. The collagen-stimulated secretion of platelet-derived growth factor (PDGF)-AB and the soluble CD40 ligand (sCD40L) release were significantly reduced by S1P. In addition, S1P suppressed the collagen-induced release of HSP27 as well as the phosphorylation of HSP27. S1P significantly suppressed the collagen-induced phosphorylation of p38 mitogen-activated protein kinase. S1P increased the levels of GTP-bound Gαi and GTP-bound Gα13 coupled to S1PPR1 and/or S1PR4. CYM50260, a selective S1PR4 agonist, but not SEW2871, a selective S1PR1 agonist, suppressed the collagen-stimulated platelet aggregation, PDGF-AB secretion and sCD40L release. In addition, CYM50260 reduced the release of phosphorylated-HSP27 by collagen as well as the phosphorylation of HSP27. The selective S1PR4 antagonist CYM50358, which failed to affect collagen-induced HSP27 phosphorylation, reversed the S1P-induced attenuation of HSP27 phosphorylation by collagen. These results strongly suggest that S1P inhibits the collagen-induced human platelet activation through S1PR4 but not S1PR1.

Prediction of hypotension during spinal anesthesia for elective cesarean section by altered heart rate variability induced by postural change

BACKGROUND Maternal hypotension is a common complication during cesarean section performed under spinal anesthesia. Changes in maternal heart rate with postural changes or values of heart rate variability have been reported to predict hypotension. Therefore, we hypothesized that changes in heart rate variability due to postural changes can predict hypotension. METHODS A total of 45 women scheduled to undergo cesarean section under spinal anesthesia were enrolled. A postural change test was performed the day before cesarean section. The ratio of the power of low and high frequency components contributing to heart rate variability was assessed in the order of supine, left lateral, and supine. Patients who exhibited a ⩾two-fold increase in the low-to-high frequency ratio when moving to supine from the lateral position were assigned to the postural change test-positive group. RESULTS According to the findings of the postural change test, patients were assigned to the positive (n=22) and negative (n=23) groups, respectively. Hypotension occurred in 35/45 patients, of whom 21 (60%) were in the positive group and 14 (40%) were in the negative group. The incidence of hypotension was greater in the positive group (P<0.01). The total dose of ephedrine was greater in the positive group (15±11 vs. 7±7mg, P=0.005). The area under the receiver operating characteristic curve was 0.76 for the postural change test as a predictor of hypotension. CONCLUSION The postural change test with heart rate variability analysis may be used to predict the risk of hypotension during spinal anesthesia for cesarean section.