Hideyuki Higuchi

Combined spinal and general anesthesia attenuates liver metastasis by preserving Th1/Th2 cytokine balance

Background: Many studies have shown that regional anesthesia improves postoperative outcome and particularly lessens infection by attenuating perioperative immunosuppression related to the stress response to surgery and general anesthesia. However, it remains to be determined whether regional anesthesia improves oncologic outcome after surgery. Methods: C57BL/6 mice were subjected to laparotomy during sevoflurane general anesthesia alone or combined with spinal block achieved with bupivacaine (5 &mgr;g) and morphine (1.25 &mgr;g). Control groups were anesthetized only or were untreated. Liver was removed 5 h after surgery to assess antitumor killer cell activity and production of interferon γ and interleukin 4 by liver mononuclear cells, or mice were inoculated intravenously with liver-metastatic EL4 cells and hepatic metastases were counted 12 days later. Results: Laparotomy during sevoflurane anesthesia significantly increased the number (± SD) of liver metastases from 15.5 ± 8.7 (control) and 19.4 ± 5.4 (sevoflurane alone) to 33.7 ± 8.9. Sevoflurane anesthesia plus spinal block significantly reduced this increase to 19.8 ± 9. The in vitro killer activity of liver mononuclear cells against EL4 cells decreased from 32.7% (control) and 29.4% (sevoflurane alone) to 18.5% after sevoflurane plus laparotomy, and the addition of spinal block increased activity to 26.6%. The interferon-γ/interleukin-4 ratio decreased from 89.3 (control) and 95.7 (anesthesia alone) to 15.7 after sevoflurane plus laparotomy, and the addition of spinal block increased the ratio to 46.5. Conclusions: The addition of spinal block to sevoflurane general anesthesia accompanying surgery attenuates the suppression of tumoricidal function of liver mononuclear cells, presumably by preserving the T helper 1/T helper 2 (Th1/Th2) balance, and thereby reduces the promotion of tumor metastasis.

Influence of Lumbosacral Cerebrospinal Fluid Density, Velocity, and Volume on Extent and Duration of Plain Bupivacaine Spinal Anesthesia

BackgroundThe current study was designed to investigate the influence of lumbosacral cerebrospinal fluid (CSF) density, velocity, and volume on the extent and duration of plain bupivacaine spinal anesthesia. MethodsForty-one patients scheduled to undergo orthopedic surgery with spinal block were enrolled. Lumbosacral CSF volumes were calculated from low thoracic, lumbar, and sacral axial magnetic resonance images. CSF velocity at the L3–L4 level was derived from phase-contrast magnetic resonance images. Spinal anesthesia was performed in the lateral decubitus position. CSF (2 ml) was sampled to measure CSF density before injection of 3 ml plain bupivacaine (0.5%). Statistical correlation coefficients (&rgr;) between CSF characteristics and measurements of spinal anesthesia were assessed by Spearman rank correlation. In addition, stepwise multiple linear regression models were used to select important predictors of measures of spinal anesthesia. ResultsThere was a significant correlation between CSF density and peak sensory block level (&rgr; = 0.33, P = 0.034). Lumbosacral CSF volume inversely correlated with peak sensory block level (&rgr; = −0.65, P < 0.0001) and positively correlated with onset time of complete motor block (&rgr; = 0.42, P = 0.008). CSF volume also inversely correlated with time required for regression of the sensory block to L1 (&rgr; = −0.35, P = 0.026) and L2 (&rgr; = −0.33, P = 0.039). There was a significant inverse correlation between peak diastolic CSF velocity and duration of motor blockade (&rgr; = −0.44, P = 0.005). Multiple regression analysis revealed that weight and CSF volume significantly contributed to the peak sensory block level (R2 = 0.46). ConclusionsThese findings indicate that CSF density and volume influence the spread of spinal anesthesia with plain bupivacaine and that CSF volume also influences the duration of spinal anesthesia. CSF velocity might also influence the duration of plain bupivacaine spinal anesthesia.

Effects of Sevoflurane and Isoflurane on Renal Function and on Possible Markers of Nephrotoxicity

Background Low‐flow sevoflurane anesthesia is associated with increasing circuit concentrations of compound A, which is nephrotoxic in rats, but the effect of compound A and low‐flow sevoflurane anesthesia on renal function in humans is unclear. The authors compared the effects of high‐ and low‐flow sevoflurane and isoflurane anesthesia on renal function and on several possible markers of nephrotoxicity in humans. Methods Forty‐two patients without preexisting renal disease underwent either low‐flow isoflurane (1 l/min, n = 14), low‐flow sevoflurane (1 l/min, n = 14), or high‐flow sevoflurane (6 l/min, n = 14) anesthesia for body‐surface‐area surgery scheduled to last at least 4 h. Twenty‐four‐hour urinary excretion of N‐acetyl‐[small beta, Greek]‐glucosaminidase (NAG), [small beta, Greek]2‐microglobulin, protein, glucose, blood urea nitrogen (BUN), and serum creatinine concentrations were measured before and after anesthesia. Results There were no differences in blood urea nitrogen, creatinine, and creatinine clearance among the three groups after anesthesia. Increased urinary N‐acetyl‐[small beta, Greek]‐glucosaminidase excretions were seen in the low‐flow and high‐flow sevoflurane groups, but not in the low‐flow isoflurane group (P < 0.01). Ten patients in the low‐flow sevoflurane group had 24‐h urinary excretion of protein that exceeded the normal ranges after anesthesia, but only one patient in the isoflurane and none in the high‐flow sevoflurane groups had this. Conclusions Low‐flow sevoflurane anesthesia was associated with mild and transient proteinuria. However, the observed proteinuria was not associated with any changes in blood urea nitrogen, creatinine, and creatinine clearance in these patients with no preexisting renal disease.

Renal function in patients with high serum fluoride concentrations after prolonged sevoflurane anesthesia

Background In studies of methoxyflurane-induced nephrotoxicity, renal-concentrating impairment has been observed only when serum inorganic fluoride concentrations exceed 50 micro Meter. Prolonged sevoflurane anesthesia can result in serum inorganic fluoride concentrations in excess of 50 micro Meter. The authors compared renal function after prolonged sevoflurane anesthesia with that after isoflurane anesthesia. In addition, they measured urinary excretion of N-acetyl-beta-glucosaminidase (NAG), a sensitive index of renal tubular damage, during the 3-day period after anesthesia.

Serum inorganic fluoride levels in mildly obese patients during and after sevoflurane anesthesia.

Serum inorganic fluoride levels in obese versus control patients were compared during and after sevoflurane anesthesia. Mean serum inorganic fluoride levels in the obese group increased more rapidly and were significantly higher than in the control group at each sampling time (P < 0.01). The area under the curve of fluoride concentration, versus time up to 24 h and 48 h in the obese patients, was significantly greater than that in the nonobese patients (P < 0.001). Peak serum fluoride level in the obese patients was 51.7 ± 2.5 μmol/L and exceeded 50 μmol/L for nearly 2 h. Our study showed that serum fluoride concentrations between mildly obese and nonobese patients differed during and after sevoflurane anesthesia.

The determinants of propofol induction of anesthesia dose

Recently it was reported that the pharmacokinetics of propofol are modified by changes in cardiac output. The objective of this study was to evaluate the effects of cardiac output and other factors on the hypnotic dose of propofol. One-hundred surgical patients were administered indocyanine green immediately before the induction of anesthesia to measure their cardiac outputs and blood volumes. Propofol (250 &mgr;g · kg−1 · min−1) was infused IV for 8 min, and the hypnotic dose of propofol and the time to hypnosis were recorded. The plasma concentration of propofol immediately after 2 mg/kg infusion was measured. Multiple regression analysis showed that, in addition to age and weight, cardiac output was a small but significant factor for predicting the hypnotic dose of propofol (R2 = 0.468, P < 0.001), the time to hypnosis (R2 = 0.454, P < 0.001), and the plasma concentration of propofol (R2 = 0.248, P < 0.01). Cardiac output, age, and weight showed similar partial coefficients for the hypnotic dose (0.128, 0.137, and 0.140, respectively).

Isoflurane anesthesia induces biphasic effect on dopamine release in the rat striatum.

The effect of isoflurane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) modulated by pargyline, monoamine oxidase inhibitor, was studied using in vivo microdialysis techniques. A microdialysis probe was implanted into the right striatum of male SD rats. Each rat (n=5-6) was given saline or the same volume of 30 or 75 mg kg(-1) pargyline intraperitoneally with or without 1 h isoflurane anesthesia (1 or 3%). Isoflurane anesthesia increased the extracellular concentration of DA in high dose (3%) and increased the metabolite concentrations in a dose-dependent manner. Pargyline administration increased the extracellular concentration of DA and 3-MT, and decreased that of other metabolites. After 30 mg kg(-1) pargyline treatment, 1% isoflurane-induced DA release and increasing of 3-MT were preserved, whereas high dose isoflurane (3%) decreased the concentration of metabolites (DOPAC and HVA), despite of the increase by low dose isoflurane (DOPAC). When 75 mg kg(-1) pargyline was administered, isoflurane anesthesia decreased the concentration of DA and DOPAC. The isoflurane-induced 3-MT increase was preserved in all experiments. Our results suggest that isoflurane anesthesia induced biphasic effect on DA regulation probably by the potentiation of DA release and the inhibition of DA synthesis. Isoflurane might modulate DA homeostasis presynaptically.

Fentanyl attenuates the hemodynamic response to endotracheal intubation more than the response to laryngoscopy.

We examined the effectiveness of avoiding laryngoscopy in reducing the hemodynamic responses to orotracheal intubation during the induction of anesthesia. One hundred surgical patients who required orotracheal intubation were randomly allocated into four groups. The first and third groups underwent fiberoptic intubation, in which an anesthesiologist inserted the endotracheal tube into the trachea under TV monitoring through a bronchoscope, and the second and fourth groups underwent conventional orotracheal intubation using a rigid laryngoscope. The third and fourth groups were pretreated with 2 &mgr;g/kg fentanyl IV immediately before the induction of anesthesia. Blood pressure and heart rate were measured noninvasively. A significant reduction in hemodynamic response was seen in only the group treated with fentanyl and intubated using the fiberoptic technique. Without fentanyl, there was no significant difference in hemodynamic changes between the groups. We conclude that the administration of fentanyl suppresses the hemodynamic responses to endotracheal intubation more than it does to laryngoscopy. There was no significant difference in the hemodynamic responses to orotracheal intubation by fiberscopy and laryngoscopy without fentanyl pretreatment, whereas 2 &mgr;g/kg fentanyl significantly reduced the hemodynamic responses in the group intubated by fiberscopy.

Effects of epidural saline injection on cerebrospinal fluid volume and velocity waveform: a magnetic resonance imaging study.

Background:The phenomenon of epidural “top-up” (increased spread of local anesthetic due to epidural fluid injection) is explained partly by an epidural volume effect. This study was designed to investigate the change in cerebrospinal fluid (CSF) volume and velocity waveform induced by epidural saline injection. Methods:(1) Lumbar epidural catheters were placed in 28 patients. Magnetic resonance images were obtained for measurements of lumbosacral CSF volume and velocity waveform. Saline was injected into the epidural space through the catheter to three groups of randomly assigned patients: 5-ml saline (n = 10), 10-ml saline (n = 9), and 15-ml saline (n = 9) groups. A repeat image series was performed after epidural injection to compare CSF volume and velocity waveform before and after epidural injection. (2) We also examined the time course of dural sac compression after epidural saline injection in a separate series. Seven axial images at disk levels from T11–T12 to L5–S1 were obtained before injection and 1, 3, 5, 10, 15, 20, 25, and 30 min after 10-ml saline injection to compare each dural area before and after injection. Results:(1) Saline injected through the epidural catheter compressed the dural sac with variability of the extent of compression, resulting in a significantly decreased CSF volume in all patients (P ≦ 0.001). The mean reductions in CSF volume were 2.0 ± 1.0 ml in the 5-ml group, 4.4 ± 1.4 in the 10-ml group, and 7.2 ± 2.6 in the 15-ml group. There were significant differences among the three groups (P < 0.05∼0.001). After the saline injection, the synchronization between the CSF velocity waveform and the cardiac cycle disappeared in significantly more patients in the 10-ml group (7 of 9 patients) than in the other groups (P < 0.05). However, there was no significant relation between measures of CSF velocity waveform and dural area in any patient. (2) The maximum reduction of the sum of the total of seven disk areas occurred 5 min after epidural saline injection; thereafter, dural compression was gradually restored but did not return to the value before injection for 30 min. Conclusions:These findings indicate that the reduction in CSF volume was injection-volume dependent, dural compression lasted at least 30 min after saline injection, and the changes of the CSF flow dynamics did not correlate with the degree of dural sac compression.

Endothelin-1 induces vasoconstriction and nitric oxide release via endothelin ETB receptors in isolated perfused rat liver

Endothelin-1 (0.1, 1 and 10 nM) induced a significant increase in portal pressure and nitric oxide (NO) release in the isolated rat liver. The endothelin ET(B) receptor agonist, IRL 1620 (Suc-[Glu9,Ala(11,15)]endothelin-1-(8-21)) (0.1, 1 and 10 nM) also elicited a marked increase in portal pressure and NO release. The potency of endothelin-1 was higher than that of IRL 1620. The endothelin ET(A) receptor antagonist, BQ-123 (cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu)) (1 and 10 microM), had no effect on the endothelin-1-induced change in portal pressure and NO current. In contrast, the endothelin ET(B) receptor antagonist, BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methyl-leucyl-D-1-++ +methoxycarbonyltryptophanyl-D-norleucine) (1 and 10 nM), attenuated the endothelin-1-induced change in portal pressure and NO current. Administration of N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, completely abolished the endothelin-1- or IRL 1620-induced NO release. L-NMMA enhanced the increase in portal pressure and decrease in O2 consumption caused by endothelin-1. These results indicated that endothelin ET(B) receptors mediate both vasoconstriction and NO release and that NO plays a significant role in stabilizing microcirculation in isolated perfused rat liver.