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Sympathetic activation after subarachnoid hemorrhage (SAH) can induce tachycardia as well as cardiac and brain injury. We examined the effects of beta1 receptor antagonist landiolol on hemodynamics and the levels of tissue injury markers in patients with SAH. Fifty-six SAH patients undergoing intracranial aneurysm surgery with tachycardia (>or=90 beats per minute) randomly allocated to landiolol (L) or control (C) group were examined. In L group, landiolol was continuously administered during anesthesia. In C group, landiolol was not administered except bolus dose used in cases that exhibited uncontrolled tachycardia. Hemodynamics, the incidence of electrocardiographic abnormality, and levels of B-type natriuretic peptide, troponin T, S-100beta, 8-Hydroxy-2'-deoxyguanosine, interleukin-6 (IL-6), and IL-1 receptor antagonist were compared. Heart rate values from time of intubation to the end of anesthesia were significantly lower in L group than in C group, whereas blood pressure was similar between the groups. Although the incidence of bradycardia (<60 beats per minute) was significantly higher in L group than in C group (57% vs. 18%, respectively), bradycardia could be recovered without any adverse effects. The serum S-100beta levels 24 hours after operation were significantly lower in L group than in C group, whereas there were no significant differences in the incidence of electrocardiographic abnormality and levels of B-type natriuretic peptide, troponin T, 8-Hydroxy-2'-deoxyguanosine, IL-6, and IL-1 receptor antagonist between groups. We conclude that landiolol can be effectively used in the treatment of tachycardia in SAH patients and significantly reduced the serum S-100beta levels 24 hours after the operation.

Background: It is not well established whether insulin protects against ischemic spinal cord injury. We examined the effects of a single dose of insulin that corrects mild hyperglycemia on the outcome after transient spinal cord ischemia in rabbits., Methods: We assigned rabbits to four groups (n = 8 in each); untreated control (C) group, preischemic insulin (Pre-I) group, preischemic insulin with glucose (GI) group (glucose concentrations were maintained at levels similar to the C group by the administration of glucose), and postischemic insulin (Post-I) group. Insulin (0.5 IU/kg) was administered 30 min before ischemia in the Pre-I and GI groups, and just after reperfusion in the Post-I group. Spinal cord ischemia was produced by occluding the abdominal aorta for 13 min. Neurologic and histopathologic evaluations were performed 7 days after ischemia., Results: The mean blood glucose concentration before ischemia in the Pre-I group (118 mg/dL) was significantly lower than in the other three groups (158-180 mg/dL) and those of 30 min after reperfusion in the Pre-I (92 mg/dL) and Post-I (100 mg/dL) groups were significantly lower than in the C (148 mg/dL) and GI (140 mg/dL) groups. The motor function score and number of normal neurons in the anterior lumbar spinal cord in the Pre-I group were significantly greater than in the other three groups., Conclusions: These results suggest that a relatively small dose of preischemic insulin protects against ischemic spinal cord injury, and that the protective effects result from tight glycemic control before ischemia.

With the introduction of bispectral index (BIS) as a measure of a patient's sedation during general anesthesia, attention has been directed toward bispectral analysis of electroencephalography (EEG). In the present study we evaluated the relationship between EEG bicoherence and sevoflurane concentration. Sixteen ASA physical status I-II patients scheduled for elective abdominal surgery were enrolled in the study. Anesthesia was induced with 5% sevoflurane and maintained with sevoflurane and oxygen (50%). Just before surgery, IV fentanyl (2 microg/kg) was given and then continuously infused (2 microg x kg(-1) x h(-1)). Using software we developed, EEG bicoherence, BIS, and 95% spectral edge frequency (SEF95) were recorded at end-tidal sevoflurane concentrations of 0.5%, 0.8%, 1.1%, 1.4%, 1.7%, 2.0%, and 2.3%. Under light anesthesia, EEG bicoherence values were low. With increasing sevoflurane concentrations, 2 peaks of bicoherence emerged along the diagonal line (f1 = f2). Both the first (at around 4 Hz) and second (at around 10 Hz) grew higher (37.7% +/- 7.5% and 35.1% +/- 9.0%, respectively) as the sevoflurane concentration increased to 1.4%. However, the first peak leveled off whereas the second tended to decrease slightly with further increases in sevoflurane concentration. The BIS value decreased as the sevoflurane concentration increased and leveled off at 1.4% and higher concentrations of sevoflurane. The SEF 95 also decreased as the sevoflurane concentration increased up to 2.3%. Thus the distribution pattern of the two bicoherence peaks is likely to be better than BIS of the anesthetic effect of sevoflurane during surgery.

We examined the effects of cyclosporin A (CsA), a drug that inhibits mitochondrial permeability transition pore, and insulin on ischemic spinal cord damage in rabbits. We assigned rabbits to 5 groups (n = 6 in each); sham barrier-opened group (sham BO), barrier-opened group (BO), barrier-opened-CsA group (BO-CsA), barrier-opened-insulin group (BO-I), and barrier-opened-CsA-insulin group (BO-CsA-I). The blood-spinal cord barrier was opened to facilitate drug penetration by a mild injury to the lumber spinal cord on day 1. CsA (10 mg/kg per day IV) was administered on day 3 to day 5 (total 30 mg/kg). Insulin was administered 30 min before ischemia. In all groups, spinal cord ischemia was produced on day 5 by occluding the abdominal aorta for 13 min. Neurological and histopathological evaluations were performed 4 days after ischemia. In group BO-CsA, blood glucose concentrations were significantly larger compared with the other four groups, and no protection was observed. In contrast, hindlimb motor function in groups BO-I and Bo-CsA-I and histopathology in group BO-CsA-I were significantly better than in groups sham BO, BO, and BO-CsA. The results indicate that insulin protects against ischemic spinal cord injury, whereas the effect of CsA is, at best, minimal.

Objectives: To identify whether differences exist in the outcomes between patients undergoing hemodialysis and elderly nonhemodialysis patients with a femoral neck fracture., Design: Retrospective review., Setting: Level 1 trauma center., Patients/interventions: A total of 71 femoral neck fractures in 62 patients undergoing hemodialysis treated nonoperatively or operatively., Main Outcome Measurements: Clinical outcomes were analyzed to identify factors that may be correlated with life expectancy and functional prognosis., Results: The overall survival rates in this study at 1-year and 5-years postfracture were found to be 89.8% and 51.5%, respectively. There were significant correlations among the survival rate, patients' age, type of treatment, prefracture ambulation status, and prefracture activities of daily living status. However, using multivariate analysis, the only significant predictor of life expectancy was prefracture ambulation status. As for functional prognosis, the rates of total ambulation recovery and total activities of daily living recovery at 1-year postfracture were 50.0% and 71.2%, respectively. Both patients' age and age at the onset of hemodialysis may contribute considerably to functional prognosis in patients undergoing hemodialysis after femoral neck fracture., Conclusions: The present study suggests that the clinical outcomes of patients with femoral neck fractures who undergo hemodialysis are considerably superior to those of previous studies. In addition, when those fractures are treated surgically with specific management in patients undergoing hemodialysis, it may be possible to expect a life expectancy and functional prognosis similar to elderly nonhemodialysis patients with hip fractures.

We have reported that large concentrations of intrathecal local anesthetics increase glutamate concentrations in the cerebrospinal fluid (CSF) and cause neuronal injury in rabbits. In the current study we determined whether an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, YM872, administered intrathecally, reduces neuronal injury caused by tetracaine. We first examined the effects of intrathecal YM872 10, 30, 100, or 300 mug in rabbits (n = 3 in each). YM872 produced reversible motor and sensory block in a dose-dependent manner. Then, we evaluated modulatory effects of YM872 (300 mug) on tetracaine-induced glutamate release and neuronal injury. Pretreatment of YM872 did not attenuate 1% or 2% tetracaine-induced increases in cerebrospinal fluid glutamate concentrations (n = 3 in each). For evaluation of neuronal injury, rabbits were assigned to 4 groups (n = 6 in each) and intrathecally received 1% tetracaine and saline (1%T), 1% tetracaine and YM872 (1%TY), 2% tetracaine and saline (2%T), or 2% tetracaine and YM872 (2%TY). The volume of saline, YM872, and tetracaine was 0.3 mL. Saline or YM872 was administered 30 min before tetracaine administration. Neurological and histopathological assessments were performed 1 wk after the administration. Two and 1 animals respectively, showed motor and sensory dysfunction in 1%T, whereas 5 animals showed both motor and sensory dysfunction in 2%T. YM872 improved 2% tetracaine-induced motor dysfunction and neuronal damage (chromatolytic neurons, identified by round-shaped cytoplasm with loss of Nissl substance from the central part of the cell and eccentric nuclei). In 2%TY, 3 animals showed normal motor function and 3 showed mild dysfunction (ability to hop, but not normally), whereas 4 animals showed moderate dysfunction (inability to hop) in 2%T (P = 0.042). Only 2 animals showed one chromatolytic neuron in 2%TY, whereas 5 animals showed 4-16 chromatolytic neurons in 2%T (P = 0.020). These results suggest that AMPA receptor activation is involved, at least in part, in the tetracaine-induced neurotoxicity in the spinal cord.

It has been speculated that the nerve root entry zone in the spinal cord, known as the Obersteiner-Redlich zone, may be more sensitive to large concentrations of local anesthetics administered intrathecally. However, there has been no morphological evidence for this. In the present study, we examined morphological changes of nerve fibers at the nerve root entry zone after administration of intrathecal tetracaine in rabbits. Rabbits were assigned to 4 groups (n = 6 in each) and received intrathecal 0.3 mL saline (control), or 1%, 2%, or 4% tetracaine. Neurological and histopathological assessments were performed 1 wk after the administration. Tetracaine 1% selectively injured the myelin sheaths made by oligodendrocytes at the nerve root entry zones of both ventral and dorsal roots, although neurological dysfunction could not be detected. With tetracaine 2% and 4%, histopathological damage extended to the dorsal funiculus, distal part of roots, and cauda equina and neurological dysfunction became apparent. These results demonstrate that the myelin sheaths made by oligodendrocytes at the nerve root entry zone are highly vulnerable to large concentrations of tetracaine given intrathecally.

Surgical stimulation typically results in an activation of electroencephalographic activity. In some instances, painful stimulation in the presence of inadequate anesthesia results in a suppression of the electroencephalogram. This phenomenon has been referred to as a "paradoxical arousal." In our daily practice, we have noted a marked decrease in the bispectral index (BIS) with large delta waves during abdominal surgery when the abdominal cavity was irrigated with normal saline. In the present study, we sought to evaluate changes in BIS during intraabdominal irrigation. Eighteen ASA physical status I-II patients scheduled for elective abdominal surgery were enrolled in the study and allocated randomly to the control group (group C) or the fentanyl group (group F). Anesthesia was induced with 3 mg/kg of thiopental and was maintained with sevoflurane and 50% nitrous oxide. BIS, 95% spectral edge frequency (SEF95), and burst-suppression ratio were recorded using a BIS monitor. Near the end of the procedure, but before irrigation of the abdominal cavity, 1.5 microg/kg fentanyl was given IV to group F. There was no significant change in BIS or SEF95 in group F patients during subsequent irrigation of the abdominal cavity. In contrast, BIS and SEF95 decreased significantly after start of irrigation in group C patients. These data show that the stimulation occurring during intraabdominal irrigation might cause a paradoxical arousal response, as evidenced by a decrease in processed electroencephalographic parameters. Pretreatment with fentanyl suppressed these changes. Anesthesiologists should be aware of this paradoxical arousal response to avoid an inappropriate decrease in the anesthetic concentration in such situations.

We describe a patient in whom the bispectral index (BIS) decreased to 0 during surgery. A 42-yr-old man with chronic renal failure was scheduled to undergo construction of an arteriovenous shunt. He had a history of acute cerebral hemorrhage. An intracranial hematoma had been removed a month earlier with almost complete neurological recovery. He had uncontrolled hypertension. His systolic blood pressure was 180 mm Hg before anesthesia induction. Anesthesia was induced with 100 mg of propofol and 3% sevoflurane. After laryngeal mask insertion, anesthesia was maintained with nitrous oxide 60% in oxygen and sevoflurane. BIS decreased to near 0 on 2 occasions: after anesthesia induction and shortly after the start of the surgery. His systolic blood pressure decreased to 110 mm Hg and BIS increased when his blood pressure was increased to 130-140 mm Hg. The decrease in BIS was suspected to be the result of decreased cerebral blood flow. The systolic blood pressure of 110 mm Hg (mean blood pressure, 80 mm Hg) was probably less than the lower limit of autoregulation. Although BIS has some limitations as a cerebral monitor, it was useful for detecting possible cerebral hypoperfusion in this case.

We performed three sets of experiments to investigate the safety of intrathecal magnesium and to determine its optimal dose for protection, if any, against ischemic spinal cord injury in rabbits. First, we examined neurotoxicity of 0.3, 1, 2, or 3 mg/kg of magnesium sulfate (n = 6 each). Significant sensory dysfunction was observed in the 3-mg/kg group 7 days after administration. Motor dysfunction was found in two rabbits in both the 2- and 3-mg/kg groups. The area of destruction in laminae V-VII was observed in one, two, and one rabbit in the 1-, 2-, and 3-mg/kg groups, respectively. Second, we investigated the temporal profile (6 h, 48 h, and 96 h [n = 3 each]) of histopathologic changes after 3 mg/kg of magnesium sulfate and confirmed similar changes in the rabbits with motor dysfunction at 48 and 96 h. Third, we evaluated the effects of 0.3 mg/kg or 1 mg/kg of magnesium sulfate or saline (n = 6 each) administered before ischemia on hindlimb motor function and histopathology after spinal cord ischemia (15 min). Magnesium did not improve neurologic or histopathologic outcome 96 h after reperfusion. The results indicate that intrathecal magnesium has a risk of neurotoxicity and shows no evidence of protective effects against ischemic spinal cord injury.

Unlabelled: Bispectral index (BIS) integrates various electroencephalographic (EEG) parameters into a single variable. However, the exact algorithm used to synthesize the parameters to BIS values is not known. The relationship between BIS and EEG parameters was evaluated during nitrous oxide/isoflurane anesthesia. Twenty patients scheduled for elective ophthalmic surgery were enrolled in the study. After EEG recording with a BIS monitor (A-1050) was begun, general anesthesia was induced and maintained with 0.5%-2% isoflurane and 66% nitrous oxide. Using software we developed, we continuously recorded BIS, spectral edge frequency 95% (SEF95), and EEG parameters such as relative beta ratio (BetaRatio), relative synchrony of fast and slow wave (SynchFastSlow), and burst suppression ratio. BetaRatio was linearly correlated with BIS (r = 0.90; P < 0.01; n = 253) at BIS more than 60. At a BIS range of 30 to 80, SynchFastSlow (r = 0.60; P < 0.01; n = 3314) and SEF95 (r = 0.75; P < 0.01; n = 3339) were linearly correlated with BIS. The correlation between BIS and SEF95 was significantly better than the correlation between BIS and SynchFastSlow (P < 0.01). At BIS less than 30, the burst suppression ratio was inversely linearly correlated with BIS (r = 0.76; P < 0.01; n = 65). At BIS less than 80, burst-compensated SEF95 was linearly correlated with BIS (r = 0.78; P < 0.01; n = 3404). In the range of BIS from 60 to 100, BIS can be calculated from BetaRatio. At surgical levels of anesthesia, BIS and SynchFastSlow (a parameter derived from bispectral analysis) or burst-compensated SEF95 (derived from power spectral analysis) are well correlated. However, our results show that SynchFastSlow has no advantage over SEF95 in calculation of BIS., Implications: The relationship between bispectral index (BIS) and electroencephalographic parameters was evaluated during nitrous oxide/isoflurane anesthesia. At surgical levels of anesthesia, BIS and the relative synchrony of fast and slow wave (a parameter derived from bispectral analysis) or burst-compensated spectral edge frequency 95% (a parameter derived from power spectral analysis) are well correlated.

Unlabelled: We have reported that increased glutamate concentrations in microdialysate of the cerebrospinal fluid (CSF) may be clue phenomena to elucidate mechanisms of neurotoxicity of intrathecal tetracaine. However, little is known about whether this is true for other local anesthetics. In this study, we compared the effects of local anesthetics on glutamate concentrations in CSF microdialysate and neurologic and histopathologic outcome. Rabbits were assigned into 5 groups (n = 6 in each) and intrathecally received 0.3 mL of NaCl solution (control), 2% tetracaine, 10% lidocaine, 2% bupivacaine, or 2% ropivacaine. Neurologic and histopathologic assessments were performed 1 wk after the administration. Intrathecal local anesthetics significantly increased glutamate concentrations with no significant differences among the four local anesthetics. The sensory and motor functions in the lidocaine group were significantly worse than in the other groups. Characteristic histopathologic changes were vacuolation in the dorsal funiculus and chromatolytic damage of motor neurons. The extent of vacuolation of the dorsal funiculus was in the order of lidocaine = tetracaine > bupivacaine > ropivacaine. Although the differences among the local anesthetics cannot be explained by glutamate concentrations, the results suggest that the margin of safety may be smallest with lidocaine., Implications: Large concentrations of local anesthetics administered intrathecally increased glutamate concentrations in the cerebrospinal fluid. The margin of safety may be smallest with lidocaine.

Unlabelled: In the present study, we sought to elucidate the temporal profile of the reaction of microglia, astrocytes, and macrophages in the progression of delayed onset motor dysfunction after spinal cord ischemia (15 min) in rabbits. At 2, 4, 8, 12, 24, and 48 h after reperfusion (9 animals in each), hind limb motor function was assessed, and the lumbar spinal cord was histologically examined. Delayed motor dysfunction was observed in most animals at 48 h after ischemia, which could be predicted by a poor recovery of segmental spinal cord evoked potentials at 15 min of reperfusion. In the gray matter of the lumbar spinal cord, both microglia and astrocytes were activated early (2 h) after reperfusion. Microglia were diffusely activated and engulfed motor neurons irrespective of the recovery of segmental spinal cord evoked potentials. In contrast, early astrocytic activation was confined to the area where neurons started to show degeneration. Macrophages were first detected at 8 h after reperfusion and mainly surrounded the infarction area later. Although the precise roles of the activation of microglia, astrocytes, and macrophages are to be further determined, the results indicate that understanding functional changes of astrocytes may be important in the mechanism of delayed onset motor dysfunction including paraplegia., Implications: Microglia and macrophages play a role in removing tissue debris after transient spinal cord ischemia. Disturbance of astrocytic defense mechanism, breakdown of the blood-spinal cord barrier, or both seemed to be involved in the development of delayed motor dysfunction.

Unlabelled: The mechanisms for delayed onset paraplegia after transient spinal cord ischemia are not fully understood. We investigated whether apoptotic motor neuron death is involved in its development. Spinal cord ischemia was induced for 15 min by occlusion of the abdominal aorta in rabbits. At 8, 24, or 48 h after reperfusion, hind limb motor function was assessed, and the lumbar spinal cord was examined morphologically (hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling staining) and biochemically (breakdown products of alpha-fodrin and patterns of DNA changes). At each time point, 14 rabbits were studied (7 for histopathology and 7 for biochemical analysis). Six rabbits served as sham controls. Delayed motor dysfunction developed in two thirds of the rabbits. The motor neurons in the rabbits with motor dysfunction (not paraplegia) showed swelling and a finely granular dispersed Nissl substance. In paraplegic rabbits, destruction of the gray matter and prominent inflammatory cell infiltration were observed. No apoptotic motor neuron was found in any rabbit. There was neither detectable increase in a caspase-3-mediated breakdown product of alpha-fodrin, nor DNA laddering in any rabbit. The results suggest that apoptosis has a negligible role in the pathophysiology of delayed paraplegia in the spinal cord ischemia model examined., Implications: Although the possibility of apoptotic motor neuron death cannot be completely excluded, delayed onset paraplegia after transient spinal cord ischemia is largely associated with necrotic cell death.

Background: The aim of this study was to determine if the ischemic tolerance could be induced in the spinal cord by pretreatment with hyperbaric oxygen (HBO) and what components of HBO (hyperoxia, hyperbaricity, and combination of these two) were critical in the induction of tolerance against ischemic injury., Methods: In experiment 1, 21 rabbits were randomly assigned to one of three groups (n = 7 each): animals in the control group received no HBO before spinal cord ischemia; animals in the HBO-1 and HBO-2 groups received HBO (2.5 atmosphere absolute [ATA], 100% O2) pretreatment 1 h/day for 3 and 5 days before ischemia, respectively. In experiment 2, 48 rabbits were randomly assigned to one of four groups (n = 12 each): the control group received no HBO (21% O2, 1 ATA, 1 h/day, 5 days) before spinal cord ischemia; the HB group received 1-h treatment in 21% O2 at 2.5 ATA each day for 5 days; the HO group received 1-h treatment in 100% oxygen at 1 ATA each day for 5 days; and the HBO group received HBO (2.5 ATA, 100% O2) treatment 1 h/day for 5 days. Twenty-four hours after the last treatment, spinal cord ischemia was induced by an infrarenal aorta clamping for 20 min. Forty-eight hours after reperfusion, hind-limb motor function and histopathology of the spinal cord were examined in a blinded fashion., Results: In experiment 1, the neurologic outcome in the HBO-2 group was better than that of the control group (P = 0.004). The number of normal neurons in the anterior spinal cord in the HBO-2 group was more than that of the control group (P = 0.021). In experiment 2, the neurologic and histopathologic outcomes in the HBO group were better than that of the control group (P < 0.01). The histopathologic outcome in the HO group was better than that in the control group (P < 0.05)., Conclusions: Serial exposure to high oxygen tension induced ischemic tolerance in spinal cord of rabbits. Simple hyperbaricity (2.5 ATA, 21% O2) did not induce ischemic tolerance.

Unlabelled: We have reported that large concentrations of intrathecal tetracaine increase glutamate concentrations in the cerebrospinal fluid (CSF) and cause neuronal injury in the spinal cord. In this study, we investigated whether the addition of epinephrine to tetracaine modulates these events. New Zealand white rabbits were assigned into five groups (six rabbits in each group) and intrathecally received 0.3 mL of epinephrine 0.1 mg/mL in NaCl solution (control), 1% tetracaine dissolved in saline (1%T), 1% tetracaine with epinephrine (1%TE), 2% tetracaine (2%T), or 2% tetracaine with epinephrine (2%TE). Glutamate concentrations in the lumbar CSF were monitored by microdialysis. Neurologic and histopathologic assessments were performed 1 wk after the administration. Glutamate concentrations significantly increased in all four groups that received tetracaine, whereas no change was observed in the Control group. The addition of epinephrine to tetracaine sustained large concentrations of glutamate. Sensory and motor dysfunction was observed in the 1%TE, 2%T, and 2%TE groups, and the dysfunction tended to be progressively exacerbated in this order. Characteristic histologic changes in animals with sensory and motor dysfunction were vacuolation in the dorsal funiculus and chromatolytic damage of motor neurons. The vacuolation of the dorsal funiculus in the 1%TE group was significantly worse than in the 1%T group. These results suggest that the addition of epinephrine to tetracaine may increase its neurotoxicity, which may possibly be related to a sustained increase of glutamate concentrations in the CSF., Implications: Sustained increase of glutamate concentrations produced by the addition of epinephrine to intrathecal tetracaine can cause neuronal injury.

We examined the time course of development of ischemic tolerance in the spinal cord and sought its mechanism exploring the expression of heat shock protein 70 (HSP70). Spinal cord ischemia was produced in rabbits by occlusion of the abdominal aorta. In Experiment 1, neurologic and histopathologic outcome was evaluated 48 h after prolonged ischemia (20 min) that was given 2 days, 4 days, or 7 days after a short period of ischemia (ischemic pretreatment) sufficient to abolish postsynaptic component of spinal cord evoked potentials. Control animals were given prolonged ischemia 4 days after sham operation. In Experiment 2, HSP70 expression in motor neurons after pretreatment without exposure to prolonged ischemia was examined by immunohistochemical staining. Ischemic pretreatment 4 days (but not 2 days or 7 days) before 20 min ischemia exhibited protective effects against spinal cord injury. In the cytoplasm, HSP70 immunoreactivity was mildly increased after 2, 4, and 7 days of ischemic pretreatment. However, the incidence of nuclear HSP70 immunoreactivity 2 days, 4 days, and 7 days after ischemic pretreatment was 2 of 6 animals, 4 of 6 animals, and 1 of 6 animals, respectively (none in the control group). These results suggest that ischemic tolerance is apparent 4 days after ischemic pretreatment and that HSP70 immunoreactivity in the nucleus may provide some insight into the mechanisms of ischemic tolerance in the spinal cord.

High concentrations of local anesthetics are neurotoxic, but the mechanism for this neurotoxicity is obscure. Here, we report increased concentrations of glutamate in the cerebrospinal fluid after intrathecal injections of high concentrations of tetracaine (a local anesthetic). The peak concentrations of glutamate after administration of 1%, 2%, and 4% tetracaine were 4-fold, 6-fold, and 10-fold higher than baseline values, respectively. Animals in the 1% group were all neurologically normal one week after tetracaine injection. In the group receiving 4%, no animal was able to hop and vacuolation of the white matter and/or central chromatolysis of the motor neurons were observed. Because high concentrations of glutamate are known to be neurotoxic, our results may provide some insight into the mechanisms for neurotoxicity of intrathecal local anesthetics.

Unlabelled: Little is known about the role of nitric oxide in the pathophysiology of spinal cord ischemia. We evaluated the effects of nitric oxide synthase (NOS) inhibition by N(G)-nitro-L-arginine-methyl ester (L-NAME) in rabbits whose abdominal aorta was occluded for 20 min (Experiment 1) or 25 min (Experiment 2). In Experiment 1, the L-NAME group (n = 6) received 3 mg/kg i.v. L-NAME, followed by an i.v. infusion of 3 mg x kg(-1). h(-1) until 6 h after reperfusion. Ischemia was induced 20 min after the start of L-NAME. The phenylephrine group (n = 6) received phenylephrine to maintain comparable blood pressure. The control group (n = 6) received saline. In Experiment 2, L-NAME (3 mg/kg i.v. L-NAME, followed by an i.v. infusion of 3 mg x kg(-1). h(-1) until 6 h after reperfusion) and phenylephrine groups (n = 6 each) were studied. Ischemia was induced 100 min after the start of L-NAME. Forty-eight hours after reperfusion, hindlimb motor function and histopathology of the spinal cord were examined. In Experiment 1, L-NAME and phenylephrine both improved neurologic outcome, with higher intraischemic blood pressures than saline. In Experiment 2, L-NAME worsened the neurologic and histopathologic outcome compared with phenylephrine. Attenuation of damage by L-NAME in Experiment 1 may be attributable to an intraischemic blood pressure increase. The worse outcome with L-NAME in Experiment 2 suggests that NOS inhibition exacerbates ischemic spinal cord damage., Implications: Nonselective inhibition of nitric oxide synthase activity has aggravating effects on the neurologic and histopathologic outcome after transient spinal cord ischemia.

Unlabelled: The aim of the present study was to compare the effects of intrathecal tetracaine (a sodium channel blocker) with those of moderate hypothermia on glutamate concentrations of intrathecal dialysate, hindlimb motor functions, and histopathology in spinal cord ischemia. New Zealand White rabbits implanted with an intrathecal dialysis probe were assigned to one of the three groups (seven in each): control (temperature 38 degrees C), tetracaine (tetracaine 0.5%, 0.6 mL, given intrathecally 30 min before ischemia, 38 degrees C), or moderate hypothermia (32 degrees C). Spinal cord ischemia (20 min) was produced by occlusion of the abdominal aorta during isoflurane (1%) anesthesia. Glutamate concentrations significantly increased during ischemia in all groups, but the levels in the moderate hypothermia group were significantly lower than those in the control and tetracaine groups. Neurologic status (24 and 48 h after reperfusion) and histopathology (48 h) in the moderate hypothermia group were significantly better than in the other two groups. There were no significant differences between the tetracaine and control groups in either glutamate concentrations, neurologic status, or histopathology. We conclude that intrathecal tetracaine does not provide any protection against ischemic spinal cord injury, whereas moderate hypothermia does., Implications: Sodium channel blockers, including local anesthetics, have been shown to reduce glutamate release in brain ischemia and have a neuroprotective effect. However, in the present study, intrathecal tetracaine did not attenuate either glutamate release or the neurologic or histopathologic outcome in spinal cord ischemia, whereas moderate hypothermia did.

Background: Diabetes mellitus (DM) and systemic atherosclerosis are risk factors for stroke. Although the origins of increased risk are complex, one possibility is that cerebrovascular reactivity is impaired and does not allow the brain to compensate for aberrations in physiology. The current study tested this issue by evaluating mean blood flow velocity of the middle cerebral artery (Vmca) and carbon dioxide reactivity during anesthesia in patients with DM and peripheral vascular disease (PVD)., Methods: Fifty-two patients were observed: 20 patients with DM (the DM group), 12 patients with PVD (the PVD group), and 20 patients classified as American Society of Anesthesiologists physical status 1 or 2 (the control group). The Vmca was measured using transcranial Doppler ultrasonography during isoflurane-nitrous oxide anesthesia. After measuring baseline Vmca at a partial pressure of carbon dioxide in arterial blood (PaCO2) of 37.7 +/- 4.5 mmHg (mean +/- SD), measurements were repeated at a PaCO of 44.2 +/- 3.8 mmHg, and the carbon dioxide reactivity (absolute value: cm x s(-1) x mmHg(-1); relative value: percentage of baseline Vmca/mmHg) was calculated., Results: The baseline Vmca of the DM group (51 +/- 12 cm/s) was significantly greater than those of the control group (42 +/- 6 cm/s) and the PVD group (42 +/- 13 cm/s). The absolute and relative values of carbon dioxide reactivity in the DM group (3.1 +/- 1.3 cm x s(-1) x mmHg(-1); 6.3 +/- 2.4%/mmHg) were significantly greater than or equivalent to those of the control group (2.3 +/- 0.8 cm x s(-1) x mmHg(-1); 5.3 +/- 1.7%/mmHg), respectively. In the PVD group, the baseline Vmca was equivalent to the control group, but the carbon dioxide reactivity (1.1 +/- 0.5 cm x s(-1) x mmHg(-1) 2.8 +/- 1.2%/mmHg) was significantly less., Conclusions: The patients with DM have increased baseline cerebral blood flow velocity and normal carbon dioxide reactivity during anesthesia. The patients with PVD have decreased carbon dioxide reactivity, but baseline flow velocity is maintained.

Neuronal degeneration after trauma is mediated in part by release of excitatory amino acids (EAAs) and oxygen free radicals (OFR). We evaluated the effect of i.v. treatment with a hydroxyl radical scavenger ((+/-)-N,N'-propylenedinicotinamide; AVS) and spinal hypothermia (33 degrees C) on spinal CSF glutamate release after spinal trauma. In a control group, spinal compression evoked at 10 min a significant increase (5-fold) in glutamate which declined over 4 h (2.1-fold). AVS treatment attenuated glutamate release but had no additive effect. These data suggest that this compound can be effective in modulating spinal excitotoxicity resulting from increased OFR synthesis and corresponding potentiation of EAA release.

Background: It is not clear whether the increase of cerebral blood flow (CBF) produced by volatile anesthetics is maintained during prolonged anesthesia. In a previous study, the authors found that CBF equivalent, an index of flow-metabolism relationship, was stable over 3 h, suggesting no decay over time in CBF for 3 h during volatile anesthesia in humans. However, it may be possible that CBF changes in a parallel fashion to functional metabolic changes. In this study, to estimate the response of CBF to three volatile anesthetics, the authors used transcranial Doppler (TCD) ultrasonography to measure time-averaged mean velocity in the middle cerebral artery (Vmca)., Methods: Twenty-four surgical patients were randomly assigned to three groups to receive halothane, isoflurane, or sevoflurane (eight patients, each). End-tidal concentration of the selected volatile anesthetic was maintained at 0.5, 1.0, and 1.5 MAC before surgery and then at 1.5 MAC during surgery, which lasted more than 3 h. Normothermia and normocapnia were maintained. Mean arterial blood pressure was kept above 70 mmHg, using phenylephrine infusion, if necessary. TCD recordings of the Vmca were performed continuously., Results: Vmca at 0.5 MAC of halothane, isoflurane, and sevoflurane was 49 +/- 19, 57 +/- 8, and 48 +/- 13 cm/s, respectively. Halothane significantly (P < 0.01) increased Vmca in a dose-dependent manner (0.5, 1.0, 1.5 MAC), whereas isoflurane and sevoflurane produced no significant dose-related changes. At 1.5 MAC for 3 h, Vmca changed significantly (P < 0.05) for the time trends, but it did not exhibit decay over time with all drugs. During burst suppression, observed electroencephalographically (EEG) on patients during isoflurane and sevoflurane anesthesia, the onset of a burst increased Vmca (approximately 5-30 cm/s), which was maintained for the duration of the burst., Conclusions: The results indicate that there was no decay in Vmca over time during prolonged (3 h) inhalation of volatile anesthetics at 1.5 MAC in humans. The fluctuation of Vmca during burst suppression on EEG at 1.5 MAC indicates that the flow-metabolism coupling occurred.

Background: Controversy exists over the efficacy of different methods for protecting the spinal cord against experimental ischemic injury. Therefore, the authors compared the protective effects of thiopental with those of hypothermia (35 degrees C and 32 degrees C) on hindlimb motor functions and histopathology after transient spinal cord ischemia., Methods: Twenty-seven New Zealand white rabbits were assigned to one of the four groups: a thiopental-normothermia group (burst-suppression dose of thiopental; esophageal temperature = 38 degrees C; n = 7), a halothane-mild hypothermia group (halothane, 1%; esophageal temperature = 35 degrees C; n = 7), a halothane-moderate hypothermia group (halothane, 1%; esophageal temperature = 32 degrees C; n = 6), and a halothane-normothermia group (halothane, 1%; esophageal temperature = 38 degrees C; n = 7). The animals were then subjected to 20 min of spinal cord ischemia produced by occlusion of the aorta distal to the origin of left renal artery. Hindlimb motor function was observed for 48 h after reperfusion. Histopathology of the lumbar spinal cord also was examined., Results: All animals in the halothane-mild hypothermia and halothane-moderate hypothermia groups were neurologically normal 48 h after ischemia. There was no statistical difference in the final neurologic status and histopathology between the thiopental-normothermia and halothane-normothermia groups. However, the final neurologic status and histopathology in both groups were worse than in the halothane-mild hypothermia or halothane-moderate hypothermia groups. There was a strong correlation between the final neurologic status and the numbers of normal neurons in the anterior spinal cord., Conclusions: These results suggest that mild and moderate hypothermia protects against ischemic spinal cord injury in rabbits, and a burst-suppression dose of thiopental does not offer any advantage over halothane.

One thousand two hundred fifty-four cases (610 colonic and 644 rectal cancers resected during 2 years from 1984 and followed up for more than 5 years) were entered from 140 institutions in Japan and analyzed by means of Cox's proportional hazards model. The analyzed pathologic variables were the size and depth of invasion, Dukes' stage, venous invasion, lymphatic permeation, and other clinical features, such as the sex and age of the patient and location of the tumor. The extent of dissection, serum carcinoembryonic antigen (CEA) level, and the presence or absence of adjuvant chemotherapy were also analyzed. Adjuvant chemotherapy consisted of three arms for both colonic and rectal cancers. For colonic cancer, arm I was a combination of i.p. (intraportal) and i.v. mitomycin C (MMC) + p.o. 5-fluorouracil (5-FU); arm II was i.v. MMC + p.o. 5-FU; and arm III was surgery only. For rectal cancer, arm IV was a combination of i.a. (inferior mesenteric artery) and i.v. MMC + p.o. 5-FU; arm V was i.v. MMC + p.o. 5-FU; and arm VI was surgery only. As for the factors affecting the disease-free survival of the patient, multivariate analysis disclosed nodal involvement, venous invasion, an elevated CEA level, and the lower part of the rectum. The effect of adjuvant chemotherapy on the patient's survival was proven for rectal cancer but not for colonic cancer. We conclude that these factors should be considered in setting the stage of tumor pre- and postoperatively.

Background: In several animal studies, an increase in cerebral blood flow (CBF) produced by volatile anesthetics has been reported to resolve over time during prolonged anesthesia. It is important to investigate whether this time-dependent change of CBF takes place in humans, especially in clinical situations where surgery is ongoing under anesthesia. In this study, to evaluate the effect of prolonged exposure to volatile anesthetics (isoflurane, sevoflurane, and halothane), the CBF equivalent (CBF divided by cerebral metabolic rate for oxygen (CMRO2) was determined every 20 min during anesthesia lasting more than 4h in patients., Methods: Twenty-four surgical patients were assigned to three groups at random to receive isoflurane, sevoflurane, or halothane (8 patients each). End-tidal concentration of the selected volatile anesthetic was maintained at 0.5 and 1.0 MAC before surgery and then 1.5 MAC for the 3 h of surgical procedure. Normothermia and normocapnia were maintained. Mean arterial blood pressure was kept above 60 mmHg, using phenylephrine infusion, if necessary. CBF equivalent was calculated every 20 min as the reciprocal of arterial-jugular venous oxygen content difference., Results: CBF equivalent at 0.5 MAC of isoflurane, halothane, and sevoflurane was 21 +/- 4, 20 +/- 3, and 21 +/- 5 ml blood/ml oxygen, respectively. All three examined volatile anesthetics significantly (P<0.01) increased CBF equivalent in a dose-dependent manner (0.5, 1.0, 1.5 MAC). AT 1.5 MAC, the increase of CBF equivalent with all anesthetics was maintained increased with minimal fluctuation for 3 h. The mean value of CBF equivalent at 1.5 MAC in the isoflurane group (45 +/- 8) was significantly (P<0.01) greater than those in the halothane (32 +/- 8) and sevoflurane (31 +/- 8) groups. Electroencephalogram was found to be relatively unchanged during observation periods at 1.5 MAC., Conclusions: These results demonstrate that CBF/CMRO2 ratio is markedly increased above normal and maintained during prolonged inhalation of volatile anesthetics in humans. It is impossible to determine whether these data indicate a stable CBF or whether CBF and CMRO2 are changing in parallel during the observation period. The unchanging electroencephalographic pattern suggests that the former possibility is more likely and that the increase of CBF produced by volatile anesthetics is maintained over time without decay, which has been reported in several animal studies. It also is suggested that isoflurane possesses greater capability to maintain global CBF relative to CMRO(2) than does halothane or sevoflurane. time.)

Using the 2-[14C]deoxyglucose method, the effects of analgesic doses of epidural bupivacaine (300 micrograms) on local spinal cord glucose utilization (SP-LGU) of the cervical, thoracic, and lumbar regions and local cerebral glucose utilization (BR-LGU) in 38 brain structures were examined in conscious rats. In addition, the effects of intramuscular bupivacaine (300 micrograms) and the spinal cord transection (T2) were examined to determine whether the induced metabolic changes, if any, are related to the drug's systemic effect and/or deafferentation. Lumbar epidural bupivacaine sufficient to produce analgesia decreased SP-LGU in the thoracic (18-28%) and lumbar (21-29%) spinal cord but not in the cervical cord. Epidural bupivacaine decreased BR-LGU (15-26%) in 35 of 38 structures examined. With intramuscular bupivacaine, SP-LGU remained unchanged in almost all regions, while BR-LGU was significantly decreased (11-23%) in 23 structures. Plasma concentrations of bupivacaine in the epidural and intramuscular groups were comparable. With spinal cord transection alone, SP-LGU significantly decreased with varying degrees depending on the structure examined, but BR-LGU did not decrease in 36 of 38 structures examined. These results indicate that analgesic doses of epidural bupivacaine decrease SP-LGU, probably reflecting decreased neuronal activity of the spinal cord, and that reduced BR-LGU by epidural bupivacaine is most likely due to the drug's systemic effect rather than deafferentation.

Enflurane-induced modulation of cerebrospinal metabolic responses to peripheral nerve stimulation was examined in 30 rats. Local glucose utilization in the brain and lumbar spinal cord was measured using the autoradiographic 2-[C]deoxyglucose method at three anesthetic concentrations (0,5, 2, and 4%) either with or without electrical stimulation (5 mA, 0.5 ms, 10 Hz) of the unilateral sciatic nerve. Stimulation produced a 71 to 111% increase in glucose utilization in the ipsilateral dorsal horn of the spinal cord at all anesthetic concentrations examined. Stimulation also produced a 32 to 48% increase in glucose utilization in the hindlimb projectionarea of the contralateral somatosensory cortex at the two lowest concentrations (0.5 and 2%), while at 4% no stimulus-induced increase in glucose utilization was observed. The results show that there is a threshold at which enflurane suppresses the metabolic responses to peripheral stimulation in the somatosensory cortex but not in the spinal cord. If electrical stimulation of a peripheral nerve is regarded as analogous to surgical stimulation, considerable increase in the spinal cord metabolism may occur during surgery even in a deeply anesthetized subject.

The effects of enflurane anesthesia on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were studied in 17 patients. The patients were divided into two groups according to the depth of anesthesia. Cerebral perfusion pressure was maintained above 60 mmHg with phenylephrine. In Group 1 (arterial enflurane concentration, 15 mg/dl), patients were studied before surgery, while in group 2 (enflurane concentration, 27 mg/dl), the measurements were performed before and during surgery. In Group 1, mean CBF and CMRO2 were 53 and 2.8 ml X 100 g-1 X min-1, respectively. These values were not significantly different from CBF (46 ml X 100 g-1 X min-1) and CMRO2 (3.1 ml X 100 g-1 X min-1) values previously obtained in awake patients. In Group 2 before surgery, mean CBF and CMRO2 were 61 and 2.6 ml X 100 g-1 X min-1, respectively, and were significantly different from the awake values, while the EEG showed frequent spikes and suppression. In Group 2 during surgery, mean CBF and CMRO2 did not differ from the values obtained before surgery, despite significant EEG changes. The results indicate that enflurane is a cerebral vasodilator and causes an increase in CBF and a decrease in CMRO2 in humans at an anesthetic level characterized by frequent spikes and suppression on the EEG.

The purpose of this study was to examine the effects of enflurane on local cerebral glucose utilization (LCGU), and to provide further insight into the mechanism of the epileptogenic properties of enflurane. Twenty-four male Wistar rats were divided into four groups; three groups with intact cortex received 0.5, 2, or 4% enflurane, and one group with unilateral cortex excised received 4% enflurane. LCGU was measured at each anesthetic concentration using the autoradiographic 2-[14C]deoxyglucose method. LCGU in ten of 33 structures examined during 2% enflurane decreased by 19-33%, and LCGU in 22 structures during 4% enflurane decreased by 19-65%, when compared with that during 0.5% enflurane. While LCGU, in most structures, decreased in a dose-related manner, LCGU in the corpus callosum, thalamic ventrobasal complex, and hippocampal CA3 field during 4% enflurane increased by 31-70%, compared with that during 0.5% and/or 2% enflurane. With unilateral cortical excision during 4% enflurane, the increase in LCGU in the ventrobasal complex was obliterated in the excision side, and the increase in the corpus callosum was attenuated. High LCGU in the hippocampal CA3 field and contralateral ventrobasal complex was not affected with cortical excision. These results indicate that intercortical and corticothalamic pathways are metabolically activated during deep enflurane anesthesia, suggesting that the epileptogenic property of enflurane is related to activation of these pathways.

The possibility of association between changes in spinal cord metabolism and changes in spinal cord neuronal activity by injection of morphine into the epidural space in amounts adequate to produce analgesia was examined. Fourteen Wistar rats were equally divided into two groups: a morphine group (epidural, 15 micrograms) and a control group (saline). Using the 2-[14C] deoxyglucose method, glucose utilization was measured in the spinal cord and in the brain, including structures related to pain modulation, in the presence and in the absence of analgesia produced by epidural morphine as confirmed by the hot plate test. Glucose utilization was shown to be similar in the spinal cord and in the brain in both groups of animals. The results suggest that analgesic doses of epidural morphine do not affect neuronal activity of the spinal cord by changing spinal cord carbohydrate metabolism.

The cerebral effects of nitrous oxide, 60 per cent, were examined in 27 dogs. During administration of halothane, 0.2 per cent, nitrous oxide increased cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMR02) to a maximum of 203 and 121 per cent of control, respectively. Cerebrospinal fluid pressure paralleled the change in CBF. The electroencephalogram (EEG) showed low-voltage slow-wave activity. With halothane, 0.8 per cent, nitrous oxide increased CBF and CMR02 to maximum values of 164 and 108 per cent of control, respectively. After administration of thiamylal, 8 mg/kg, intravenously, nitrous oxide did not increase CBF or CMR02 for the first 30-min period, but thereafter, CMR02 increased to 11 per cent above control. Pretreatment with reserpine, 0.5 mg/kg, intramuscularly, for two days did not modify the cerebral circulator and metabolic responses to nitrous oxide. These results indicate that nitrous oxide causes cerebral metabolic stimulation accompanied by an increase in CBF and slowing of the EEG. Sympathoadrenal stimulation would appear not to be the mechanism for the increases in CBF and CMR02. The cerebral effects of nitrous oxide are modified by the background anesthesia.

The effects of succinylcholine (SCh: 2 mg/kg) alone and in combination with lidocaine (4.5 mg/kg in two increments) on muscle oxygen consumption (VO2) and blood flow (MBF) in normal and denervated gastrocnemius muscle were studied in 18 dogs anesthetized with halothane (0.94%, end tidal) to examine the interactions of both drugs at the neuromuscular junction. In an additional five dogs with normal gastrocnemius muscle, the effects of lidocaine alone on VO2 and MBF were also studied. In normal muscle, VO2 increased as much as 150% with SCh alone, while with the combination of lidocaine and SCh, VO2 remained unchanged. MBF remained unchanged with SCh alone and the combined use of lidocaine and SCh. Neither the VO2 nor MBF was affected by lidocaine alone. In denervated muscle, VO2 increased as much as 304% with SCh alone and MBF increased 115%. With the combined use of SCh and lidocaine the VO2 in denervated muscle increased up to 360% with a 290% increase in MBF. These findings indicate different effects of lidocaine on metabolic and circulatory responses to SCh in normal and in denervated muscles in dogs.

Local cerebral glucose utilization was measured in rats during nitrous oxide and pentobarbital anesthesia, using the 2-[14C]-deoxyglucose method. During nitrous oxide anesthesia, 67%, marked heterogeneity of glucose utilization was observed. During pentobarbital anesthesia (30 mg/kg), glucose utilization decreased, the decrease being pronounced in the structures where glucose utilization was high during nitrous oxide anesthesia. During combined use of nitrous oxide and pentobarbital (30 mg/kg), with an electroencephalogram (EEG) consisting of 4-6 Hz wave super-imposed by 10-15 Hz wave, glucose utilization was higher in many brain structures, including the midbrain reticular formation, than that observed during pentobarbital (30 mg/kg) anesthesia alone. With pentobarbital, 125 mg/kg, the EEG became nearly flat and a dose-related decrease in glucose utilization was observed in the cerebral cortices and inferior colliculus but not observed in any other structures. During the combined use of nitrous oxide and pentobarbital (125 mg/kg), the EEG was nearly flat, and no statistically significant differences in glucose utilization were observed as compared with those during pentobarbital (125 mg/kg) anesthesia in any of the structures examined. The results suggest that nitrous oxide and pentobarbital affect local cerebral glucose metabolism differently and that nitrous oxide acts as cerebral metabolic stimulant in the presence of cortical function during pentobarbital anesthesia.