Takashi Mashimo

Effects of Crystalloid and Colloid Preload on Blood Volume in the Parturient Undergoing Spinal Anesthesia for Elective Cesarean Section

BACKGROUND The role of crystalloid preloading to prevent hypotension associated with spinal anesthesia in parturients during cesarean section has been challenged. Direct measurement of blood volume should provide insight regarding the volume-expanding effects. The aim of the current study was to clarify the effects of volume preload with either crystalloid or colloid solution on the changes in blood volume of parturients undergoing spinal anesthesia for cesarean section. METHODS Thirty-six healthy parturients scheduled for elective cesarean section during spinal anesthesia were allocated randomly to one of three groups receiving 1.5 l lactated Ringers solution (LR; n = 12), 0.5 l hydroxyethylstarch solution, 6% (0.5 l HES; n = 12), and 1.0 l hydroxyethylstarch solution, 6% (1.0 l HES; n = 12), respectively. Blood volume and cardiac output were measured before and after volume preloading with indocyanine green (ICG), and the indocyanine green blood concentrations were monitored by noninvasive pulse spectrophotometry. RESULTS After volume preload, the blood volume significantly increased in all three groups (P < 0.01). The volume of infused solution remaining in the vascular space in the LR, 0.5-l HES, and 1.0-l HES groups were 0.43+/-0.20 l, 0.54+/-0.14 l, and 1.03+/-0.21 l, respectively, corresponding to 28% of lactated Ringers solution and 100% of hydroxyethylstarch solution infused. Significant increases in cardiac output were observed in the 0.5-l and 1.0-l HES groups (P < 0.01). A significant correlation between the percentage increase in blood volume and that of cardiac output was observed by volume preloading (r2 = 0.838; P < 0.001). The incidence of hypotension was 75% for the LR group, 58% for the 0.5-l HES group, and 17% for the 1.0-l HES group, respectively. CONCLUSIONS The incidence of hypotension developed in the 1.0-l HES group was significantly lower than that in the LR and 0.5-l HES groups, showing that greater volume expansion results in less hypotension. This result indicates that the augmentation of blood volume with preloading, regardless of the fluid used, must be large enough to result in a significant increase in cardiac output for effective prevention of hypotension.

Evidence for the involvement of GABAA receptor blockade in convulsions induced by cephalosporins

There is accumulating evidence that most beta-lactam antibiotics (i.e., cephalosporins and penicillins) have some degree of convulsive activity, both in laboratory animals as well as in clinical settings. The proposed mechanism is suppression of inhibitory postsynaptic responses, mainly mediated by gamma-amino butyric acid (GABA)(A)-receptors (GABA(A)-R). However, comprehensive studies on the convulsive activities of various beta-lactam antibiotics in vivo and in vitro have not been performed. We have therefore examined the convulsive activities of seven different cephalosporins using both in vivo and in vitro models: intracerebroventricular (ICV) administration in mouse; [(3)H]muscimol binding assay (BA) in mouse brain synaptosome; and inhibition of recombinant mouse alpha1beta2gamma2s GABA(A)-Rs in Xenopus oocyte (GR). The rank orders of convulsive activities in mouse (cefazolin>cefoselis>cefotiam>cefpirome>cefepime>ceftazidime>cefozopran) correlated with those of inhibitory potencies on [(3)H]muscimol binding and GABA-induced currents of GABA(A)-R in vitro, with correlation coefficients of ICV:GR, ICV:BA and BA:GR of 0.882, 0.821 and 0.832, respectively. In contrast, none of the antibiotics had affinities for N-methyl-D-aspartate (NMDA) receptors nor facilitatory actions on NMDA receptor-mediated current in oocytes. These results clearly demonstrate that the mechanism of cephalosporin-induced convulsions is mediated predominantly through the inhibition of GABA(A)-R function and not through NMDA receptor modulation.

Experimental Neuropathy in Mice Is Associated with Delayed Behavioral Changes Related to Anxiety and Depression

BACKGROUND:Patients with chronic pain frequently suffer affective disorders, particularly anxiety and depression. Although clinical research on the relationship between pain and depressive symptoms has been done, it is not clear whether pain causes depression or depression exaggerates pain. To investigate the relation between pain and affect, we measured anxiety and depression-related behaviors in mice after spinal nerve ligation using classical behavioral tests. METHODS:After unilateral ligation of the left fifth lumbar nerve, we measured pain behaviors using von Frey and radiant heat tests. Activity level, anxiety-related behaviors, and depression-related behaviors were tested with open field, light-dark exploration, elevated plus-maze, and forced swim tests. RESULTS:Sensory hypersensitivity was observed within a few days after ligation. Anxiety and depression-related behaviors were not seen 2 and 7 days after ligation. However, 15 and 30 days after ligation we found clear evidence of anxiety and depression-related behaviors, without loss of mobility. CONCLUSIONS:Nerve injury can trigger affective disturbances in mice that appear much later than sensory hypersensitivity.

Practical issues in bispectral analysis of electroencephalographic signals.

IMPLICATIONS The aim of this report was to confirm the methodology of bispectral analysis of electroencephalogram. In developing a software for real-time bispectral analysis, we encountered several practical problems in bispectrum calculation. We settled those and concluded that 3 min of monitoring are required to obtain reliable and reproducible bicoherence values.

Spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury.

Objective: We investigated whether potentially injurious transpulmonary pressure could be generated by strong spontaneous breathing and exacerbate lung injury even when plateau pressure is limited to <30 cm H2O. Design: Prospective, randomized, animal study. Setting: University animal research laboratory. Subjects: Thirty-two New Zealand White rabbits. Interventions: Lavage-injured rabbits were randomly allocated to four groups to receive low or moderate tidal volume ventilation, each combined with weak or strong spontaneous breathing effort. Inspiratory pressure for low tidal volume ventilation was set at 10 cm H2O and tidal volume at 6 mL/kg. For moderate tidal volume ventilation, the values were 20 cm H2O and 7–9 mL/kg. The groups were: low tidal volume ventilation + spontaneous breathingweak, low tidal volume ventilation + spontaneous breathingstrong, moderate tidal volume ventilation + spontaneous breathingweak, and moderate tidal volume ventilation + spontaneous breathingstrong. Each group had the same settings for positive end-expiratory pressure of 8 cm H2O. Measurements and Results: Respiratory variables were measured every 60 mins. Distribution of lung aeration and alveolar collapse were histologically evaluated. Low tidal volume ventilation + spontaneous breathingstrong showed the most favorable oxygenation and compliance of respiratory system, and the best lung aeration. By contrast, in moderate tidal volume ventilation + spontaneous breathingstrong, the greatest atelectasis with numerous neutrophils was observed. While we applied settings to maintain plateau pressure at <30 cm H2O in all groups, in moderate tidal volume ventilation + spontaneous breathingstrong, transpulmonary pressure rose >33 cm H2O. Both minute ventilation and respiratory rate were higher in the strong spontaneous breathing groups. Conclusions: Even when plateau pressure is limited to <30 cm H2O, combined with increased respiratory rate and tidal volume, high transpulmonary pressure generated by strong spontaneous breathing effort can worsen lung injury. When spontaneous breathing is preserved during mechanical ventilation, transpulmonary pressure and tidal volume should be strictly controlled to prevent further lung injury.

Intravenous anesthetic, propofol inhibits invasion of cancer cells.

Intravenous anesthetic, propofol (2,6-diisopropylphenol), is extensively used for general anesthesia without knowing the effects on cancer. We found here that clinically relevant concentrations of propofol (1-5 microg/ml) decreased the invasion ability of human cancer cells (HeLa, HT1080, HOS and RPMI-7951). In the HeLa cells treated with propofol, formation of actin stress fibers as well as focal adhesion were inhibited, and propofol had little effect on the invasion ability of the HeLa cells with active Rho A (Val(14)-Rho A). In addition, continuous infusion of propofol inhibited pulmonary metastasis of murine osteosarcoma (LM 8) cells in mice. These results suggest that propofol inhibits the invasion ability of cancer cells by modulating Rho A and this agent might be an ideal anesthetic for cancer surgery.

Prolongation of canine epidural anesthesia by liposome encapsulation of lidocaine.

The purpose of our study was to produce a long-acting lidocaine by using a liposome that would entrap the drug. Egg yolk phosphatidylcholine and cholesterol were used as liposome materials. After epidural administration, the pharmacodynamics and pharmacokinetics of liposomal and free lidocaine were studied in 20 dogs. Two percent liposomal or free lidocaine (3.0 mL) was injected into the lumbar epidural space. Nerve blocking effects were estimated by measuring somatosensory evoked potentials. Recovery time from the epidural block in the liposomal lidocaine group (170 +/- 49.5 min) was approximately three times longer than that in the free lidocaine group (61 +/- 18.1 min). The areas under the drug concentration-time curves (AUC0-infinity) and time to maximal concentration (Tmax) in the liposomal lidocaine group were significantly larger than those in the free lidocaine group. These results suggest that the prolongation of epidural blockade by liposomal lidocaine is caused by a slow release of the drug from liposomes. The present study suggests that liposomal lidocaine can be used as a long-acting local anesthetic.

A comparative study of the antinociceptive action of xenon and nitrous oxide in rats

We attempted to clarify the mechanism of antinociceptive action induced by xenon and nitrous oxide.Eighty percent of nitrous oxide or 80% xenon was applied to rats inside enclosed clear plastic glass cylinders with their tails protruding for assessment of the tail-flick response to radiant heat. With repeated testing, there was a rapid reduction to nitrous oxide antinociception within 90 min, which was interpreted as development of tolerance, but not to xenon antinociception. Nitrous oxide antinociception was blocked by the intraperitoneal administration of 0.1 or 1.0 mg/kg yohimbine, but not by 1.0 or 5.0 mg/kg L659-066 or by 5.0 or 10 mg/kg naloxone. Xenon antinociception was not affected by any of these drugs. Yohimbine and L659-066 are characterized as alpha2-adrenoceptor antagonists. Although yohimbine penetrates the blood-brain barrier after systemic administration, L659-066 does not penetrate it and act peripherally. Therefore, the results indicate that alpha2-adrenoceptors, but not opioid receptors, may play a key role in antinociception induced by nitrous oxide in the central nervous system. Furthermore, the mechanism of xenon antinociception differs from that of nitrous oxide because it does not involve either alpha2 or opioid receptors. Implications: The precise mechanism of antinociceptive action of nitrous oxide and xenon remains unknown. It is still controversial whether an opioid system plays a role in antinociception induced by nitrous oxide. The results of the study showed that antagonism of central alpha2-adrenoceptors, but not opioid receptors, reverses the antinociception induced by nitrous oxide but not by xenon, which indicates that alpha2-adrenoceptors may play a key role in nitrous oxide antinociception. (Anesth Analg 1997;85:931-6)

Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia

&NA; Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. We demonstrated that very rapid phosphorylation of p38 mitogen‐activated protein kinase occurred in dorsal root ganglion (DRG) neurons that were participating in the transmission of noxious signals. Capsaicin injection induced phosphorylated‐p38 (p‐p38) in small‐to‐medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p‐p38 labeling in the DRG after noxious thermal stimuli and found a stimulus intensity‐dependent increase in labeled cell size and the number of activated neurons. Most of these p‐p38‐immunoreactive (IR) neurons were small‐ and medium‐sized neurons, which coexpressed transient receptor potential ion channel TRPV1 and phosphorylated‐extracellular signal‐regulated protein kinase. Intrathecal administration of the p38 inhibitor, FR167653, reversed the thermal hyperalgesia produced by the capsaicin injection. Inhibition of p38 activation was confirmed by the decrease in the number of p‐p38‐IR neurons in the DRG following capsaicin injection. Taken together, these findings suggest that the activation of p38 pathways in primary afferents by noxious stimulation in vivo may be, at least in part, correlated with functional activity, and further, involved in the development of thermal hyperalgesia.

The Comparison of Spontaneous Breathing and Muscle Paralysis in Two Different Severities of Experimental Lung Injury.

Objectives:The benefits of spontaneous breathing over muscle paralysis have been proven mainly in mild lung injury; no one has yet evaluated the effects of spontaneous breathing in severe lung injury. We investigated the effects of spontaneous breathing in two different severities of lung injury compared with muscle paralysis. Design:Prospective, randomized, animal study. Setting:University animal research laboratory. Subjects:Twenty-eight New Zealand white rabbits. Interventions:Rabbits were randomly divided into the mild lung injury (surfactant depletion) group or severe lung injury (surfactant depletion followed by injurious mechanical ventilation) group and ventilated with 4-hr low tidal volume ventilation with spontaneous breathing or without spontaneous breathing (prevented by a neuromuscular blocking agent). Inspiratory pressure was adjusted to control tidal volume to 5–7 mL/kg, maintaining a plateau pressure less than 30 cm H2O. Dynamic CT was used to evaluate changes in lung aeration and the regional distribution of tidal volume. Measurements and Results:In mild lung injury, spontaneous breathing improved oxygenation and lung aeration by redistribution of tidal volume to dependent lung regions. However, in severe lung injury, spontaneous breathing caused a significant increase in atelectasis with cyclic collapse. Because of the severity of lung injury, this group had higher plateau pressure and more excessive spontaneous breathing effort, resulting in the highest transpulmonary pressure and the highest driving pressure. Although no improvements in lung aeration were observed, muscle paralysis with severe lung injury resulted in better oxygenation, more even tidal ventilation, and less histological lung injury. Conclusions:In animals with mild lung injury, spontaneous breathing was beneficial to lung recruitment; however, in animals with severe lung injury, spontaneous breathing could worsen lung injury, and muscle paralysis might be more protective for injured lungs by preventing injuriously high transpulmonary pressure and high driving pressure.