A proposed mechanism for amitriptyline neurotoxicity based on its detergent nature.

Although amitriptyline has gained attention as a potent local anesthetic, recent animal studies showed that it can cause irreversible neural impairment. We hypothesized that nerve membrane disruption caused by solubilization, a common detergent property, accounted for amitriptyline neurotoxicity. We used a two-phase approach to test our hypothesis. Firstly, we determined (1) the molecular aggregation concentration of amitriptyline, (2) the concentration of amitriptyline that disrupts artificial lipid membranes and (3) the concentration of amitriptyline that causes hemolysis. Secondly, we compared these levels with neurotoxic concentrations determined from assessment in a rat model of spinal anesthesia using changes in cutaneous stimulus threshold (CST). Amitriptyline concentrations that caused molecular aggregation, model membrane disruption and hemolysis were 0.46%, 0.35% and 0.3%, respectively. Animal study showed a significant increase in CST at >or=0.3% of amitriptyline, indicating neurological impairment. Since amitriptyline caused model membrane disruption and hemolysis at the molecular aggregation concentration, solubilization plays a role in the destruction of artificial membranes and erythrocytes. Furthermore, these concentrations are also in good agreement with the minimum concentration causing neurological injury. Therefore, while additional studies, including histopathology, are necessary to clarify this observation, amitriptyline neurotoxicity appears to be associated with its detergent nature.

Primary palmar hyperhidrosis locus maps to 14q11.2-q13.

Primary palmar hyperhidrosis (PPH) is a unique disorder of unknown cause. It is characterized by excessive perspiration of the eccrine sweat gland in the palm, sole, and the axilla. It is presumed that PPH results from overactivation of the cholinergic sympathetic nerve or dysfunction of the autonomic nervous system. There have been no genetic studies on the disease. We performed a linkage analysis of 11 families including 42 affected and 40 unaffected members using genome-wide DNA polymorphic markers to identify the disease locus. Diagnosis of their PPH was made by direct inspection, interviewing and measurement of the sweating rate with perspirometer. Consequently, from data of three of the 11 families examined, the combined maximum two-point LOD scores of 3.08 and 3.16 (recombination fraction = 0) were obtained at the D14S283 and D14S264 loci, respectively, on chromosome 14q11.2-q13, under an assumption that two liability conditions depend on age. These regions were ruled out in eight other families. Haplotype analysis of the three families supported that one of the PPH locus is assigned at minimum to about a 6-cM interval between D14S1070 and D14S990 and at maximum to about a 30-cM interval between D14S1070 and D14S70. This is the first report of systemic mapping of the PPH locus.

Tramadol produces outward currents by activating mu-opioid receptors in adult rat substantia gelatinosa neurones.

1. An action of a tramadol metabolite, mono-O-dimethyl-tramadol (M1), on substantia gelatinosa (SG) neurones in adult rat spinal cord slices was examined by using the whole-cell patch-clamp technique. 2. In 41% of the neurones examined, superfusing M1 produced an outward current at -70 mV; this response reversed at a potential close to the equilibrium potential for K(+). M1 current hardly declined and persisted for >30 min after its washout. 3. M1 current correlated in amplitude with current produced by mu-opioid receptor agonist DAMGO in the same neurone, and largely reduced in amplitude in the presence of mu-opioid receptor antagonist CTAP but not alpha2-adrenoceptor antagonist yohimbine. In a neurone where M1 had no effect on holding currents, noradrenaline produced an outward current at -70 mV. 4. The amplitude of the M1 response, relative to that of the DAMGO response, exhibited an EC(50) value of 300 microM. 5. We conclude that M1 produces a persistent hyperpolarization by activating mu-opioid receptors in adult rat SG neurones. This could contribute to at least a part of pain alleviation produced by tramadol.

[Anesthetic management of combined lung volume reduction surgery and off-pump coronary artery bypass grafting].

A 54-year-old man with severe emphysema and stenosis of coronary artery was scheduled for combined surgery of lung volume reduction and an off-pump coronary artery bypass grafting. His FEV1.0 was 600 ml and %FEV1.0 was 18%. Coronary angiography showed 99% stenosis of the left anterior descending artery. Anesthesia was induced with propofol, fentanyl and vecuronium, and was maintained with sevoflurane and continuous epidural anesthesia. In order to avoid high airway pressure, a pressure-controlled ventilation (less than 15 cmH2O) was carried out. A laryngeal mask airway was replaced with an endotracheal tube after surgery to avoid bucking during extubation, and this was removed after recovery from anesthesia successfully. No complications were observed during anesthesia. Lung volume reduction surgery after coronary reconstruction by off-pump coronary artery bypass grafting may be beneficial for patients with emphysema and ischemic heart disease.

Quantitative and fiber-selective evaluation of dose-dependent nerve blockade by intrathecal lidocaine in rats.

We investigated whether cutaneous stimulus threshold (CST), as determined using a Neurometer, could be used for quantitative and differential nerve evaluation of reversible and irreversible nerve block following intrathecal lidocaine administration in rats. Rats with intrathecal catheters were randomly assigned to one of five groups (saline or 2, 5, 10, or 20% lidocaine). Prior to and 4 days after drug administration, CST was determined at 5, 250, and 2000 Hz. In the 2% lidocaine group, CST from end of lidocaine infusion to recovery from anesthesia was also monitored. Skin-clamp testing and gait observation were performed for comparison with CST findings. Behavioral examinations revealed persistent sensory or motor impairment lasting 4 days in groups receiving >/=5% lidocaine but not in the saline and 2% lidocaine groups. With 2% lidocaine, return to baseline CSTs at 5 and 250 Hz was delayed compared with thresholds at 2000 Hz. Although CSTs in the 5% group at 5 and 250 Hz increased significantly, thresholds at 2000 Hz did not differ from those in rats administered saline. CSTs with >/=10% lidocaine displayed no differences between frequencies. At each frequency, CSTs for rats with >/=5% lidocaine increased in a clearly concentration-dependent manner. These results suggest that CST testing enables evaluation of the different nerve functions for Abeta, Adelta, and C fibers in rats for lidocaine concentrations

Proper shoulder position for subclavian venipuncture: a prospective randomized clinical trial and anatomical perspectives using multislice computed tomography.

BACKGROUND: Although the Trendelenburg position and shoulder bracing are recommended for safe subclavian venipuncture, the optimal shoulder position remains unclear. The current study observed spatial relations between the subclavian vein and surrounding structures using multislice computed tomography to determine optimal shoulder position for safe subclavian venipuncture and then conducted a small follow-up clinical trial to confirm these findings. METHODS: Thoracic multislice computed tomography was performed for seven adult volunteers at three shoulder positions: elevated (up); neutral; and lowered caudally (down). Overlap and distance between the clavicle and the subclavian vein and the diameter of the subclavian vein were measured. Anatomical relations between the subclavian artery and vein were also observed. The success rate for subclavian venipuncture was then compared between the up and down shoulder positions in 30 patients. RESULTS: In the multislice computed tomography study, the mean overlap ratios between clavicle and subclavian vein in the up, neutral, and down positions were 33.5, 36.9, and 40.0%, respectively. Overlap increased with lower shoulder position (up < neutral < down; P < 0.05). The mean distances between the clavicle and the subclavian vein in the up, neutral, and down positions were 6.8, 5.0, and 3.6 mm, respectively. Again, distance decreased with lower shoulder position (up < neutral < down; P < 0.05). The diameter of the subclavian vein did not differ among the three shoulder positions. The success rate for subclavian venipuncture was significantly higher in the down position compared with the up position (P = 0.003). CONCLUSIONS: Lowered shoulder position increases both overlap and proximity between the clavicle and the subclavian vein, producing a more constant relation between the clavicle and the subclavian vein, without affecting vein diameter. Proper use of a lowered shoulder position should thus increase the safety and reliability of subclavian venipuncture compared with other shoulder positions.

Neurological evaluation by intraoperative wake-up during carotid endarterectomy under general anesthesia.

Although general anesthesia allows relief from stressors such as pain, discomfort, or anxiety for patients undergoing carotid endarterectomy, neurologic assessment is less reliable than under local anesthesia. We describe a unique anesthetic management strategy for carotid endarterectomy patients incorporating the advantages of both general and local anesthesia. The technique allows thorough assessment of neurologic function during carotid cross-clamping by intraoperative wake-up, and guarantees airway management by tracheal intubation.

NOS II inhibition restores attenuation of endothelium-dependent hyperpolarization in rat mesenteric artery exposed to lipopolysaccharide.

The aim of this study was to assess the effects of lipopolysaccharide (LPS) exposure on the endothelium-dependent hyperpolarization in the rat mesenteric artery using isometric tension recordings and electrophysiological studies. Mesenteric arterial rings of male Sprague-Dawley rats were incubated with LPS for 6 hours. All experiments were performed in the presence of indomethacin to inhibit the formation of vasoactive prostanoids. Contraction to phenylephrine was significantly reduced in rings incubated with LPS, which was restored in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). L-NAME resistant relaxation to acetylcholine was attenuated in LPS-treated rings. LPS exposure hyperpolarized resting membrane potentials of arterial smooth muscle cells, which was repolarized by incubation with either L-NAME or 1400W, a selective inhibitor of nitric oxide synthase II (NOS II). Endothelium-dependent hyperpolarization to acetylcholine was attenuated in arteries incubated with LPS, while incubation with LPS and 1400W restored EDHF-mediated hyperpolarization. LPS-induced membrane potential change was mimicked by incubation with either SIN-1 or diethylamine NONOate, a donor of nitric oxide. These data suggest that LPS exposure attenuates EDHF-mediated both relaxation and hyperpolarization in the rat mesenteric artery. The possible mechanisms underlying decreased EDHF-mediated responses might be due to, at least in some part, massive nitric oxide induced by NOS II.

Possible mechanism of irreversible nerve injury caused by local anesthetics: detergent properties of local anesthetics and membrane disruption.

BACKGROUND: Irreversible nerve injury may result from neural membrane lysis due to the detergent properties of local anesthetics. This study aimed to investigate whether local anesthetics display the same properties as detergents and whether they disrupt the model membrane at high concentrations. METHODS: Concentrations at which dodecyltrimethylammonium chloride and four local anesthetic (dibucaine, tetracaine, lidocaine, and procaine) molecules exhibit self-aggregation in aqueous solutions were measured using an anesthetic cation-sensitive electrode. Light-scattering measurements in a model membrane solution were also performed at increasing drug concentrations. The concentration at which drugs caused membrane disruption was determined as the point at which scattering intensity decreased. Osmotic pressures of anesthetic agents at these concentrations were also determined. RESULTS: Concentrations of dodecyltrimethylammonium chloride, dibucaine, tetracaine, lidocaine, and procaine at which aggregation occurred were 0.15, 0.6, 1.1, 5.3, and 7.6%, respectively. Drug concentrations causing membrane disruption were 0.09% (dodecyltrimethylammonium chloride), 0.5% (dibucaine), 1.0% (tetracaine), 5.0% (lidocaine), 10.2% (procaine), and 20% (glucose), and osmotic pressures at these concentrations were 278, 293, 329, 581, 728, and 1,868 mOsm/kg H2O, respectively. CONCLUSIONS: These results show that all four local anesthetics form molecular aggregations in the same manner as dodecyltrimethylammonium chloride, a common surfactant. At osmotic pressures insufficient to affect the membrane, local anesthetics caused membrane disruption at the same concentrations at which molecular aggregation occurred. This shows that disruption of the model membrane results from the detergent nature of local anesthetics. Nerve membrane solubilization by highly concentrated local anesthetics may cause irreversible neural injury.

Lidocaine spray used to capture a live Clinostomum parasite causing human laryngitis.

This case report describes a patient who developed Clinostomum laryngitis after eating raw fresh-water fish. Parasite removal was performed under general anesthesia using a laryngomicroscopic method. Because it was difficult to capture the worm intact using forceps, it was sprayed with 8% lidocaine solution. This immediately inhibited peristaltic movement of the parasite allowing easy retrieval without tearing any part of the organism, thus facilitating parasite identification.

[Survey Report on International Cooperation 2001--report of the Japanese Society of Anesthesiologists Committee on International Affairs].

A survey was conducted in November 2001 with a questionnaire entitled "Survey Report on International Cooperation" compiled by the International Affairs of the Japanese Society of Anesthesiologists (JSA). The survey focused on member awareness of the importance of international cooperation by sending the questionnaire to its entire membership. Replies were received from approximately 15.6% of the membership or, to be exact, 1,353 JSA members. The survey produced several remarkable findings, which are as follows: 57.8% of the respondents are interested in international cooperation, 86.8% regard international cooperation as necessary, and 38.4% are willing to participate in international cooperation. Those who have actually engaged in international cooperation in the past account for only 7.5%, indicating that there are a good number of members who have not had a chance to provide assistance in international cooperation, their willingness notwithstanding. Regarding their employers' levels of understanding of this issue, 30.6% responded that their managements either recommend active participation or approve of the respondents' intention. Another 24.9% replied that their managements agreed to their participation on condition that they do so privately. Thus, a total of 55.5% of the respondents have permission to participate in international cooperation. Regarding the level of understanding from family members, 41.2% replied that their families agree to their desire irrespective of whether or not their services overseas are relevant to their profession. This figure became 72.4% when their services abroad would be relevant to their profession. On the other hand, 16.0% of the respondents (216 members) stated that they have no interest in international cooperation. For the reasons, 38.8% replied that the issue cannot be viewed as a matter worthy of immediate attention, 10.2% replied that it is not their problem, and 24.1% replied that this will involve dangers. When questioned about their overall impressions from actual participation in international cooperation in the past, among the 102 members responding, 88.2% said they are satisfied with what they have done, 4.9% were undecided as to whether or not they are satisfied, while none of them responded negatively about their services. Of those who are satisfied with their services, as many as 54.4% found their services "worthy of the time spent because of all the excitement involved and because each activity involved work other than their own profession," and 40.0% found them "worthy of their time and labor." Particularly noteworthy is the fact that 6.7% now consider activities in international cooperation "their divinely appointed work in life," and 65.7% hope to participate in international cooperation again. From these findings, it can be deduced that there are few obstacles to the members' international cooperation and that JSA's potential as a promoter of international cooperation may be highly estimated.

Detection of acetazolamide-induced increase in organ blood flow in rabbits by laser flowmetry.

PURPOSE: We investigated the mechanism by which inhibition of carbonic anhydrase (CA) increases organ blood flow. METHODS: Regional blood flow (rBF) in white rabbits anesthetized with ketamine/urethane was measured in the kidney, liver, stomach wall, and abdominal muscle by means of laser blood flow probes. Data obtained from rabbits receiving acetazolamide (AZ) to inhibit CA were compared with those obtained from rabbits ventilated with air containing increased concentrations of CO2. RESULTS: Systolic blood pressure, body temperature, hemoglobin, and base excess were unaffected by either treatment. Inhalation of CO2 increased blood flow in all organs tested as well as the cardiac output and PCO2 but decreased pH. Inhibition of CA by AZ administration increased the rBF only in the liver and kidney and did not increase cardiac output or decrease pH. CONCLUSION: Administration of AZ increased rBF in the tissues and organs that contained large amounts of CA without increasing the cardiac output or decreasing the pH, which suggests a direct local effect. A differential sensitivity to the retention of CO2 is suggested as a possible mechanism of the selectivity of the increase in rBF.

Cutaneous distribution of sympathetic postganglionic fibers from stellate ganglion: A retrograde axonal tracing study using wheat germ agglutinin conjugated with horseradish peroxidase.

Sympathetic postganglionic cells of the stellate ganglion (SG) projecting to the skin in young dogs were labeled retrogradely with wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP). After application of WGA-HRP into the dermis and/or subcutaneous tissue of the upper extremity, numerous labeled cells were observed in the SG. The sympathetic postganglionic fibers from the SG were distributed in the skin area between the third cervical vertebra and the level of the thirteenth rib. These fibers decreased in number toward the rostral and caudal skin area with a peak on the upper extremity. Sympathetic postganglionic cells in the SG projecting to these skin areas were found ipsilaterally to the injection side. No labeled cells were observed in the SG after injecting WGA-HRP into the epidermis and/or subcutaneous tissue of the face, the level of the second cervical vertebra, and the lower extremity.Sympathetic postganglionic neurons of the SG which project in the cervical and thoracic sympathetic trunks were labeled retrogradely with unconjugated horseradish peroxidase (HRP) applied to the cut end of the sympathetic trunks proximal to the SG. The application was made in the cervical sympathetic trunk (CST) caudal to the superior cervical ganglion (SCG). In the thoracic sympathetic trunk (TST), the application was made between the fourth and fifth thoracic sympathetic ganglia (T4 and T5), and between T10 and T11. Labeled cell bodies were observed in SG bilaterally.

Anterior spinal artery syndrome--a complication of cervical intrathecal phenol injection.

Spinal nerve block by intrathecal phenol-glycerine infusion is commonly employed for relief of severe pain in terminal carcinomatosis and, frequently, a dramatic regional anesthetic effect is achieved. However, nerve block by this procedure may in very rare instances give rise to serious complications. We have seen a case of terminal malignant melanoma in which clinical manifestations, indicative of anterior spinal artery syndrome, developed following the injection of 0.3 ml of 10% phenol-glycerine into the cervical subarachnoid space at the C4--C5 level for the control of severe right arm pain. This report describes the clinical course of the patient over a period of 4 months after the nerve block and the post-mortem findings along with a brief review of the literature.