High gender -specific susceptibility to curare- a neuromuscular blocking agent

Curare, a selective skeletal muscle relaxant, has been used clinically to reduce shivering and as an anesthetic auxiliary in abdominal surgery. It is also widely used in animal experiments to block neuromuscular junction activity. Effective doses of curare diminish muscle contraction without affecting brain function, but at higher doses it is known to be lethal. However, the exact dose of curare initiating muscle relaxation vs. lethal effect has not been fully characterized in mice. In this study we carefully examined the dose-response for achieving muscle inactivity over lethality in both male and female mice (C57BL6/J). The most striking finding of this study is that female mice were highly susceptible to curare; both the EDm and LDm were at least 3-fold lower than male littermates. This study shows that gender-specific differences can be an important factor when administering skeletal muscle relaxants, particularly curare or other analogous agents targeted to the neuromuscular junction.

The History of Myasthenia Gravis

Since Willis described 'fatigable weakness' in 1672, most physicians consider it as a kind of hysteria due to the inconsistent fluctuation of symptoms. Erb presented three cases of 'bulbal palsy' in the 1870s, and Oppenheim and Hopper considered myasthenia gravis as a disease similar to curare poisoning and as a disease induced by attack of the motor centers by intrinsic toxins, respectively. In 1903, Elliot suggested that a 'chemical substance' mediates the nerve impulses at synapse. However, it was not until 1921 that this was demonstrated by Loewi, who provided evidence from the famous two-frog-hearts experiment. Dale later revealed the substance to be acetylcholine, and he also suggested that myasthenia gravis is due to a problem with the motor end plate. In 1934, Walker was prompted by the resemblance between myasthenia gravis and curare poisoning to apply physostigmine, a curare-poisoning antidote, to a patient, which produced a dramatic result. Since then the use of anticholinesterase inhibitors has been adopted for standard therapeutic modality. Some prominent surgeons have also applied thymectomy as a surgical modality. The most recent focus of myasthenia gravis has been immunological. In 1960, Simpson proposed the autoimmune hypothesis, and Chang et al. showed that snake venom contained a selective antagonist of the nicotinic acetylcholine receptor, alpha-bungarotoxin. The immunization of rabbits with acetylcholine receptor purified from the electrical organs of electric eels by Patrick et al. induced myasthenic symptoms and signs, and these were reversed by acetylcholinesterase inhibitors. The role of the autoimmune system has led to the introduction of an immunosuppressive modality and plasma exchange to the field of clinical neurology.

Neuromuscular Block and Reversal

The Griffith and Johnson's report of the successful use of curare in 1942 brought a revolution in anesthetic care. The only depolarizing agent still in use is succinylcholine due to its rapid onset of action and rapid recovery. However, its use is limited by serious side effects (hyperkalemia, malignant hyperthermia, arrhythmia, etc). New non-depolarizing neuromuscular blocking agents have been studied to replace succinylcholine, which are still at a preclinical level. Rocuronium is an aminosteroid compound and has an intermediate duration of action, but the onset is shorter. A new method of reversing neuromuscular blockade has been advocated by the introduction of a cyclodextrin, sugammadex (Org 25969), which is still at the investigational stage in humans. It has a high affinity for rocuronium, with which it forms a complex. Sugammadex has a lower affinity for other steroidal neuromuscular blocking agents such as vecuronium and pancuronium, and does not bind benzylisoquinoline-type neuromuscular blocking agents. The ability to produce a rapid return of twitch height even at deep levels of paralysis and the lack of side effects make this compound a promising new agent for anesthesia.

Unusual Capnography due to Incorrect Assembly of Spring with Absorber Valve into Breathing Circuit - Experience of Normocarbia: A Case Report / 대한구급학회지

A focus on patient safety has heightened the awareness of pateint mornitoring. The importantce of clinical application of capnography continues to grow, as reflected by the increasing number of medical societies recommending its use. We recently encountered an abnormal capnography undergoing gastrectomy. It was noted that the waveform was not sustained zero-baseline formation as seen during inspiratory phase, immediately upsloping for expiratory plateau followed by inspiratoy downsloping as like a shape of curare cleft. But PaCO2 was within normal range. We found that the source of the problem was the incorrect (bottom up) assembly of spring with absorber valve into the CUBE, the circle breathing system of Dameca Ventilator. Spring with absorber valve divides CUBE circle into inspiratory and expiratory space. We concluded that the unusual capnography was resulted from the incorrect assembly of it, subsequently mixing of inspiratory and exhaled gases and rebreathing was occurred with the block of a gas flow to CO2 canister. After correcting assembly, the capnography was normalized.

Empleo del curare como cebado del atracurio / Employ of curare how atracurium priming

Veintitrés pacientes ASA I y II a quienes se les practicaría cirugía electiva y además estaba indicado el uso de relajantes musculares no despolarizantes e intubación traqueal, los cuales se anestesiaron con Enflurano (1 CAM espiratotio), fueron asignados aleatoriamente para recibir, bien 250 ug/kg de Atracurio en forma de Bolus ó 50 ug/kg de d'Tubocurarina tres minutos antes de 150 ug/kg de Atracurio. El tiempo necesario para alcanzar un bloqueo del 80 por ciento fue significativamente menor en el grupo cebado con curare (p<0,001), esta droga también potencia el máximo efecto del Atracurio (p<0.01) y acorta el tiempo para lograrlo (p<0.001). El cebado en esta experiencia enlentece los índices de recuperación (no significativamente) y prolonga la duración de su efecto clínico (p<0,01). Se notó una tendencia a mejorar las condiciones para la intubación en este grupo cebado

Direct negative chronotropic and inotropic efects of curare on isolated and perfused frog's heart

It has been stated that curare has no direct effect upon the heart because the cardiac muscle is deprived of nicotine receptors. While performing an experimental work, we noticed that when high doses of curare were administered to frogs, a change in cardiac activity occurred. In order to elucidate whether the cardiac effects of curare wee the results of a direct action or a reflex response, we studie the effects of increasing doses of d-tubocurarine on the rate and contractility of 8 isolated and perfused frogs'hearts. After testing the d-tubocurarine effects on the heart rate and contractility, we added either acetylcholine, atropine, atenonol or verapamil in orden to find out whether any change ocurred in the cardiac effects produced byd-tubocurarine. Thirty seven measurements were carriet out and it wasfound that 1) high doses (between 1 and 15 micrograms) of d-tubocurarine produced a highly significant decrease in heart rate an contractility; 2) d-tubocurarine did not avoid the acetycholine effect; 3) atropine, atenonol and verapamil did not interfere with d-tubocurarine effects. We conclude that high doses of d-tubocurarine produce "dosis-dependent" heart rate and contratility reductions. These effects are not mediated by muscarinic receptors beta-1 receptors or the show calcium channels

Does the " Curare Cleft " on the Capnogram always mean that the Patient is in Need of Relaxant ? / 대한마취과학회지

A fifty-eight years old male patient was given general anesthesia for the clipping of aneurysm on the posterior communicating artery. The respiration of the patient was controlled with Ohmeda 7000 anesthesia ventilator. During the surgery there appeared curare cleft on the capnogram which did not disappear after the administration of neuromuscular blocker, but disappeared after the change of the anesthesia ventilator with another one. After that another curare cleft was made by the transient obstruction of the outlet of the excess patient circuit gas of the new anesthesia ventilator. It may be said that inappropriately functioning pop-off valve of the anesthesia ventilator can be one of the causes of curare cleft on the capnogram.

Regional curare test in the study of neuromuscular transmission in hyperthyroidism.

The findings in this study suggest that there is defect in the neuromuscular transmission in hyperthyroidism. This abnormality was detected in 62 per cent of the patients and did not directly correlate with proximal muscle weakness present in most of the patients. It seems that the weakness in hyperthyroidism is the result of myopathy as well as neuromuscular transmission both of which might be due to the same metabolic derangement but are not directly related. After treatment, the muscle power became normal in all of the patients and the neuromuscular transmission was normalized in most but not all of them. It is possible that this transmission defect may be due to other mechanisms apart from the hormonal disorder e.g. the same processes as that which occurs in myasthenia gravis. The underlying pathophysiology is worth further exploration.

A Study of Succinylcholine Dose Response Using Isolated Arm Test / 대한마취과학회지

Succinylcholine is still widespread use, despite the lack of understanding of the mechanisms of its action at the neuromuscular junetion. It is assumed that succinylcholine acts exclusively on the post-junctional structure of the neuromuscular junction, phase I block, but after administration of additional large doses, this phase I block is followed by the appearance of phaae II block, curare like. These phase I and II block are purely descriptive terms and do not imply a mechanism of action. Not only would administration of repeat of large doses of succinylcholine for study in vivo be dangerous but objective measurement of their effect can be difficult to interpret. Therefore, the present study was designed to determine succinylcholine doses response relationships for the incremental bolus and its divided doses using isolated arm test which is isolated from systemic circulation appling tourniquet on upper arm and using small dose of muscle relaxant safely, and measuring the force of contraction of adductor pollicis with Accelograph under the enflurane and 50% N2O anesthesia. The tourniquet was kept inflated for 4 minutes to allow retrograde spread of some of the succinylcholine into the capillary bed where neuromuscular block was established. At the end of 4 minutes, the tourniquet was released and the interpretation of twitch response was started: 1. The incremental doses of succinylcholine induced significantly prolongation of duration (p< 0.005) but no significant different in recovery index. 2. TOF ratio runs down definitely from over 40 mg incremental doses with bolus injection and more in divided doses than bolus. 3) The relationship between incremental doses and TOF ratio decreasing was statistically signifi-cant (y=-0.49x+84.5, r= 0.65, p<0.005)

A Study of Succinylcholine Dose Response Using Isolated Arm Test / 대한마취과학회지

Succinylcholine is still widespread use, despite the lack of understanding of the mechanisms of its action at the neuromuscular junetion. It is assumed that succinylcholine acts exclusively on the post-junctional structure of the neuromuscular junction, phase I block, but after administration of additional large doses, this phase I block is followed by the appearance of phaae II block, curare like. These phase I and II block are purely descriptive terms and do not imply a mechanism of action. Not only would administration of repeat of large doses of succinylcholine for study in vivo be dangerous but objective measurement of their effect can be difficult to interpret. Therefore, the present study was designed to determine succinylcholine doses response relationships for the incremental bolus and its divided doses using isolated arm test which is isolated from systemic circulation appling tourniquet on upper arm and using small dose of muscle relaxant safely, and measuring the force of contraction of adductor pollicis with Accelograph under the enflurane and 50% N2O anesthesia. The tourniquet was kept inflated for 4 minutes to allow retrograde spread of some of the succinylcholine into the capillary bed where neuromuscular block was established. At the end of 4 minutes, the tourniquet was released and the interpretation of twitch response was started: 1. The incremental doses of succinylcholine induced significantly prolongation of duration (p< 0.005) but no significant different in recovery index. 2. TOF ratio runs down definitely from over 40 mg incremental doses with bolus injection and more in divided doses than bolus. 3) The relationship between incremental doses and TOF ratio decreasing was statistically signifi-cant (y=-0.49x+84.5, r= 0.65, p<0.005)

Control of Intraoeular Pressure by Intravenous Lidocaine Pretreatment / 대한마취과학회지

It is a known fact that the increase of intraocular pressure results from the action of succinylcholine, endotracheal stimulation to carina, bucking and coughing etc during the induction arid recovery periods. Efforts have been made by several inveatigators to prevent intraocular hypertension by giving trimetaphan, inderal or curare. However, their effects were not remarkable. In this study, lidocaine Img/tg was administered intravenously to selectee patients 2-3 minutes hefore induction ; followed by regular induction with pentothal, succinylcholine and incubation. Intraocular pressures were measured at the pre-induction and post-intutation time, and every 30 minutes until the early recovery period, thereafter. The result of this study showed that the post-intubational increase of intraocular pressure was prevented in 86.7% of the lidocaine pretreated cases. The increase of post-extuba-tional intraocular pressure was also reduced significantly in the lidocaine pretreated group-as well. We came to the conclusion that lidocaine pretreatment technic can be used effectively to prevent intraocular hyperteilsion caused by induction and extubation in clinical practice.

Isolation of [+] -tubocurarine and an unknown alkaloid from curare resin by a new chromatographic technique

This paper describes a new TLC method which gives an excellant resolution of the 12 alkaloids present in curare resin. The method is simple, suitable for isolation of [+]-tubocurarine alkaloid and the interferred unknown alkaloid in commercial curare resin. The unidentified laevorotatory alkaloid gives rise to particular problems in the production of pure d-tubocurarine chloride as it interferes in the crystallization process of d-tubocurarine. Pure crystalline [+]-tubocurarine and the unidentified alkaloid can be prepared by this method. It is also suitable for control analysis of commercial curare resin and [+]-tubocurarine chloride alkaloid

nature of acetylcholine receptor

The present work with consideration to the autoradiographic pictures, suggests that cholinergic receptors are located at the gate of a channel originating from synaptic cleft coming to lie within the muscle fibre. ACHE molecules stand at the gate of this channel;controlling the entrance of different cholinergic agents. It was reported previously that dtc molecules stabilize the ACHE molecules and will obstruct the gate. This blocks the acess of ionic flux within the channel thus producing a non-depolarizing neuromuscular paralysis.The presented experiments imply that depolarizing agent will bring a considerable change in conformation of ACHE molecule and this causes the opening of the gate allowing ionic flux and depolarization .In case of ACh this process is repeated in a fraction of milli second, due to rapid regeneration of AChE while in case of suxamethonium and neostigmine [given in high dose], the regeneration of AChE takes much longer time thus will produce a depolarizing blockade. In this hypothesis the main responsability of AChE is confined to identification of cholinergic agents and cooperation in their function so, it can be accepted as cholinergic receptor. In regard to clinic, this work suggests that only the use of minimum effective dose of neostigmine is advisable fin reversing curarisation. In contrast to general belief the dose of neostigmine should be selected in relation to receptor dtc occupation and not depending on patient's weight. As it was demonstrated the early use of high dose of neostigmine may also potentiate curarisation

Jackson Rees Technique for Pediatric Anesthesia (1235 Cases) / 대한마취과학회지

The Jackson Rees technique has become increasingly popular in pediatric anesthesia. This article presents an original Jackson Rees technique that we have used on 1235 cases for the past 7 years, and which is known as Pentothal-Curare-Hyperventilation technique or the Liverpool technique because of its origin and agents used. Technique 1) Atropine and demerol generally are given as premedication but atropine is only given in the newborn baby. 2) Patients are given pentothal 4mg/kg to sleep. 3) A dose of curare 0.6mg/kg is administered to paralyse and the patient is intubated with an appropriate size tube. 4) The patient is hyperventilated with three times the minute volume of N2O/O2 in a 1:2 ratio using a Jackson Rees modification unit. 5) At the end of surgery N2O is discontinued and curare is reversed with prostigmine 0.1mg/kg and atropine 0.03mg/kg. As a result of our experience this technique has been considered to be a very satisfactory technique in all fields of pediatric andsthesia. The advantages and controverses are discussed.