Change in jaw occlusive power by paralysis of masseter muscle with a neuromuscular blocker: Sion's masseter muscle paralysis.

STUDY OBJECTIVE: We aimed to determine whether jaw occlusive power decreases with the injection of neuromuscular blocking agents in masseter muscle - a method we named Sion's masseter muscle paralysis (SMP). METHODS: A randomized, placebo-controlled animal study was conducted in which researchers were blinded to group allocation. We used 12 male mongrel dogs aged 10-12 months and weighing 30-35 kg. Four groups were formed: a conventional dose (CD) group (0.004 mg/kg succinylcholine in 4 ml normal saline [NS]); a high dose (HD) group (0.04 mg/kg succinylcholine in 4 ml NS); a placebo group (4 ml NS); and no intervention group. To measure the jaw occlusive power, 1 kg weight was hung sequentially on a specifically designed device on the animal's lower jaw. At -4, -2, 0', +2, +4, +6, +8, +10, +20, and +30 min, we measured the jaw occlusive power, oxygen saturation (SpO2), and end-tidal carbon dioxide (ETCO2). RESULTS: After SMP, jaw occlusive power began to decline in CD and HD group. The arithmetical mean jaw occlusive power values at -4, -2, 0', +2, +4, +6, +8, and +10 min were 9.7, 9.7, 9.7, 8.7, 8.3, 7.3, 6.7, and 6.3 kgw in the CD group and 9.7, 9.3, 8.7, 8.0, 6.7, 5.0, 5.0, and 5.3 kgw in the HD group. No abnormalities in SpO2or ETCO2were detected. CONCLUSION: Jaw occlusive power was decreased after SMP with succinylcholine, without inducing respiratory complication.

The Place of Erythroidines in the History of Neuromuscular Blockers.

Between 1938 and 1951 erythroidine derivatives were seriously considered as alternatives to curare for the provision of muscle relaxation. This has been overlooked in the published history of anaesthesia. The first publication on the paralysing effect of an extract of Erythrina americana was in 1877, but this was in a Mexican journal, which was not widely read. Sixty years later erythroidine was isolated, and in 1938 it was first used clinically to treat spastic dystonia, preceding the use of Intocostrin for this purpose. By 1943 dihydro-ß-erythroidine was prepared in crystalline form, which was equipotent with curarine and of acceptable duration; it was used in clinical anaesthesia in 1946. In the 1940s curare was presented in solutions with potency stated in units, determined by bioassay, which was a disadvantage compared with the straightforward mg of dihydro-ß-erythroidine. However, by the early 1950s, improvement in the pharmaceutical presentation of d-tubocurarine and new neuromuscular blockers, displaced the erythroidines.

Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Structure-activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by L-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program. METHODS: Adduction of CW 1759-50 with L-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee-approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by L-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared. RESULTS: The half-time of adduction of L-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of L-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% Δ [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium. CONCLUSIONS: CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by L-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.

Mechanism of Rhinella icterica (Spix, 1824) toad poisoning using in vitro neurobiological preparations.

The biological activity of Rhinella icterica toxic secretion (RITS) was evaluated on chick neuromuscular junctions, rat heart́s tissue and mice hippocampal slices. At chick biventer cervicis preparation, RITS (5, 10 and 20µg/mL) produced a concentration-independent irreversible neuromuscular blockade, which was preceded by a transitory increase of muscle twitch tension with the lowest concentration, in 120min recordings. In this set of experiments, RITS incubation partially prevented the curare neuromuscular blockade. The assessment of chick biventer cervicis muscle acetylcholinesterase (AChE) in the presence of RITS showed a significant inhibition of the enzyme, similarly to neostigmine. The incubation of muscles with digoxin or ouabain mimicked the poison activity by increasing the amplitude of the twitches followed by a progressive depression of the muscle strength. In addition, RITS demonstrated a digitalic-like activity, by inhibiting significantly the cardiac Na+, K+-ATPase. When the central nervous system was accessed, RITS induced an increase in the cell viability, in the lowest concentration. In addition, the poison protected slices subject to oxygen/glucose deprivation. Altogether, these data indicate that the poisonous extract of R. icterica is able to interfere with peripheral and central neurotransmission, probably due to a direct interaction with AChE, calcium channels and Na+, K+-ATPase. A further investigation upon the poison toxic components will unveil the components involved in such a pharmacological activity and the potential biotechnological application of this poison.

The effect of general anaesthesia and neuromuscular blockade on Eustachian tube compliance: a prospective study.

OBJECTIVE: The most common complications of hyperbaric oxygen treatment (HBOT) are related to pressure changes on gas-containing cavities. Therefore, inability to auto-inflate the middle ear may result in transient or permanent hearing loss. However, it seems that middle ear barotrauma (MEBt) does not develop more often in mechanically ventilated patients than in ambulatory patients. This might be explained by deep sedation of these patients. Therefore, the aim of this study was to determine whether anaesthesia and/or neuromuscular blockade can influence Eustachian tube (ET) function. METHODS: Forty patients who were undergoing surgery under general anaesthesia were enrolled in this prospective study. ET function was evaluated by tympanography performed three times: before induction of general anaesthesia (baseline), after induction with sufentanyl/propofol and after full blockade was achieved with a long-acting neuromuscular blocking agent. RESULTS: There were no differences in ear volume (P = 0.19) and ear pressure (P = 0.07). There was a significant variation in compliance on tympanography after the induction of general anaesthesia (P = 0.009). Compared to the baseline, this variation was characterized by an increase after induction of anaesthesia (24 ± 7.13%, P 〈 0.01) and neuromuscular blockade (23 ± 8.9%, P 〈 0.05). The difference between after induction and after neuromuscular blockade was not statistically significant (P = 0.13). DISCUSSION: The findings of this trial suggest that the administration of hypnotic drugs associated with opioids improves ET compliance. Therefore it may have favourable prophylactic effects on MEBt in ventilated intensive care unit patients scheduled for HBOT.

Pancuronium enhances isoflurane anesthesia in rats via inhibition of cerebral nicotinic acetylcholine receptors.

PURPOSE: This study was conducted to elucidate the mechanism of enhancement of volatile anesthetics by neuromuscular blocking agents in rats and to consider the relevance of this enhancement to clinical anesthesia. METHODS: Male Sprague-Dawley rats were used. After confirming a movement in response to tail clamping under 1.1 % isoflurane anesthesia, response was determined when the tail clamp was applied at several points after microinjection of pancuronium into the lateral ventricle. Arousal responses to microinjection of nicotine into the lateral ventricle were assessed with or without pretreatment with intraventricular pancuronium. The intravenous 50 % effective dose (ED50) and 95 % effective dose (ED95) for neuromuscular blockade with pancuronium administered in a cumulative fashion at 1.1 % isoflurane were calculated. RESULTS: Intraventricular pancuronium dose-dependently reduced the response to tail clamping, and the dose required to show immobilization of 50 % of rats (intraventricular ED50) was 1.62 µg/kg. Pretreatment with pancuronium at 6 µg/kg significantly reduced the effect of awakening by nicotine under isoflurane anesthesia (P = 0.044). The intravenous ED50 and ED95 for neuromuscular blockade were 63 µg/kg (90 % confidence interval [CI] 52-75 µg/kg) and 133 µg/kg (90 % CI 109-158 µg/kg), respectively. The ratio of intraventricular ED50 to intravenous ED50 was 0.026. CONCLUSION: Pancuronium microinjection into the lateral ventricle dose-dependently enhances the depth of isoflurane anesthesia, which might be caused by inhibition of neuronal nicotinic acetylcholine receptor transmission in the cerebrum. Intravenous injection of pancuronium at high doses might increase the cerebrospinal concentration to a level at which an effect can be observed.

Purification and partial characterization of a novel neurotoxic protein from eggs of black widow spiders (Latrodectus tredecimguttatus).

Up to now, there have been a few reports on the toxic components purified from black widow spider (Latrodectus tredecimguttatus) eggs. In the present study, a novel neurotoxic protein was purified from the eggs by gel filtration combined with ion-exchange chromatography. Its molecular weight was 23.752 kDa determined by electrospray mass spectrometry. The protein could block the neuromuscular transmission in mouse-isolated phrenic nerve-hemidiaphragm preparations completely in a reversible manner and activate tetrodotoxin-sensitive sodium current in rat dorsal root ganglion cells. The N-terminal sequence of the protein was identified by the Edman degradation to be N-S-I-A-D-D-R-Y-R-W-P-G-Y-P-G-A-G-L-I-P-Y-I-I-D-S-. When the sequence was used to search against protein database with a sequence query in Mascot engine there was no matched sequence or protein whereas the Basic Local Alignment Search Tool (BLAST) analysis indicated that no significant similarity was found. These results demonstrated that the protein (named Latroeggtoxin-I) is a novel neurotoxic protein purified from the eggs of black widow spiders.

Relaxant effects of Artemisia ludoviciana on isolated rat smooth muscle tissues.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia ludoviciana spp. mexicana (Willd. Ex.) Spring D.D. Keck (Asteraceae), known as "estafiate" is employed for the treatment of diarrhea, dysentery, parasites, abdominal pain, vomiting, stomach ache, and also as antispasmodic agent. The aim of the present study was to evaluate the relaxant effect of hexanic (HEAl), dichloromethanic (DEAl) and methanolic (MEAl) extracts on isolated trachea, ileum and aorta rat rings, and to establish the tracheo-relaxant mode of action of DEAl. MATERIALS AND METHODS: All extracts were investigated based on their capacity of to inhibit the rat ileum spontaneous contraction, to relax contraction induced by noradrenaline (0.1 µM) on endothelium-intact and endothelium-denuded thoracic aorta rat rings, and also to inhibit contraction provoked by carbachol (1 µM) on rat trachea. RESULTS: Organic extracts had no spasmolytic action on ileum strips compared to positive control (papaverine, p<0.05). On the other hand, all extracts induced a significant concentration- and partial endothelium-dependent vasorelaxant activity. Extracts also showed significant relaxant effect on pre-contracted tracheal tissue in a concentration-dependent manner. In last two experiments, DEAl was the most potent and efficient extract; however, it was less potent than papaverine and theophylline, used as positive controls (p<0.05). In tracheal preparation, DEAl shifted to the right, in a parallel manner, the concentration-response curves induced by carbachol (p<0.05). Also, DEAl induced a significant relaxant effect on the contraction produced by potassium chloride (KCl, 80 mM). Pre-incubation with 1-H-[1,2,4]-oxadiazolo-[4,3a]-quinoxalin-1-one (ODQ, 10 µM), indomethacin (10 µM), N(ω)-nitro-L-arginine methyl ester (L-NAME, 10 µM), glibenclamide (10 µM) and 2-aminopyridine (2-AP, 100 µM) did not modify the DEAl-relaxant curves. CONCLUSIONS: Functional experiments suggest that the most active extract, DEAl, induced its relaxant effect by possible muscarinic receptors antagonism and calcium channel blockade in tracheal rings. On the other hand, significant vasorelaxant activity showed by DEAl is partially endothelium-dependent. Finally, spasmolytic activity induced by the extracts in the rat ileum was not significant, which suggests that the antidiarrheic effect of the plant is related to antimicrobial and antiparasitic properties previously described.

SNARE-wedging polyphenols as small molecular botox.

Most cosmetic and therapeutic applications of Clostridium botulinum neurotoxin (BoNT) are related to muscle paralysis caused by the blocking of neurotransmitter release at the neuromuscular junction. BoNT specifically cleaves SNARE proteins at the nerve terminal and impairs neuroexocytosis. Recently, we have shown that several polyphenols inhibit neurotransmitter release from neuronal PC12 cells by interfering with SNARE complex formation. Based on our previous result, we report here that myricetin, delphinidin, and cyanidin indeed paralyze muscle by inhibiting acetylcholine release at the neuromuscular junction. While the effect of myricetin on muscle paralysis was modest compared to BoNT/A, myricetin exhibited a shorter response time than BoNT/A. Intraperitoneally-injected myricetin at an extreme dose of 1000 mg/kg did not induce death of mice, alleviating the safety issue. Thus, these polyphenols might be useful in treating various human hypersecretion diseases for which BoNT/A has been the only option of choice.

Noninvasive cardiac output monitoring with bioreactance as an alternative to invasive instrumentation for preclinical drug evaluation in beagles.

INTRODUCTION: Non-invasive measurement of cardiac output (CO) using bioreactance signals (NICOM) was recently validated in swine and human adults. The present study was designed to test the hypothesis that NICOM flow measurements can accurately measure CO and detect acute drug-induced changes in aortic blood flow (AoQ)≥10% in beagles. METHODS: Data from 5 anesthetized, open chest beagles used for preclinical screening of novel neuromuscular blocking drugs were analyzed for the study. AoQ was measured beat-to-beat with a probe on the aortic root and averaged over 30s intervals. NICOM CO measurements were simultaneously obtained every 30s. NICOM precision (random variation) and accuracy relative to AoQ were assessed from individual segments of steady-state data. The ability of NICOM to detect acute alterations in AoQ≥10% was determined from other segments with dynamic change. RESULTS: 516 simultaneous CO measurements between 826 and 2436 mL/min were analyzed. Steady-state measurements (20% of the dataset) revealed an average AoQ-NICOM difference (bias) of 63±38 mL/min, a percent error of 6.1%, and a NICOM precision of 6.1%. Within the acute change dataset, 21/23 events reflecting a ≥10% change in beat-to-beat AoQ were detected by the NICOM (sensitivity of 0.91). In none of 10 instances where drug or fluid injection altered AoQ<10% did the NICOM indicate a change (specificity of 1.0). DISCUSSION: Continuous, non-invasive measurement of CO by bioreactance provides data that satisfactorily approximates invasive measurement of aortic blood flow in beagles. In addition, despite a 30s interval between measurements, the NICOM appears to have sufficient fidelity to detect and quantify acute, drug-induced changes in CO. These data suggest that the NICOM may represent an alternative to open chest instrumentation for CO measurement in preclinical drug evaluation studies.

Cysteine reversal of the novel neuromuscular blocking drug CW002 in dogs: pharmacodynamics, acute cardiovascular effects, and preliminary toxicology.

BACKGROUND: CW002 is a neuromuscular blocking drug that is inactivated by endogenous L-cysteine. This study determined the exogenous L-cysteine dose-response relationship for CW002 reversal along with acute cardiovascular effects and organ toxicity in dogs. METHODS: Six dogs were each studied four times during isoflurane-nitrous oxide anesthesia and recording of muscle twitch, arterial pressure, and heart rate. CW002 (0.08 mg/kg or 9 x ED95) was injected, and the time to spontaneous muscle recovery was determined. CW002 was then administered again followed 1 min later by 10, 20, 50, or 100 mg/kg L-cysteine (1 dose/experiment). After twitch recovery, CW002 was given a third time to determine whether residual L-cysteine influenced duration. Preliminary toxicology was performed in an additional group of dogs that received CW002 followed by vehicle (n = 8) or 200 mg/kg L-cysteine (n = 8). Animals were awakened and observed for 2 or 14 days before sacrificing and anatomic, biochemical, and histopathologic analyses. RESULTS: L-cysteine at all doses accelerated recovery from CW002, with both 50 and 100 mg/kg decreasing median duration from more than 70 min to less than 5 min. After reversal, duration of a subsequent CW002 dose was also decreased in a dose-dependent manner. Over the studied dose range, L-cysteine had less than 10% effect on blood pressure and heart rate. Animals receiving a single 200-mg/kg dose of L-cysteine showed no clinical, anatomic, biochemical, or histologic evidence of organ toxicity. CONCLUSION: The optimal L-cysteine dose for rapidly reversing the neuromuscular blockade produced by a large dose of CW002 in dogs is approximately 50 mg/kg, which has no concomitant hemodynamic effect. A dose of 200 mg/kg had no evident organ toxicity.

[Assessing the depth-of-hypnosis]. / Måling av narkosedybde.

BACKGROUND: There has been a breakthrough in the understanding of anaesthetic drug effects during the last two decades, and new monitors aimed at quantifying such effects have been developed. MATERIAL AND METHODS: This review is based on publications from the last 15 years, oral presentations, and rewritten parts of the author's PhD thesis. RESULTS: General anaesthesia can be regarded as a combination of hypnosis (sleep), analgesia and muscle relaxation. Modern anaesthetic drugs aim at each of these effects separately. Pharmacological variation makes it impossible to find one dose suitable for all, so tools for measuring drug effects in the individual patient are warranted. Monitors for measuring depth-of-hypnosis and partly analgesic effect are commercially available. Among these, BIS (bispectral index), based on EEG, is by far the best documented. BIS is proven useful for preventing undesired awareness and overdosing, but there are major limitations. Use of such technology in clinical practice is under constant debate. INTERPRETATION: Even though the BIS technology is promising and used widely, no health authorities have so far recommended that such monitors should be compulsory during general anaesthesia, but rather that it should be considered on an individual basis. So far, it seems like this is a sensible approach in Norway as well.

Comparative study of neuromuscular blocking and hemodynamic effects of rocuronium and cisatracurium under sevoflurane or total intravenous anesthesia.

UNLABELLED: Neuromuscular blockers (NMB) are important adjuvant to general anesthesia. Rocuronium bromide and cisatracurium besylate are considered relatively recently introduced non-depolarizing muscle relaxants. OBJECTIVES: This study evaluates the enhancement of cisatracurium and rocuronium-induced neuromuscular block during anesthesia with 1.5 MAC sevoflurane or total i.v. anesthesia (TIVA), hemodynamic effects and side effects. METHODOLOGY: 80 patients were randomly allocated into one of four equal Groups to receive either rocuronium (under sevoflurane or propofol TIVA) or cisatracurium (under sevoflurane or propofol TIVA). The NMB effects ofrocuronium and cisatracurium were studied by constructing dose-effect curves. Acceleromyography (TOF-Guard) and train-of-four (TOF) stimulation of the ulnar nerve were used (2 Hz every 15 sec). Cisatracurium and rocuronium were administered in increments until depression of T1/T0 > 95% was reached. Hemodynamic effects of both muscle relaxants together with sevoflurane or propofol were assessed using thoracic bioimpendance. RESULTS: Depression ofT1/T0 was enhanced under sevoflurane compared to TIVA. ED50 and ED95 values of both drugs were significantly lower under sevoflurane more than TIVA. Recovery index 25-75% and time to a TOF ration of 0.70 were prolonged significantly by sevoflurane compared to TIVA. Hemodynamically, rocuronium and cisatracurium did not exert significant changes, but the interaction of the relaxants and the anesthetic agents resulted in statistically significant decline in some hemodynamic parameters at certain periods which are not clinically significant and required no medications. CONCLUSION: We conclude that the effects of rocuronium and cisatracurium are significantly enhanced during sevoflurane compared with propofol anesthesia and the recovery is lower.

Site selectivity of competitive antagonists for the mouse adult muscle nicotinic acetylcholine receptor.

The muscle-type nicotinic acetylcholine receptor has two nonidentical binding sites for ligands. The selectivity of acetylcholine and the competitive antagonists (+)-tubocurarine and metocurine for adult mouse receptors is known. Here, we examine the site selectivity for four other competitive antagonists: cisatracurium, pancuronium, vecuronium, and rocuronium. We rapidly applied acetylcholine to outside-out patches from transfected BOSC23 cells and measured macroscopic currents. We have reported the IC(50) of the antagonists individually in prior publications. Here, we determined inhibition by pairs of competitive antagonists. At least one antagonist was present at a concentration producing > or =67% receptor inhibition. Metocurine shifted the apparent IC(50) of (+)-tubocurarine in quantitative agreement with complete competitive antagonism. The same was observed for pancuronium competing with vecuronium. However, pancuronium and vecuronium each shifted the apparent IC(50) of (+)-tubocurarine less than expected for complete competition but more than expected for independent binding. The situation was similar for cisatracurium and (+)-tubocurarine or metocurine. Cisatracurium did not shift the apparent IC(50) of pancuronium or vecuronium, indicating independent binding of these two pairs. The data were fit to a two-site, two-antagonist model to determine the antagonist binding constants for each site, L(alphaepsilon) and L(alphadelta). We found L(alphaepsilon)/L(alphadelta) = 0.22 (range, 0.14-0.34), 20 (9-29), 21 (4-36), and 1.5 (0.3-2.9) for cisatracurium, pancuronium, vecuronium, and rocuronium, respectively. The wide range of L(alphaepsilon)/L(alphadelta) for some antagonists may reflect experimental uncertainties in the low affinity site, relatively poor selectivity (rocuronium), or possibly that the binding of an antagonist at one site affects the affinity of the second site.

Inhibition of SNARE-driven neuroexocytosis by plant extracts.

Neuronal soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins mediate membrane fusion between synaptic vesicle and presynaptic membrane, resulting in neurotransmitter release. SNARE proteins are specific substrates of botulinum neurotoxins (BoNT) which are now widely used for therapeutic and cosmetic purposes. While BoNT blocks neuroexocytosis by cleaving SNAREs, inhibiting SNARE assembly process might exert the same effect on neurotransmission. In the present study, some extracts of 100 plants reduced neurotransmitter release by inhibiting SNARE complex formation in neuronal cells. The extracts effectively paralyzed muscle of rat phrenic nerve-hemidiaphragm preparation. Our results raise the possibility that SNARE folding inhibitors from natural resources might replace some special BoNT application fields.

Responsiveness to stimuli of bispectral index, middle latency auditory evoked potentials and clinical scales in critically ill children.

SUMMARY: We performed simultaneous recordings of Bispectral Index (BIS) and middle latency auditory evoked potentials. We also recorded two clinical scales, the Modified Ramsay scale and the COMFORT scale. Heart rate and blood pressure were measured once a day, for a maximum of 5 days, in 81 critically ill children. Changes with tactile, auditory, and painful stimuli were analysed. All the stimuli significantly increased the BIS value, the painful stimulus having the greatest effect. The painful stimulus was the only one that altered the middle latency auditory evoked potentials. Although the responses of the clinical scales to stimuli were statistically significant, they were of little clinical relevance. None of the stimuli used significantly altered the heart rate or blood pressure. We conclude that tactile, auditory and painful stimuli produced changes of little relevance in the clinical scales, BIS or middle latency auditory evoked potentials. We found the BIS was the most sensitive method and the painful stimulus had the greatest effect.

Clinical pharmacology of cisatracurium during nitrous oxide-propofol anesthesia in children.

STUDY OBJECTIVE: To describe, in pediatric patients, the effects of three doses of cisatracurium during nitrous oxide-propofol anesthesia and to determine if larger doses result in faster onset time. SETTING: College hospital. SUBJECTS: 75 ASA physical status I and II children, aged 15 to 60 months, undergoing surgery for hypospadias or undescendent testis. INTERVENTIONS: Patients were randomly assigned to one of three groups according to the dose of cisatracurium: Group A = 0.1 mg/kg (two x effective dose), Group B = 0.15 mg/kg (three x effective dose), and Group C = 0.2 mg/kg (4 x effective dose). MEASUREMENTS: Neuromuscular block was assessed with TOF-Guard (Biometer International, Odense, Denmark) accelerometry. Onset time (from cisatracurium injection to maximal depression of time to first twitch), duration of peak effect (time from cisatracurium injection to 5% recovery of time to first twitch), duration of clinical action (time from cisatracurium injection to 25% recovery of time to first twitch), and recovery index (recovery of time to first twitch from 25% to 75%) were recorded. MAIN RESULTS: Cisatracurium had no effect on heart rate or blood pressure at any dose. Compared with Group A, onset times in Groups B and C were shorter; and durations of peak effect and clinical action in Groups B and C were longer (P < 0.01) than those in Group A. There was no difference in recovery index among the three groups. There was no difference in onset times between Groups B and C. Compared with Group B, durations of peak effect and clinical action in Group C were longer (P < 0.05 or P < 0.01). CONCLUSION: Four times the effective dose of cisatracurium did not significantly shorten onset time beyond that produced with three times the effective dose in young children.

[Analgesia, sedation and relaxation in the child with mechanical ventilation]. / Analgesia, sedación y relajación en el niño con ventilación mecánica.

The basic concepts of sedation and analgesia and the tools to asses the level of sedation and analgesia are review. The different methods of sedation and the non pharmacological interventions are described. Sedatives, analgesics and muscle relaxants, their pharmacodynamics and pharmacokinetics in children, their indications in specific situations (intubation, pain control, sedation and neuromuscular blocking) are reviewed. The etiology of patient-ventilator asynchrony in ventilated children and how to treat it are analyzed, giving guides of how to adapt sedation to the level of mechanical ventilation therapy. Finally, general recommendations are given for the analgesia and sedation in mechanically ventilated children.

Infusions of rocuronium and cisatracurium exert different effects on rat diaphragm function.

OBJECTIVE: Aminosteroidal and benzylisoquinoline neuromuscular blocking agents are used in the intensive care unit to facilitate mechanical ventilation. The use of these agents has been associated with development of critical illness myopathy; however, the relative frequency of myopathy development among agents is not known. The aim of our study was to compare the effects of 24 h infusion of rocuronium or cisatracurium on the diaphragm in mechanically ventilated rats. DESIGN: Randomized, controlled experiment. SETTING: Basic animal science laboratory. SUBJECTS: Male Wistar rats, 14 weeks old. INTERVENTIONS: Rats were divided into four groups to receive either saline, rocuronium (low dose) or cisatracurium (low or high dose). MEASUREMENTS AND RESULTS: After 24 h, in vitro diaphragm tetanic force was decreased after rocuronium (-33% vs. saline), while the force was more preserved after cisatracurium, even in the high-dose group. Cross-sectional areas of the different diaphragm and gastrocnemius fibers were unaltered. Diaphragmatic MURF-1 mRNA was increased after rocuronium (+44% vs. saline), while unchanged in both cisatracurium groups. Calpain activity was increased after rocuronium (+75% vs. saline) and unchanged in the cisatracurium groups. MURF-1 mRNA expression and calpain activity were negatively correlated with diaphragm force. CONCLUSIONS: Cisatracurium infusion during controlled mechanical ventilation exerted less detrimental effects on diaphragm function and proteolytic activity than infusion of rocuronium, even with the higher effective dose. These data suggest that increased calpain activity and increased activation of the ubiquitin proteasome system play a role in the different effects of these agents.

Neurosedative and muscle-relaxant activities of ethyl acetate extract of Baphia nitida AFZEL.

The sedative, anxiolytic and muscle-relaxant effects of the ethyl acetate leaf extract of Baphia nitida (BN) was investigated in intact mice, using the hole-board head-dip test for exploratory behavioural effect, elevated plus maze (EPM) and Y-maze (YM) models of anxiety; chimney, inclined screen, traction and climbing tests for muscle-relaxant effects. In each of these tests, BN (100-400mg/kg, p.o.), diazepam (1mg/kg, i.p.) or distilled water (10ml/kg, p.o.) was administered, 30 or 60min before performing the tests in mice. For exploratory behavioural test, number of head-dip within 15min was counted. For EPM and YM tests, the cumulative time spent in open and closed arms was recorded within 5min. In the muscle-relaxant tests, mice were subjected to modified models such as chimney, inclined screen, traction and climbing tests. BN produced a significant (P<0.05) dose-related decrease in exploratory behaviour in the head-dip test and prolongation of cumulative time spent in open arms of both EPM and YM. BN did not show any significant effect in the chimney and traction tests, but produced significant, dose-dependent muscle relaxation in the inclined screen and climbing tests. Furthermore, BN (200-1200microg/ml) non-competitively shifted the curves of acetylcholine contractions of the toad Rectus abdominis muscle to the right. Oral doses of BN (0.1-20g/kg) did not produce mortality, but the LD(50) when given intraperitoneally, was 645.65mg/kg. Results suggest that the leaf extract of Baphia nitida has sedative, anxiolytic and skeletal muscle-relaxant effects and support its neurosedative use in traditional African medicine.