[Update on muscle relaxation : What comes after succinylcholine, rocuronium and sugammadex?] / Update Muskelrelaxation : Was kommt nach Succinylcholin, Rocuronium und Sugammadex?

Due to the great advantages, it is not possible to imagine current practice in anesthesia without the adminstration of muscle relaxants. For a long time the administration of succinylcholine for rapid sequence induction (RSI) was considered to be the state of the art for patients at risk for aspiration. The favorable characteristics are, however, accompanied by many, sometimes severe side effects. Due to the development of non-depolarizing muscle relaxants, in particular rocuronium in combination with sugammadex, there is the possibility to achieve a profile of action similar to succinylcholine with low side effects. After the introduction of sugammadex onto the market, further substances were conceived, which enable a complete encapsulation of muscle relaxants. Calabadion is a very promising new substance for the antagonization of muscle relaxants, which can antagonize the action of steroid as well as benzylisoquinoline types. In the USA new muscle relaxants are currently being tested, which have a rapid onset and the effect can be reversed by L­cysteine. One of the most promising substances is gantacurium, which is currently being tested in the USA in phase III trials. It remains to be seen whether these muscle relaxants, which are not yet on the market and drugs for reversal of neuromuscular blockade have the potential to become a real alternative to the combination of rocuronium and sugammadex.

[New aspects of common antagonists used in the perioperative period: preface and comments].

Anesthesia is a state made by multiple pharmacological agents that affect the functions of central, peripheral and autonomic nervous systems. Antagonists are often used to reverse the effects of anesthetic agents, muscle relaxants, and so forth. Antagonists often have side effects other than their specific antagonistic effect. Some side effects may be clinically useful. Ketamine was found to be a NMDA receptor antagonist. Ketamine potentially has neuroprotective, and anti-tumor effect. Local anesthetic agent also has been known to have anti-NMDA receptor effect. Although the mechanisms of local anesthetics to prevent or treat chronic pain have not been clearly elucidated, local anesthetics may have a place in the treatment of chronic pain. Naloxone may have spinal protective effects when used during thoracic aortic aneurysm surgery and stent placement. Peripherally and centrally active anticholinesterase agents have unique effects. Centrally active anticholinesterase agents such as donepezil and revastigmine, and galantamine have been used to treat patients with Alzheimer's disease. These agents may antagonize the effects of non-depolarizing muscle relaxants. Flumazenil may have adverse effects in patients on chronic benzodiazepines and tricyclic or tetracyclic antidepressants. Because sugammadex has little adverse effects, it has become a popular agent to reverse muscle relaxation by rocuronium in Japan.

[Muscle relaxants and neuromuscular monitoring - Introduction for a safe clinical application]. / Muskelrelaxanzien und neuromuskuläres Monitoring - Einführung für eine sichere klinische Anwendung.

The use of muscle relaxants facilitates endotracheal intubation and ameliorates the conditions of surgery. But, their use should be controlled - otherwise there will be postoperative residual curarisation which can lead to patient discomfort up to severe medical complications. Therefore, an appropriate surveillance via objective neuromuscular monitoring is essential. This article gives a review of the basic principles of muscle relaxants, their clinical application and the surveillance of their effects and degradation.

The influence of unrestricted use of sugammadex on clinical anaesthetic practice in a tertiary teaching hospital.

This retrospective casenote audit involving 374 patients requiring intubation for an anaesthetic found that when the availability of sugammadex became unrestricted, its use increased from 7.1 to 65.3% (P <0.0001) of all muscle relaxant reversals, while neostigmine use decreased from 59.6 to 12.5%. Rocuronium use decreased slightly (90.8 to 79.2%, P=0.006) but vecuronium use increased (2.1 to 8.3%, P=0.02). Cisatracurium and suxamethonium use were unchanged. Total rocuronium dose (55.9 ± 24.1 vs 60.4 ± 22.3 mg) and the number of doses (1.9 ± 1.48 to 1.96 ± 1.27) were unchanged, but the time between the last dose and reversal decreased (91.7 ± 68.1 to 62 ± 52.4 minutes, P=0.0002). There appeared to be no change in postoperative nausea and vomiting, or post-anaesthesia care unit time or oxygen saturation levels. Anaesthetic theatre time fell from 143.5 ± 85.8 to 120 ± 71.2 minutes (P=0.01) and remained significant when adjusted for confounding variables (ratio of means 1.17, 95% confidence interval 1.03 to 1.34, P=0.02), although inferences in relation to causality are limited by the retrospective and observational design of the study. Hospital stay also appeared to fall (4.2 ± 3.5 to 3.4 ± 3.0 days, P=0.035), but was not statistically significant when adjusted for confounding variables (ratio of means 1.04, 95% confidence interval 0.89 to 1.2, P=0.59). These observations suggest that the unrestricted availability of sugammadex will change how steroid-based neuromuscular blocking drugs are used and reversed, but further research is needed to determine if patient outcomes will improve.

Carisoprodol tolerance and precipitated withdrawal.

AIMS: Carisoprodol is a muscle relaxant that acts at the GABA(A) receptor. Concerns about the abuse liability of carisoprodol are increasing, but evidence that carisoprodol produces tolerance and a significant withdrawal syndrome has yet to be established. The purpose of the current study was to determine if repeated administration of carisoprodol produces tolerance and withdrawal signs in a mouse model. METHODS: Carisoprodol (0, 100, 200, 300, or 500 mg/kg bid, i.p.) was administered to Swiss-Webster mice for 4 days and loss-of-righting reflex was measured 20-30 min following each administration. On the fourth day, bemegride (20 mg/kg), flumazenil (20 mg/kg), or vehicle was administered following carisoprodol and withdrawal signs were measured. Separate groups of mice receiving the same treatment regimen and dose range were tested for spontaneous withdrawal at 6, 12 and 24 h after the last dose of carisoprodol. RESULTS: The righting reflex was dose-dependently impaired following the first administration of carisoprodol. A 75-100% decrease in the magnitude of the impairment occurred over the four days of exposure, indicating the development of tolerance to the carisoprodol-elicited loss-of-righting reflex. Withdrawal signs were not observed within 24h following spontaneous withdrawal; however, bemegride and flumazenil each precipitated withdrawal within 15-30 min of administration. CONCLUSIONS: Carisoprodol treatment resulted in tolerance and antagonist-precipitated withdrawal, suggesting it may have an addiction potential similar to that of other long-acting benzodiazepine or barbiturate compounds.

Risk factors for nausea and vomiting after day care general anesthesia in mentally challenged patients undergoing dental treatment.

Clinically, the incidence of postoperative nausea and vomiting (PONV) may be higher in mentally challenged patients than in normal healthy patients. The aim of this study was to investigate the risk factors for PONV after day care general anesthesia in mentally challenged patients undergoing dental treatment. We analyzed data on 231 day care general anesthesia cases involving mentally challenged patients undergoing dental treatment. Anesthetic records for the past 5 years were investigated retrospectively. Ten items (age, body weight, sex, duration of general anesthesia, use of propofol, use of sevoflurane, use of nitrous oxide, use of neostigmine, treatment accompanied with bleeding, and transfusion volume) were selected as risk factors for PONV. Postoperative nausea and vomiting was evaluated using the postoperative check sheet and linear discriminant analysis was performed to distinguish PONV incidence using the 10 items as independent variables. The reliability of the linear discriminant function was evaluated using a misjudgment rate and information criteria (AIC). Postoperative nausea and vomiting was observed in 13 cases out of 231 cases. The discriminant function with the smallest AIC (-25.0718) consisted of two independent variables: y=-0.077x(1)-0.001x(2)+0.0716(x(1)=use of propofol, x(2)=age). The misjudgment rate was 31.6%. This result suggests that PONV decreases when propofol is used and that the incidence of PONV decreases with age. To investigate other risk factors, an additional analysis was performed using 83 out of the 231 cases in which sevoflurane was used as an anesthetic agent. The results of the subgroup analysis suggest that the incidence of PONV decreases in male patients and higher weight patients, although the patient's body weight may be related to age, as the study cohort included many children. It is suggested that the major risks for PONV in mentally challenged patients after day care general anesthesia are no use of propofol, lower age, female sex and lower weight.

Sugammadex: a selective relaxant-binding agent providing rapid reversal.

PURPOSE OF REVIEW: Sugammadex is a new reversal agent with a unique mechanism of action in anaesthesia. Because of its rapid onset of action and its efficacy in determining neuromuscular blockade at any time, it opens up new perspectives in anaesthesia. RECENT FINDINGS: During the last few years, a lot of phase II and III studies have been published, investigating various groups of patients and clinical situations. Sugammadex has been shown to be a well tolerated drug, which appears to meet every challenge it is presented with in daily clinical practice. SUMMARY: Sugammadex binds amino-steroidal muscle relaxants by encapsulation. It enables rapid reversal of neuromuscular blockade at any time point and at any depth of block. Its effects are predictable and very reliable, in contrast to cholinesterase inhibitors. This opens up new perspectives in anaesthesia. Even an emergency reversal of high-dose rocuronium-induced neuromuscular blockade is possible with sugammadex and times to full recovery (TOF 0.9) are faster than after spontaneous recovery from suxamethonium.

[Short acting muscle relaxants: is neuromuscular monitoring still necessary?]. / Ist neuromuskuläre Uberwachung bei kurzwirkenden Muskelrelaxanzien noch erforderlich?

Neuromuscular blocking agents are used to facilitate intubation and to establish muscle paralysis during surgery. However, postoperative residual blocks are a significant complication following the use of neuromuscular blocking agents with an incidence of approximately 30 % at arrival in the post operative care unit. If they are not identified and adequately treated, residual neuromuscular blocks would increase the risk for muscle fatigue, hypoventilation, swallowing disorders, and aspiration. These complications may result in postoperative pulmonary disease. Therefore, monitoring of neuromuscular block is essential not only to detect residual paralysis postoperatively but also to maintain adequate muscle paralysis for surgery. Moreover, the response of individual patients to a particular drug can be variable and needs to be determined for the individual patient in a clinical situation. Sugammadex, the newly developed steroidal muscle relaxant encapsulator, is another important step to optimize treatment with neuromuscular blocking agents but will not replace neuromuscular monitoring. Since qualitative assessment has been shown to be insufficient to validly measure neuromuscular block in the anesthetized patient, it should be monitored quantitatively. Only using this technique and treating residual blocks where required, life threatening complications can certainly be avoided.

Effect of novel anti-inflammatory ethanolamine derivatives with antioxidant properties on drug metabolising enzymes.

The influence of four ethanolamine derivatives with anti-inflammatory and antioxidant activity on the in vitro aminopyrine N-demethylation was studied. It was found that these compounds inhibit the N-demethylation of aminopyrine. 1-Cyclohexyl-5-(2-hydroxy-ethylamino)-pentan-2-one (compound 4), possessing the highest inhibitory activity and found earlier to be a potent anti-inflammatory agent, is further tested in vivo on zoxazolamine-induced paralysis, after a single administration to rats, and on aminopyrine N-demethylation, rat hepatic total cytochrome P450 and protein (postmitochondrial and microsomal) content, after a prolonged treatment. It was found that the examined compound had no significant influence on the above biotransformations, however, it could decrease the catalytically active hepatic cytochrome P450 content. These results, considered together with some structural and physicochemical properties of the compound, indicate that this compound may act as a CYP2D6 substrate.

Reversal of benzodiazepine-induced renal vasculature relaxation with flumazenil.

The effects of the central-type benzodiazepine receptor antagonist flumazenil on renal vascular tone and its ability to reverse the benzodiazepine-induced vasodilation were investigated. The isolated and perfused rat kidney model was used. Flumazenil was unable to modify renal vascular resistance under basal conditions and in noradrenaline-pretreated kidneys. Relaxation induced by diazepam or clonazepam of noradrenaline-preconstricted renal vasculature was blunted by 10 microM flumazenil. These results suggest that central-type benzodiazepine receptors could be involved in benzodiazepine-induced renal vasodilation.

Interaction of taurine on baclofen intestinal absorption: a nonlinear mathematical treatment using differential equations to describe kinetic inhibition models.

Previous studies showed that the in situ absorption of baclofen in rat jejunum was inhibited by beta-alanine, a nonessential amino acid, and therefore mediated, at least in part, by some beta-amino acid carrier. In this paper a similar study was undertaken using taurine, a sulfonic beta-amino acid, in order to evaluate its effect and to establish a general inhibition model. To achieve this goal, remaining concentrations of inhibitor were also measured and incorporated into the model. Previously, kinetic absorption in situ parameters for taurine in free solution were obtained: Vm = 27.73 +/- 9.99 mM h-1, K(m) = 8.06 +/- 2.82 mM, Ka (passive difussion component) = 0.40 +/- 0.28 h-1. Isotonic solutions containing 0.5 mM baclofen with starting taurine concentrations ranging from 0 to 100 mM were perfused in rat jejunum, and the remaining concentrations of both compounds were measured. The apparent rate pseudoconstant of the drug clearly decreased as the remaining taurine concentration increased. The interaction can be described as a complete competitive inhibition plus a second component, K, noninhibited, K = 0.58 (+/- 0.03) h-1, Ki = 20.62 (+/- 4.04) mM, Vmi = 28.12 (+/- 6.12) mM h-1, Kmi = 11.71 (+/- 2.53) mM, Kai = 0.47 (+/- 0.10) h-1. A residual absorption of baclofen in the presence of high taurine concentrations was observed, which should be attributed to another transport system not associated with the taurine carrier. In order to elucidate whether or not taurine and beta-alanine carriers are two separate entities that baclofen can use for absorption, further experiments using beta-alanine and taurine together as inhibitors (baclofen, 0.5 mM; beta-alanine, 50 mM, and taurine, 50 mM) were developed. Results indicated that baclofen and both amino acids share the same carrier in the intestinal absorption process. We have completed studies using leucine, taurine, and GABA together as inhibitors of drug absorption. An isotonic perfusion solution of 0.5 mM baclofen in the presence of 50 mM leucine, 25 mM taurine, and 25 mM GABA was perfused. Under these conditions the absorption rate pseudoconstant of baclofen decreases until 0.080 h-1 (+/- 0.069). Practical implications of these phenomena are briefly discussed.

Flumazenil: an unreliable antagonist in baclofen overdose.

We report a case of inadvertent overdose of baclofen given intrathecally resulting in coma. This was unresponsive to flumazenil and required supportive intensive therapy. With the increasing use of baclofen intrathecally for spasticity and its wide interpatient dose variability, there is a need to find a safe antagonist to baclofen for routine medical use.

Effect of the centrally acting muscle relaxant tizanidine on spinal reflexes: involvement of descending noradrenergic systems.

Experiments were performed on intact and spinalized rats anesthetized with urethane and alpha-chloralose. In intact rats, administration of tizanidine (0.1 mg/kg, i.v.) decreased the mono- (MSR) and polysynaptic reflex potentials (PSR). Blood pressure was initially elevated and then lowered by tizanidine. Although pretreatments with hexamethonium and phentolamine prevented the tizanidine-induced decrease in blood pressure, the depressant effects of tizanidine on the reflexes remained. The alpha 2-antagonist idazoxan inhibited the tizanidine-induced decrease in spinal reflexes, suggesting that central alpha 2-adrenoceptors are involved in the depression of the reflexes. In spinalized rats, tizanidine transiently increased the MSR and gradually decreased the PSR. Blood pressure was elevated transiently by tizanidine. Although the hypertensive effect of tizanidine was inhibited by phentolamine, the effect of tizanidine on the PSR did not change. Prazosin blocked the stimulatory effect of tizanidine on the MSR and caused a rapid decrease of the PSR, suggesting that spinal alpha 1-adrenoceptors are involved in the enhancement of the reflexes. These results suggest that the depressant effects of tizanidine on spinal reflexes are due to the supraspinal and spinal effects of the drug, and not to changes in blood pressure.