[Dental treatment under general anaesthesia in young children]. / Algehele anesthesie bij jonge kinderen in de tandheelkunde.

General anaesthesia in children younger than 4 years of age can cause brain damage with cognitive and behavioral problems as a result. The chance of these side effects is small, but increases with prolonged duration of the anaesthesia or when the general anaesthesia is provided more frequently. It goes without saying that the indication for anaesthesia should be very strictly set. In order to reduce the chance of damage, the anaesthesia itself should be performed in consultation between the anaesthesiologist and care provider, according to a set protocol. The parents need to be informed of the potential risks of general anaesthesia. Delayed treatment (and thereby provision of the anaesthesia) should be considered.

[Neurotoxicity of sedatives and anaesthetics in young children]. / Neurotoxiciteit van sedativa en anesthetica bij jonge kinderen.

Many histological studies, animal experiments and also human studies during the past 30 years have proven that the use of general anaesthesia in young children under the age of four can have a permanent effect on the brain, which is still developing, and can therefore cause learning and/or behaviour problems later in life. This knowledge has to be taken seriously into account in the discussion with parents whether general anaesthesia is really necessary for the treatment of Early Childhood Caries in very young children.

[The risk of general anaesthesia and sedation in the older people]. / Gevaar van algehele anesthesie en sedatie bij ouderen.

Temporary memory problems and aggravation of pre-existing memory disorders may occur after treatment under general anaesthesia. A frequency of postoperative cognition disorders between 10 and 50% has been identified in the literature. Risk factors for the occurrence of postoperative memory disorders are advanced age, low level of education, intellectual comorbidity, the onset of dementia and other neurodegenerative disorders, existing sleep disorders and the experience of postoperative pain. The morphological changes seen in the brain after general anaesthesia are similar to the changes occurring in Alzheimer's disease. In addition to metabolic changes, general anaesthetics directly enhance the apoptosis of brain cells. Older people are already familiar with a decrease in the number of neurons, which provides them with a limited spare capacity. Moreover, older people are often known to have the risk factors for the occurrence of postoperative memory disorders as mentioned before. Caution and restraint in the indication for dental -treatment under general anaesthesia or sedation is therefore required.

A systematic review and meta-regression analysis of mivacurium for tracheal intubation.

We systematically reviewed factors associated with intubation conditions in randomised controlled trials of mivacurium, using random-effects meta-regression analysis. We included 29 studies of 1050 healthy participants. Four factors explained 72.9% of the variation in the probability of excellent intubation conditions: mivacurium dose, 24.4%; opioid use, 29.9%; time to intubation and age together, 18.6%. The odds ratio (95% CI) for excellent intubation was 3.14 (1.65-5.73) for doubling the mivacurium dose, 5.99 (2.14-15.18) for adding opioids to the intubation sequence, and 6.55 (6.01-7.74) for increasing the delay between mivacurium injection and airway insertion from 1 to 2 min in subjects aged 25 years and 2.17 (2.01-2.69) for subjects aged 70 years, p < 0.001 for all. We conclude that good conditions for tracheal intubation are more likely by delaying laryngoscopy after injecting a higher dose of mivacurium with an opioid, particularly in older people.

The relation between skin temperature increase and sensory block height in spinal anaesthesia using infrared thermography.

BACKGROUND AND OBJECTIVES: To evaluate the feasibility of determining the extent of sympathetic blockade by skin temperature measurement with infrared thermography and relate the cranial extent of the temperature increase to that of the sensory block after spinal anaesthesia. METHODS: Before and 5, 10 and 20 min after the administration of spinal anaesthesia, skin temperatures were measured with infrared thermography at the dermatomes T2-L3, in 12 male patients scheduled for lower limb surgery. The most cephalad dermatome at which sensory blockade occurred was related to the dermatome at which the largest temperature jump (corrected for baseline temperature) occurred. RESULTS: The baseline temperatures showed considerable variation across the dermatomes, being lower below T12 than at the thoracic dermatomes. The mean difference between the level of the cephalad skin temperature elevation front (mean 1.03 °C, SD 0.8 °C) and cranial sensory block height was 0.10 dermatomes (SD 1.16), correlation coefficient (0.88, P<0.001). CONCLUSION: The varying baseline temperatures across the trunk, the limited sympathetic block-induced increase in skin temperature at the trunk and the difficult control of influences from the surroundings partly obscured the extent of the skin temperature increase and its correlation to sensory block height. These factors have to be controlled to improve the use of infrared cameras as an easy bedside tool for predicting the cranial extent of (sympathetic blockade during) spinal anaesthesia.

Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1.

We measured acceleromyography and mechanomyography simultaneously with monitoring of rocuronium-induced neuromuscular block in four patients with myotonic dystrophy type 1. Furthermore, we compared neuromuscular block measures from these patients with those from normal controls from previous studies. In myotonic dystrophy type 1 patients, the dose-response curve obtained with acceleromyography was steeper and right-shifted compared with that obtained using mechanomyography. However, the effective doses to produce 95% neuromuscular block determined with both acceleromyography and mechanomyography were similar to each other and to values found in normal patients. In the three myotonic dystrophy type 1 patients with mild to moderate disease, times to recovery from block were similar to those observed in normal controls. In both patients and normal controls, neuromuscular block recovered faster with acceleromyography. However, in one patient with severe muscle wasting, recovery of neuromuscular block was prolonged. We conclude that mechanomyography and acceleromyography cannot be used interchangeably to monitor neuromuscular block in myotonic dystrophy type 1 patients.

A new approach to anesthesia management in myasthenia gravis: reversal of neuromuscular blockade by sugammadex.

A neuromuscular blocking drug (NMBD) induced neuromuscular blockade (NMB) in patients with myasthenia gravis usually dissipates either spontaneously or by administration of neostigmine. We administered sugammadex to a patient with myasthenia gravis to reverse a rocuronium-induced profound NMB. NMBDs predispose such patients to severe postoperative residual paralysis and respiratory complications. Sugammadex binds steroidal NMBDs and, therefore reverses a rocuronium or vecuronium-induced NMB, without interfering with cholinergic transmission. A rapid and complete recovery from profound NMB was achieved and no adverse events were observed. This case suggests that sugammadex is a safe and effective antagonist of a rocuronium induced NMB blockade in patients with myasthenia gravis.

Cyclodextrins and the emergence of sugammadex.

Residual paralysis, with its subsequent postoperative pulmonary sequelae, is one of the major complications of anaesthesia, and was recognised shortly after the introduction of neuromuscular blocking drugs into routine clinical practice. Although its incidence decreased with the introduction of intermediate duration drugs, and further diminished with routine neuromuscular monitoring and reversal with cholinesterase inhibitors, residual paralysis still remained a problem. In the search for alternatives to stop the effect of neuromuscular blocking drugs and to match their duration of action to clinical need, chelation of the non-depolarising neuromuscular blocking drugs was considered. It was recognised that cyclodextrins could encapsulate steroidal molecules and thereby inactivate the aminosteroidal neuromuscular blocking drugs. In order to improve the binding of rocuronium to the cyclodextrin and to increase the compound's water solubility, the molecule was modified. This led to the development of sugammadex (Org 25969), a modified gamma-cyclodextrin. The modification of the molecule and the initial in vitro studies that led to in vivo and later human studies of this conceptually new drug for anaesthesia are described.

In vivo animal studies with sugammadex.

A review is presented of animal studies of the selective steroidal neuromuscular blocking drug binding agent sugammadex. These studies demonstrate that sugammadex is faster in onset than the currently used acetylcholinesterase inhibitors, has no muscarinic effects, and is characterised by lack of adverse effects on other organs. These results offer support for the further development of sugammadex for clinical use in humans.

[Sugammadex. New pharmacological concept for antagonizing rocuronium and vecuronium]. / Sugammadex. Neues pharmakologisches Konzept zur Antagonisierung von Rocuronium und Vecuronium.

Up to now only acetylcholine esterase inhibitors, such as neostigmine, were available as antagonists of residual neuromuscular blocks. Sugammadex is a modified gamma-cyclodextrin that binds rocuronium and chemically similar aminosteroidal muscle relaxants, such as vecuronium. The underlying mechanism of action is new and differs completely from that of acetylcholine esterase inhibitors. This review summarizes data published so far within the framework of the licensing procedure about the efficacy, safety and side-effects of sugammadex and presents potential new anesthesiological concepts using this compound.

Non-depolarizing neuromuscular blocking activity of bisquaternary amino di- and tripeptide derivatives.

Herein we describe the synthesis of novel di- and tripeptide derivatives with two quaternary nitrogen groups attached and the biological testing of these compounds for neuromuscular blocking (NMB) activity in vitro and in vivo. The short peptide scaffold was selected because it offers potential for desired distance between the two pharmacophoric quaternary nitrogen groups, short duration of action, straightforward synthesis, and compatibility with an injectable formulation. From a small series of compounds 20c,e are identified as effective non-depolarizing NMB agents in vitro and in vivo in anesthetized cats and Rhesus monkeys with potencies similar to those of the clinical reference compounds rocuronium (4) and suxamethonium (2) (monkey ED(90) = 0.68, 0.23, 0.16, 5.04 micromol/kg, respectively). These new peptide derivatives 20c,e have similar potency and onset time but longer duration and slower recovery than the clinically used reference compounds. The structure-activity relationships described for this chemical series lead to the conclusion that the di- or tripeptide fragment can be regarded as an alternative template to the steroid or aliphatic ester of previously reported NMBs and within this tripeptide-derived series clog P correlates well with in vitro NMB activity.

Influence of ketanserin (serotonin antagonist) on bladder and urethral function.

As it is known that serotonin or 5-hydroxytryptamine can enhance bladder activity, we studied urodynamically the effect of ketanserin, a serotonin antagonist, in 17 patients, in the hope that this drug might be useful in treating unstable bladders. However, a relaxant effect on bladder contractility could not be demonstrated. On the contrary, a significant decrease of the urethral pressure was observed, suggesting that ketanserin might still have a possible role in promotion of bladder emptying. The relaxant effect on the urethra suggests some alpha-sympathicolytic activity of ketanserin.

Intrathecal somatostatin produces effects dependent on the interval between catheter implantation and drug injection.

Intrathecal (i.t.) injection of somatostatin has been reported to depress nociceptive reflexes as well as to cause severe disturbance of somatomotor performance. The present study was designed to assess the dependence of these effects on the dose and the interval between implantation of the catheter and i.t. injection of somatostatin in rats. The effects produced by i.t. injection of somatostatin consisted of an increase in the response latencies of nociceptive responses to noxious heat, impairment of motor performance and grooming behavior, convulsions, and death. Except for grooming behavior, these were related in incidence and degree to the dose and the interval, the potency of somatostatin being highest at short intervals. Sham operations also affected the effectiveness of somatostatin.

Site- and test-dependent antinociceptive efficacy of amitriptyline in rats.

The antinociceptive efficacy of systemic- (IV), spinal- (IT), and global supraspinal (ICV)-administered amitriptyline (AMIT) was compared in three different tests for nociception: the hot-plate test, the tail-flick test, and the withdrawal reflex test. Systemic AMIT inhibited the responses in each of the three tests, with distinct dose-effect relationships. Spinal AMIT reduced in a dose-dependent fashion the force of withdrawal to noxious electrical stimulation but was ineffective in the hot-plate test and facilitated the responses in the tail-flick test. Supraspinal AMIT inhibited in dose-dependent fashion the response to the stimulus of the hot plate, reduced the force of withdrawal after a dose that was effective by the IV route, and again facilitated the responses in the tail-flick test. The results suggest that spinal sites mediate the inhibition of the withdrawal reflex and the supraspinal site the inhibition of the hot-plate test. Two conclusion are drawn: First, AMIT's site of action varies among the pain modalities; and, second, augmentation of the reactions can occur. The complex interaction accords with the clinical experience that the benefits of AMIT in pain treatment are hard to predict.

Similar motor block effects with different disposition kinetics between lidocaine and (+ or -) articaine in patients undergoing axillary brachial plexus block during day case surgery.

AIM: The aim of this investigation was to compare the clinical effects and pharmacokinetics of lidocaine and articaine in two groups of 15 patients undergoing axillary brachial plexus anesthesia. METHOD: The study had a randomized design. Thirty patients were allocated to one of the two groups. Each patient received either lidocaine (600 mg = 2.561 mMol + 5 microg/ml adrenaline) or articaine (600 mg = 2.113 mMol + 5 microg/ml adrenaline), injected via the axilla of the brachial plexus over a period of 30 seconds. Onset of surgical analgesia was defined as the period from the end of the injection of the local anesthetic to the loss of pinprick sensation in the distribution of all three nerves. RESULTS: The mean onset time of sensory block of the median nerve of both lidocaine and articaine were approximately 10 min. Lidocaine is biexponentially eliminated with a t1/2alpha of 9.95 +/- 14.3 min and a t1/2beta of 2.86 +/- 1.55 h. Lidocaine is metabolized into MEGX (mono-ethyl-glycyl-xilidide) (t(max) 2.31 +/- 0.84 h; C(max) 0.32 +/- 0.13 mg/l; t1/2beta 2.36 +/- 2.35 h). Lidocaine total body clearance was 67.9 +/- 28.9 l/h. Articaine is rapidly and monoexponentially eliminated with a t1/2beta of 0.95 +/- 0.39 h. The total body clearance of articaine is higher than that of lidocaine, 1,133 +/- 582 l/h vs 67.9 +/- 28.9 l/h, respectively (p < 0.0001). The volume of distribution (V(d)), of articaine is a factor 16 higher times than that of lidocaine (p < 0.0001). CONCLUSION: For the axillary administration, lidocaine and articaine show similar pharmacodynamics with a different pharmacokinetic behavior and can therefore be used to the clinical preference for this regional anesthetic technique.

The bioavailability of intramuscularly administered nicomorphine (Vilan) with its metabolites and their glucuronide conjugates in surgical patients.

The kinetics of 20 mg nicomorphine intramuscularly were described in 8 patients under combined general and epidural anesthesia. The half-life of nicomorphine was 0.32 +/- 0.20 h (mean +/- SD) and is governed by the absorption-rather than the elimination rate. The half-life of 6-mononicotinoylmorphine (0.39 +/- 0.09 h) was identical to that of the parent compound (p = 0.29), suggesting it is directly related to the absorption rate of nicomorphine. Morphine had a half-life of 1.38 +/- 0.31 h. Morphine is subsequently metabolized into morphine-3-glucuronide and morphine-6-glucuronide. The half-life of these 2 glucuronide conjugates was about 2.6 h (p = 0.07). A glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In urine only morphine and its glucuronides are found, with renal clearance values of 214 ml.min-1 for morphine and 132 ml.min-1 for the glucuronides. The bioavailability of this pharmaceutical formulation after intramuscular administration equals that of intravenous administration in surgical patients (at the same dose).

Epidural metabolism of articaine to its metabolite articainic acid in five patients after epidural administration of 600 mg articaine.

The clinical pharmacokinetics, metabolism and renal excretion of articaine and its metabolite articainic acid have been investigated in man after epidural administration. (+/-)-Articaine and its metabolite (+/-)-articainic acid have different pharmacokinetic constants (P = 0.0079) except for lag-time (tlag; 0.06 min), first phase distribution of elimination (t 1/2 alpha; 0.49 +/- 0.21 h), and elimination half life (t 1/2 beta; 2.19 +/- 0.98 h), which are all the same for both compounds. The total body clearance of articaine (103 +/- 57 L h-1) is 10 times higher than that of the metabolite articainic acid (10.7 +/- 1.80 L h-1, P = 0.0079). With similar half-life (t 1/2 beta) values (2h), the volumes of distribution (V beta) are 10 times higher for the parent drug than for the metabolite ((329 +/- 212 L compared with 38.4 +/- 7.5 L, respectively; P = 0.0079). The difference between the areas under the curves for total plasma articainic acid and that formed in the plasma gives an indication of the percentage metabolism during epidural transfer (5.38 +/- 1.51%). This percentage of metabolism corresponds to a mean epidural transfer time of 5 min. The main compound in the urine is articainic acid (64.2 +/- 14.4%), followed by articainic acid glucuronide (13.4 +/- 4.97%) and the parent drug (1.45 +/- 0.77%). In total, 79.0 +/- 18.5% of the dose is recovered in the urine. The renal clearance of articaine is 22.5 +/- 13.9 mL min-1, whereas that of articainic acid is 119.6 +/- 30.1 mL min-1 (P < 0.0001). The apparent renal clearance of articainic acid glucuronide was 25.4 +/- 12.0 mL min-1. This value does not differ from that of the parent drug (P > 0.8). Articainic acid glucuronide is not present in plasma, but has an apparent renal clearance of 25 mL min-1. These results suggest that articainic acid is glucuronidated by the tubular cells and then excreted.

Potentiation of neostigmine and pyridostigmine by 4-aminopyridine in the rat.

The interaction between 4-aminopyridine and neostigmine or pyridostigmine was studied in vivo in the rat sciatic nerve-anterior tibialis preparation using the constant infusion of pancuronium technique. The ED50 (dose of drug which produced a 50% antagonism) of neostigmine, pyridostigmine and 4-aminopyridine were 18, 49 and 440 microgram kg(-1) respectively. The addition of 100 microgram kg(-1) of 4-aminopyridine, which produced no antagonism by itself, decreased the neostigmine ED50 to 7.4 microgram kg(-1). The addition of 200 microgram kg(-1) of 4-aminopyridine, which produced a 30% antagonism by itself, decreased the ED50 of pyridostigmine to 11 microgram kg(-1). We conclude that both neostigmine and pyridostigmine interact with 4-aminopyrine synergistically.

Effect of some benzodiazepines on peripheral neuromuscular function in the rat in-vitro hemidiaphragm preparation.

The effect of equimolar cumulative concentrations of 11 different benzodiazepines on the indirectly evoked twitch contraction was investigated in the rat in-vitro phrenic nerve-hemidiaphragm preparation. Depending on the pattern of the concentration-response curves two groups of benzodiazepines can be distinguished: (i) a first group with a biphasic action, e.g. potentiation of twitch tension in low concentrations and depression of twitch tension in high concentrations, and (ii) a second group with primary depression of twitch tension with increasing concentrations. All of the tested compounds ultimately caused a 100% depression of twitch tension at concentrations ranging from 0.175 to 0.35 mmol litre-1. Although this peripheral effect of benzodiazepines on neuromuscular function is not the main site of action of these compounds, there are enough arguments to state that it is not a simple toxic effect. There is some evidence from this study that the peripheral component of the benzodiazepine effect on muscle relaxation may involve a multi- rather than one single receptor system.