[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.

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.

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.

[The agent used to free the hostages in Moscow and the insufficient Dutch preparations in case of a terrorist chemical disaster]. / Het bij de beëindiging van de schouwburggijzeling in Moskou gebruikte middel en de ontoereikende voorbereiding van Nederland op een terroristische chemische calamiteit.

In its attempt to liberate the hostages in Moscow, the government used a gas or vapour. Classical war gases are not appropriate for such a task because they cause irreparable damage, while inhalation anaesthetics are inappropriate because they take too long to take effect, and because hundreds of litres would have been required for a sufficient effect. Following the liberation of the hostages, it was reported that a fentanyl derivative had been used, most likely carfentanyl. From the way that the hostages, in Moscow were liberated, it is clear that terrorist attacks in which chemicals are used may also take place in the future in the Netherlands. In order to be able to react adequately to such situations, additional training for physicians and other health-care personnel is urgently necessary and the hospitals must also be better prepared for this task, especially for the artificial respiration of large numbers of patients and for the administration of large amounts of antidote in easy-to-use dosage units. From now on, on-site treatment and stabilisation will not be reserved only for trauma cases.

Takotsubo cardiomyopathy and anaesthesia: case report and review of the literature.

Takotsubo cardiomyopathy is an acute syndrome characterized by cardiac failure from disturbances in the contractility of the left ventricle. It is presumably caused by sympathetic over stimulation. We describe a case of postoperatively developed Takotsubo cardiomyopathy in a 69-year-old female. The syndrome developed in connection with awareness during complete residual paralysis. The literature on this syndrome is reviewed and implications for anaesthesia described.

Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in the anaesthetized Rhesus monkey.

BACKGROUND: Binding of the steroidal molecule of rocuronium by a cyclodextrin is a new concept for reversal of neuromuscular block. The present study evaluated the ability of Sugammadex Org 25969, a synthetic gamma-cyclodextrin derivative, to reverse constant neuromuscular block of about 90% induced by rocuronium or the non-steroidal neuromuscular blocking drugs, mivacurium or atracurium, in the anaesthetized Rhesus monkey. METHODS: After a bolus injection of rocuronium, mivacurium or atracurium, a continuous infusion of these drugs was started to maintain the first twitch contraction of the train-of-four at approximately 10% of its baseline value. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either sugammadex 0.5 or 1.0 mg kg(-1) was given in the rocuronium-induced blockade and sugammadex 1.0 mg kg(-1) was given in the mivacurium- and atracurium-induced blockade. RESULTS: Sugammadex caused a rapid and complete reversal of rocuronium-induced neuromuscular block. The recovery time to train of four ratio=0.9 after spontaneous recovery was 14.4 min (sd=3.4 min; n=14). This was reduced significantly (P<0.001) to 3.7 min (sd=3.3 min; n=4) with sugammadex 0.5 mg kg(-1) and to 1.9 min (sd=1.0 min; n=4) with sugammadex 1.0 mg kg(-1). Signs of residual blockade or re-curarization were not observed. Reversal of mivacurium- or atracurium-induced neuromuscular block (n=2 in each experiment) by sugammadex (1.0 mg kg(-1)) was not effective. In all experiments, injection of sugammadex had no effects on blood pressure or heart rate. CONCLUSIONS: Sugammadex is effective in reversing rocuronium, but not mivacurium- or atracurium-induced neuromuscular block.

Chemical encapsulation of rocuronium by synthetic cyclodextrin derivatives: reversal of neuromuscular block in anaesthetized Rhesus monkeys.

BACKGROUND: At present, reversal of neuromuscular block induced by steroidal neuromuscular blocking agents (NMBAs) is achieved by administration of cholinesterase inhibitors. Chemical encapsulation of steroidal NMBAs, such as rocuronium, by a cyclodextrin is a new concept in neuromuscular block reversal. The present study evaluates the capacity of nine synthetic cyclodextrin derivatives (Org 25288, Org 25289, Org 25467, Org 25168, Org 25169, Org 25555, Org 25166, Org 26142, and Org 25969) to reverse constant neuromuscular block of approximately 90%, induced by rocuronium infusion in the Rhesus monkey, using single twitch stimulation. The ability of these cyclodextrin derivatives to reverse neuromuscular block was compared with the reversal of the same neuromuscular block by the commonly used combination of neostigmine and atropine. METHODS: After a bolus injection of rocuronium, continuous infusion was started to reduce twitch contractions to approximately 10% of baseline values. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either one of the nine cyclodextrin derivatives or a combination of neostigmine and atropine was given. RESULTS: Recovery with cyclodextrin derivatives Org 26142 and Org 25969 was faster than after a combination of neostigmine and atropine (P<0.05). Injection of these cyclodextrin derivatives did not affect blood pressure or heart rate. Signs of residual block or recurarization were not observed in any of these experiments. In the experiments in which a combination of neostigmine and atropine was given, two animals showed signs of abdominal discomfort as frequently seen after the administration of neostigmine and significant changes in circulatory variables. CONCLUSIONS: Chemical encapsulation or chelation of rocuronium is a new concept in reversing neuromuscular block induced by rocuronium.

An effective correlation dimension and burst suppression ratio of the EEG in rat. Correlation with sevoflurane induced anaesthetic depth.

BACKGROUND AND OBJECTIVE: Anaesthesiologists need parameters that measure the depth of anaesthesia. In the context of this need, the present study investigated in rats how two variables from the electroencephalogram, the burst suppression ratio and effective correlation dimension correlated with a measure of anaesthetic depth as measured in the strength of a noxious withdrawal reflex. METHODS: Eight rats were exposed to different inspiratory concentrations of sevoflurane, each rat in two separate experiments. In the first experiment, spontaneously breathing animals could move freely and no painful stimuli were applied. In the second experiment, in mechanically ventilated restrained anaesthetized rats, the withdrawal reflex was measured every 80 s. In both experiments the electroencephalogram was continuously recorded. The concentration in the effector compartment was estimated using a first order two compartment model. Correlation dimension was computed following the Grassberger/Procaccia/Takens approach with optimized parameter settings to achieve maximum sensitivity to anaesthetic drug effects and enable real-time computation. The Hill, equation was fitted to the data, describing the effect as a function of sevoflurane concentration. RESULTS: Good correlations of Depth of Anaesthesia with correlation dimension as well as burst suppression ratio were established in both types of experiments. Arousal by noxious stimuli decreased burst suppression ratio and increased correlation dimension. The effective sevoflurane concentration associated with 50% of the maximum effect (C50) was higher in experiment II (stimulation) than in experiment I (no stimulation): i.e. for correlation dimension 2.18% vs. 0.60% and for burst suppression ratio 3.07% vs. 1.73%. The slope factors were: gammaCD = 4.15 vs. gammaCD = 1.73 and gammaBSR = 5.2 vs. gammaBSR = 5.4. Correlation dimension and burst suppression ratio both correlated with the strength of the withdrawal reflex with correlation coefficients of 0.46 and 0.66 respectively (P < 0.001). CONCLUSIONS: Both correlation dimension and burst suppression ratio are related to anaesthetic depth and are affected by noxious stimuli. The relationship between anaesthetic depth and burst suppression ratio is confirmed and the potential of correlation dimension is demonstrated.

Time course of action of sugammadex (Org 25969) on rocuronium-induced block in the Rhesus monkey, using a simple model of equilibration of complex formation.

BACKGROUND: Reversal of neuromuscular block can be accomplished by chemical encapsulation of rocuronium by sugammadex (Org 25969), a synthetic gamma-cyclodextrin derivative. The present study determined the time course of the reversal action of sugammadex on rocuronium-induced block in the anaesthetized Rhesus monkey using train-of-four stimulation. METHODS: A bolus injection of rocuronium 100 microg kg(-1) (about 1xED(90)) was given to determine the degree of neuromuscular block reached by this dose. After complete spontaneous recovery, a rapid bolus injection of sugammadex, 1 mg kg(-1), was given and at different time intervals (15, 30 or 60 min, in three different experiments) the effect of another rocuronium bolus injection of 100 microg kg(-1) was determined. RESULTS: Injection of the first dose of rocuronium resulted in a mean neuromuscular block (depression of first twitch) of 93 (SEM=1.6)%. Fifteen minutes after injection of sugammadex the same rocuronium dose resulted in 17% (SEM=5.6) block. After 30 and 60 min these maximum blocks amounted to 49% (SEM=7.6) and 79% (SEM=4.2), respectively. The estimated half-life of sugammadex in Rhesus monkey is 30 (SEM=4.9) min. CONCLUSIONS: The half-life of sugammadex (Org 25969), a new fast and efficient reversal agent for rocuronium-induced block, is relatively short in the Rhesus monkey, implying the possibility to perform neuromuscular block by rocuronium shortly after reversal of a prior block. In translation to the human situation differences in rocuronium sensitivity and kinetics should be taken into account.

Pharmacokinetics and pharmacodynamics of rocuronium in patients with and without renal failure.

BACKGROUND AND OBJECTIVE: This study clarifies the relationship between the neuromuscular blocking effects of rocuronium 0.6 mg kg(-1) and its pharmacokinetics in patients with renal failure. METHODS: Seventeen healthy patients and 17 patients with renal failure were studied under propofol anaesthesia in this prospective open label study. Rocuronium 0.6 mg kg(-1) was given after induction of anaesthesia. The train-of-four mechano-myographic response of the thumb to supramaximal stimulation of the ulnar nerve at 2 Hz every 12 s was measured. Venous blood samples (4 mL) were obtained at 0, 2, 4, 7, 10, 15, 20, 30, 60, 120, 180, 240 and 360 min after relaxant administration. Samples were centrifuged, separated and stored at -20 degrees C until plasma levels of rocuronium and its metabolites were measured. Two- and three-exponential equations were used to describe the pharmacokinetic data in each group and these were compared to each other using the Wilcoxon signed rank sum test as was the pharmacodynamic data. P < 0.05 was significant. RESULTS: Onset of block was similar in both groups. Clinical duration and the time to recovery of the train-of-four to 70% were prolonged in the renal failure group compared to control; 49 vs. 32 min (P < 0.004, 95% confidential, interval 17, difference 5-28) and 88 vs. 55 min (P < 0.001, 95% confidential interval 33, difference 17-50), respectively. Clearance of rocuronium was reduced by 39% in the renal failure patients compared to control, with an 84% increase in the mean residence time. The volume of distribution was unaffected by renal failure. CONCLUSIONS: The duration of action of a bolus dose of 0.6 mg kg(-1) rocuronium is increased significantly in patients with end-stage renal failure compared to healthy controls. This increase may be due to a decreased clearance of rocuronium, the disease process causing the renal failure and/or the medication which patients with renal failure need in their treatment.

Acceleromyography in neonates and small infants: baseline calibration and recovery of the responses after neuromuscular blockade with rocuronium.

BACKGROUND: We have evaluated the use of the TOF-Guard (TOF, train-of-four) acceleromyographic thumb responses to ulnar nerve stimulation in neonates and infants and the return of the responses after neuromuscular blockade. METHODS: Baseline acceleromyographic recording of thumb adduction to ulnar nerve stimulation during volatile anaesthesia was performed in 22 babies aged less than 30 weeks. At the start of stimulation the automatic set-up procedure of the TOF-Guard was used to see if a 100% control twitch height could be achieved. Irrespective of the ability to achieve a 100% control twitch height, TOF stimulation was used thereafter. When no automatic 100% control twitch could be reached, the transducer signal gain factor was set manually to obtain a 100% value. In 14 of the 22 children the recovery after neuromuscular blockade with rocuronium 0.3 mg kg(-1) was recorded. RESULTS: In nine of 22 patients a 100% baseline twitch height was obtained with the automatic set-up. In the other 13 babies the TOF-Guard display indicated that the transducer signal was too low. The mean time to recovery of control twitch to 75% of baseline after rocuronium 0.3 mg kg(-1) was 51 min (SD = 21) and the time to recovery of the TOF ratio to 70% was 49 min (SD = 19). The mean final twitch height and TOF after recovery from rocuronium blockade were 101% (SD = 15) and 92% (SD = 12), respectively. CONCLUSION: The recovery of the responses after neuromuscular blockade to near baseline values shows that acceleromyography can be used to measure neuromuscular block and recovery in neonates and infants.

Model-based administration of inhalation anaesthesia. 3. Validating the system model.

BACKGROUND: We quantified the predictive performance of our computer model of the administration of inhalation anaesthesia from a Datex-Ohmeda Modulus CD circle-absorber system. METHODS: In 50 patients, desflurane anaesthesia was maintained with a fresh-gas flow (FGF) of 0.5 litres min(-1) of both nitrous oxide and oxygen, preceded by fast (n=14) or slow (n=36) induction: FGF greater than total ventilation, Group F; FGF equal to 1.0 litres min(-1), Group S. The two versions of the model studied differed in the size of their inter-tissue diffusion, as 0 (version 1) and 3% (version 2) of the cardiac output was shifted from the viscera to adipose tissue. Model performance was judged by comparing measured and predicted gas concentrations in terms of three variables for each gas concentration in each patient: root mean squared error (rmse=total error), bias (mean predicted - measured) (systematic error), and scatter (error around bias). These variables were then averaged over all patients. These measures were calculated overall, and separately for each group and each stage (1 = induction or 2 = maintenance). RESULTS: Model predictions were in reasonable to very good agreement with clinically obtained data. Version 2 performed better than version 1. Differences between groups were not demonstrated. The model performed better for stage 2, but only for desflurane. In group S, results (mean (SD); as percentages of the measured values for nitrous oxide, oxygen and desflurane) in the order rmse, bias, and scatter were for end-tidal concentrations of nitrous oxide: 8 (4), 8 (5), 2 (1)%; oxygen: 11 (4), -10 (6), 2 (1.1)%; nitrogen: 0.9 (0.6), -0.8 (0.6), 0.2 (0.1) vol%; carbon dioxide: 1.8 (0.6), 1.8 (0.6), 0.2 (0.1) vol%; desflurane, stage 2: 8 (4), 4 (7), 4 (2)%, vs 15 (6), -10 (8), 9 (4)% for stage 1. CONCLUSION: Administration of inhalation anaesthesia can be based on version 2 of this model, but must be guided by active monitoring.

Takotsubo cardiomyopathy and anaesthesia: case report and review of the literature / La miocardiopatía de Takotsubo y la anestesia: caso clínico y evaluación de la bibliografía

Takotsubo cardiomyopathy is an acute syndrome characterized by cardiac failure from disturbances in the contractility of the left ventricle. It is presumably caused by sympathetic over stimulation. We describe a case of postoperatively developed Takotsubo cardiomyopathy in a 69-year-old female. The syndrome developed in connection with awareness during complete residual paralysis. The literature on this syndrome is reviewed and implications for anaesthesia described (AU)

La miocardiopatía de Takotsubo es un síndrome agudo que se caracteriza por una insuficiencia cardíaca debida a alteraciones de la contractilidad ventricular izquierda. Posiblemente derive de una sobreestimulación simpática. Presentamos el caso de una mujer de 69 años con miocardiopatía de Takotsubo que se produjo en el postoperatorio. Durante la parálisis residual completa, el síndrome apareció cuando la paciente recuperó la consciencia. Se analiza la bibliografía con respecto a este síndrome y se describen las implicaciones anestésicas (AU)

Postpartum post-dural puncture headache: is your differential diagnosis complete?

We describe a patient with an intracerebral haemorrhage following an accidental dural puncture during an attempted epidural for pain relief in labour. Anaesthetists need to include intracerebral haemorrhage in the differential diagnosis of post-dural puncture headache in the puerperium.

Severe myocardial ischaemia during mask induction of anaesthesia in an infant with unknown critical supravalvular aortic stenosis.

Congenital supravalvular aortic stenosis is an uncommon type of aortic obstruction. When critical, it represents an extreme variant of outflow tract obstruction with increased risk of cardiovascular instability during exercise or anaesthesia. We present a case of severe myocardial ischaemia during induction of anaesthesia with sevoflurane in a 3-month baby with a presumed diagnosis of valvular aortic stenosis for which a percutaneous balloon dilatation of the aortic valve was scheduled.

Model-based administration of inhalation anaesthesia. 4. Applying the system model.

BACKGROUND: We developed and tested a simple dosing strategy for rapid induction with isoflurane followed by maintenance under minimal-flow conditions, that is 0.5 litre min(-1) total fresh gas flow (FGF). An end-expired concentration was to be achieved within 5 min in a desired therapeutic window, that is 0.8-1.1 vol%, and to be maintained within it for at least 30 min. METHODS: With our new model we computed a three-stage regimen using one fixed vaporizer setting: 3 vol% isoflurane in a FGF of 3 and 1.5 litre min(-1), each for 3 min, and 0.5 litre min thereafter. The ratio of nitrous oxide:oxygen was, consecutively, 2:1, 2:1, and 2:3. We evaluated this scheme in 58 adult patients (body mass 74 (SD 13) kg), mostly during eye and ear, nose, and throat surgery. RESULTS: Measured oxygen (33-45 vol%) and nitrous oxide concentrations (66-50 vol%) evolved in accordance with those computed. In five patients with a median of body mass 92 kg (range 76-126 kg), inspired oxygen concentrations decreased to less than 30 vol%. End-expired isoflurane concentration entered the window after 2 min (range 1.0-5.67 min) and attained its maximum, that is 0.96 vol% (0.8-1.2 vol%), after 3.45 min (1.67-6.33 min). The mean end-expired concentration was in the desired window from 3-60 min and an average of 72% of individual measurements were within the window from 3-30 min. The scheme was adapted in six patients (excluded from analysis) because of hypotension. CONCLUSION: The regimen is easily remembered, reliable, and lends itself to alternative strategies, but must be guided by the monitoring of gas and vapour concentrations and haemodynamic variables.