Model-based control of neuromuscular block using mivacurium: design and clinical verification

BACKGROUND: Short-acting agents for neuromuscular block (NMB) require frequent dosing adjustments for individual patient's needs. In this study, we verified a new closed-loop controller for mivacurium dosing in clinical trials. METHODS: Fifteen patients were studied. T1% measured with electromyography was used as input signal for the model-based controller. After induction of propofol/opiate anaesthesia, stabilization of baseline electromyography signal was awaited and a bolus of 0.3 mg kg-1 mivacurium was then administered to facilitate endotracheal intubation. Closed-loop infusion was started thereafter, targeting a neuromuscular block of 90%. Setpoint deviation, the number of manual interventions and surgeon's complaints were recorded. Drug use and its variability between and within patients were evaluated. RESULTS: Median time of closed-loop control for the 11 patients included in the data processing was 135 [89-336] min (median [range]). Four patients had to be excluded because of sensor problems. Mean absolute deviation from setpoint was 1.8 +/- 0.9 T1%. Neither manual interventions nor complaints from the surgeons were recorded. Mean necessary mivacurium infusion rate was 7.0 +/- 2.2 microg kg-1 min-1. Intrapatient variability of mean infusion rates over 30-min interval showed high differences up to a factor of 1.8 between highest and lowest requirement in the same patient. CONCLUSIONS: Neuromuscular block can precisely be controlled with mivacurium using our model-based controller. The amount of mivacurium needed to maintain T1% at defined constant levels differed largely between and within patients. Closed-loop control seems therefore advantageous to automatically maintain neuromuscular block at constant levels.

Ultrasound-guided spermatic cord block for scrotal surgery

Performing spermatic cord block for scrotal surgery avoids the potential risks of neuraxial and general anaesthesia and provides long-lasting postoperative analgesia. A blindly performed block is often inefficient and bears its own potential risks (intravascular injection of local anaesthetics, haematoma formation and perforation of the deferent duct). The use of ultrasound may help to overcome these disadvantages. The aim of this study was to test the feasibility and monitor the success rate of a new ultrasound-guided spermatic cord block.

Ultrastructural changes in diaphragm neuromuscular junctions in a severe mouse model for Spinal Muscular Atrophy and their prevention by bifunctional U7 snRNA correcting SMN2 splicing

In Spinal Muscular Atrophy (SMA), the SMN1 gene is deleted or inactivated. Because of a splicing problem, the second copy gene, SMN2, generates insufficient amounts of functional SMN protein, leading to the death of spinal cord motoneurons. For a "severe" mouse SMA model (Smn -/-, hSMN2 +/+; with affected pups dying at 5-7 days), which most closely mimicks the genetic set-up in human SMA patients, we characterise SMA-related ultrastructural changes in neuromuscular junctions (NMJs) of two striated muscles with discrete functions. In the diaphragm, but not the soleus muscle of 4-days old SMA mice, mitochondria on both sides of the NMJs degenerate, and perisynaptic Schwann cells as well as endoneurial fibroblasts show striking changes in morphology. Importantly, NMJs of SMA mice in which a modified U7 snRNA corrects SMN2 splicing and delays or prevents SMA symptoms are normal. This ultrastructural study reveals novel features of NMJ alterations - in particular the involvement of perisynaptic Schwann cells - that may be relevant for human SMA pathogenesis.

Block training periodization in alpine skiing: effects of 11-day HIT on VO2max and performance

Attempting to achieve the high diversity of training goals in modern competitive alpine skiing simultaneously can be difficult and may lead to compromised overall adaptation. Therefore, we investigated the effect of block training periodization on maximal oxygen consumption (VO2max) and parameters of exercise performance in elite junior alpine skiers. Six female and 15 male athletes were assigned to high-intensity interval (IT, N = 13) or control training groups (CT, N = 8). IT performed 15 high-intensity aerobic interval (HIT) sessions in 11 days. Sessions were 4 x 4 min at 90-95% of maximal heart rate separated by 3-min recovery periods. CT continued their conventionally mixed training, containing endurance and strength sessions. Before and 7 days after training, subjects performed a ramp incremental test followed by a high-intensity time-to-exhaustion (tlim) test both on a cycle ergometer, a 90-s high-box jump test as well as countermovement (CMJ) and squat jumps (SJ) on a force plate. IT significantly improved relative VO2max by 6.0% (P < 0.01; male +7.5%, female +2.1%), relative peak power output by 5.5% (P < 0.01) and power output at ventilatory threshold 2 by 9.6% (P < 0.01). No changes occurred for these measures in CT. tlim remained unchanged in both groups. High-box jump performance was significantly improved in males of IT only (4.9%, P < 0.05). Jump peak power (CMJ -4.8%, SJ -4.1%; P < 0.01), but not height decreased in IT only. For competitive alpine skiers, block periodization of HIT offers a promising way to efficiently improve VO2max and performance. Compromised explosive jump performance might be associated with persisting muscle fatigue.

Synthesis of the Sugar Building Block of Bicyclo-RNA

We present the novel synthesis of two sugar units that are central intermediates for the formation of members of the bicyclo-DNA and -RNA family. The synthesis starts from commercially available 1,2: 5,6-di-O-isopropylidene-alpha-D-glucofuranose. The key step involves the elaboration of a carbocyclic ring in a furanoside by rhodium(I)-catalyzed hydroacylation. Via this pathway, one of the sugar units is available in 8 steps and in an overall yield of 27%, while its deoxy derivative is obtained in 11 steps, which is 5 steps fewer than in our previous synthesis of this compound.

Different Learning Curves for Axillary Brachial Plexus Block: Ultrasound Guidance versus Nerve Stimulation

Little is known about the learning of the skills needed to perform ultrasound- or nerve stimulator-guided peripheral nerve blocks. The aim of this study was to compare the learning curves of residents trained in ultrasound guidance versus residents trained in nerve stimulation for axillary brachial plexus block. Ten residents with no previous experience with using ultrasound received ultrasound training and another ten residents with no previous experience with using nerve stimulation received nerve stimulation training. The novices' learning curves were generated by retrospective data analysis out of our electronic anaesthesia database. Individual success rates were pooled, and the institutional learning curve was calculated using a bootstrapping technique in combination with a Monte Carlo simulation procedure. The skills required to perform successful ultrasound-guided axillary brachial plexus block can be learnt faster and lead to a higher final success rate compared to nerve stimulator-guided axillary brachial plexus block.

Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization

The hERG voltage-gated potassium channel mediates the cardiac I(Kr) current, which is crucial for the duration of the cardiac action potential. Undesired block of the channel by certain drugs may prolong the QT interval and increase the risk of malignant ventricular arrhythmias. Although the molecular determinants of hERG block have been intensively studied, not much is known about its stereoselectivity. Levo-(S)-bupivacaine was the first drug reported to have a higher affinity to block hERG than its enantiomer. This study strives to understand the principles underlying the stereoselectivity of bupivacaine block with the help of mutagenesis analyses and molecular modeling simulations. Electrophysiological measurements of mutated hERG channels allowed for the identification of residues involved in bupivacaine binding and stereoselectivity. Docking and molecular mechanics simulations for both enantiomers of bupivacaine and terfenadine (a non-stereoselective blocker) were performed inside an open-state model of the hERG channel. The predicted binding modes enabled a clear depiction of ligand-protein interactions. Estimated binding affinities for both enantiomers were consistent with electrophysiological measurements. A similar computational procedure was applied to bupivacaine enantiomers towards two mutated hERG channels (Tyr652Ala and Phe656Ala). This study confirmed, at the molecular level, that bupivacaine stereoselectively binds the hERG channel. These results help to lay the foundation for structural guidelines to optimize the cardiotoxic profile of drug candidates in silico.

Sciatic-femoral nerve block with bupivacaine in goats undergoing elective stifle arthrotomy

The aim of this study was to describe the sciatic-femoral nerve block (SFNB) in goats and to evaluate the peri-operative analgesia when the goats underwent stifle arthrotomy. The animals were randomly assigned to one of four treatment groups: groups 0.25, 0.5 and 0.75 received 0.25%, 0.5% and 0.75% of bupivacaine, respectively, while group C (control group) received 0.9% NaCl. In all groups, the volume administered was 0.2 mL/kg. Intra-operatively, the proportion of animals receiving rescue propofol was significantly lower in groups 0.5 and 0.75, compared to group C. Post-operatively, the visual analogue scale (VAS) and total pain score were significantly higher in group C than in the other groups. Group 0.75 had the highest percentage of animals showing motor blockade. SFNB performed with bupivacaine resulted in better intra- and post-operative analgesia than SFNB performed with saline. Compared to the other concentrations, 0.5% bupivacaine resulted in satisfactory analgesia with acceptable side effects.

Ultrasound-guided suprascapular nerve block, description of a novel supraclavicular approach

The suprascapular nerve (SSN) block is frequently performed for different shoulder pain conditions and for perioperative and postoperative pain control after shoulder surgery. Blind and image-guided techniques have been described, all of which target the nerve within the supraspinous fossa or at the suprascapular notch. This classic target point is not always ideal when ultrasound (US) is used because it is located deep under the muscles, and hence the nerve is not always visible. Blocking the nerve in the supraclavicular region, where it passes underneath the omohyoid muscle, could be an attractive alternative.

Ultrasound imaging to estimate risk of esophageal and vascular puncture after conventional stellate ganglion block

The most common techniques to perform stellate ganglion blocks (SGBs) are the blind C6 approach and the fluoroscopic-controlled paratracheal C7 approach, both after manual dislocation of the large vessels. Complications due to vascular or esophageal puncture have been reported. The goal of this ultrasound imaging study was to determine how frequently hazardous structures are located along the needle path of conventional SGB and to determine the influence of the dislocation maneuver on their position.