Liposomal Bupivacaine for Peripheral Nerve Blockade: A Randomized, Controlled, Crossover, Triple-blinded Pharmacodynamic Study in Volunteers.

BACKGROUND: Little is known about the pharmacodynamic characteristics of liposomal bupivacaine. Hypothesizing that they would not identify pharmacodynamic differences from plain bupivacaine during the initial period after administration, but would find better long-term pharmacodynamic characteristics, the authors designed a randomized, controlled, triple-blinded, single-center study in volunteers. METHODS: Volunteers aged 18 to 55 yr (body mass index, 18 to 35 kg/m2) received two ulnar nerve blocks under ultrasound guidance. Using a crossover design with a washout phase of 36 days or more, one block was performed with liposomal and one with plain bupivacaine. Which came first was determined by randomization. Sensory data were collected by pinprick testing and motor data by thumb adduction, either way in comparison with the contralateral arm. Endpoints included success, time to onset, and duration of blockade. Residual efficacy was assessed by the volunteers keeping a diary. Statistical analysis included Wilcoxon signed-rank and exact McNemar's tests, as well as a generalized estimation equation model. RESULTS: Successful sensory blockade was noted in 8 of 25 volunteers (32%) after liposomal and in 25 of 25 (100%) after plain bupivacaine (P < 0.0001). Significant differences emerged for time to onset, defined as 0% response to pinpricking in four of five hypothenar supply areas (P < 0.0001), and for time from onset to 80% or 20% in one of five areas (P < 0.001; P < 0.001). Carryover effects due to the randomized sequencing were unlikely (estimate, -0.6286; sequence effect, 0.8772; P = 0.474). Self-assessment greater than 3.5 days did reveal, for liposomal bupivacaine only, intermittent but unpredictable episodes of residual sensory blockade. CONCLUSIONS: The results show that liposomal bupivacaine is not a suitable "sole" drug for intraoperative regional anesthesia. Findings of its limited long-term efficacy add to existing evidence that a moderate effect, at best, should be expected on postoperative pain therapy.

The effect of preload on electromyographic train-of-four ratio at the first dorsal interosseous muscle during spontaneous recovery from neuromuscular blockade.

Accurate and reliable quantitative neuromuscular function monitoring is desirable for the optimal management of neuromuscular blockade, selection of the most appropriate reversal agent and dosage, and assessing the completeness of reversal to exclude residual neuromuscular blockade. Applying preload to the thumb may affect the precision of electromyography. This study compared the precision and agreement of electromyography with and without preload during recovery from non-depolarising neuromuscular blockade. After induction of anaesthesia and before neuromuscular blockade, the supramaximal current required at the first dorsal interosseous muscle with and without preload was determined. During recovery, train-of-four ratios were recorded using electromyography every 20 seconds. Alternating pairs of measurements (with and without preload) were obtained until spontaneous recovery was achieved. The preload device applied a resting tension of 75-150 g to the thumb. Bland-Altman analysis for repeated measurements was used to assess precision and agreement of electromyography responses with and without muscle preload. Two hundred and seventy-five sets of repeated measurements were collected from 35 participants. The repeatability coefficient for train-of-four ratios recorded by electromyography with a preload was 0.030 (95% confidence intervals, CI, 0.028 to 0.031) versus 0.068 (95% CI 0.064 to 0.072) without. Train-of-four ratios with preload demonstrated a bias of +0.038 (95% CI 0.037 to 0.042) compared to electromyography without, with 95% limits of agreement of 0.035-0.111. Preload significantly improved the precision of electromyographic train-of-four ratios, with 95% of consecutive measurements differing by less than 3%. Furthermore, electromyography with preload demonstrated a positive bias of 0.04 compared with electromyography alone, the clinical significance of which requires further research.

Attenuation of hypertension by C-fiber stimulation of the human median nerve and the concept-based novel device.

High blood pressure (BP) is a highly controllable risk factor for cardiovascular diseases; however, awareness of this condition and the rates of controlled hypertension are low. Experimental animal studies have shown that stimulation of the median nerve or PC6 acupoint over the wrist has effects on cardiovascular activities, including reductions in systolic and diastolic BPs. A proof-of-concept study was conducted in humans to investigate whether stimulation of median nerve near PC6 acupoint decreased high BP, identify the optimal stimulation parameters for the BP-lowering effects of median nerve stimulation, and determine the specific peripheral nerves or types of afferent fibers mediating the BP-lowering effects. Median nerve stimulation was carried out bilaterally or unilaterally with different stimulation parameters, and the BP and heart rate were monitored. The afferent mechanisms underlying the effects of median nerve stimulation on hypertension were investigated via microneurography, A-fiber blocking experiments, and localized chemical or electrical stimulation. Bilateral median nerve stimulation at either low or high frequencies produced profound but transient reductions in systolic BP, which were elicited when median nerve stimulation was unilaterally applied at interelectrode distances of 2 and 4 cm. Systolic BP was also reduced by electrical stimulation of the thumb on the palm side. Although microneurographic recordings revealed the excitation of both A- and C-fibers following median nerve stimulation, the median nerve-mediated reductions in BP were not affected by A-fiber blockade, and they were mimicked by the activation of C-fibers with capsaicin. The present results indicate that activation of C-fibers in the median nerve generates BP-lowering effects in humans. Based on our clinical study, an optimized median nerve stimulator was built and combined with a wrist BP monitor for simultaneous BP measurements and median nerve stimulation.

Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone.

KEY POINTS: In the adult turtle spinal cord, action potential generation in motoneurones is inhibited by spillover of serotonin to extrasynaptic serotonin 1A (5-HT1A ) receptors at the axon initial segment. We explored whether ingestion of the 5-HT1A receptor partial agonist, buspirone, decreases motoneurone excitability in humans. Following ingestion of buspirone, two tests of motoneurone excitability showed decreases. F-wave areas and persistence in an intrinsic muscle of the hand were reduced, as was the area of cervicomedullary motor evoked potentials in biceps brachii. Our findings suggest that activation of 5-HT1A receptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones. ABSTRACT: Intense serotonergic drive in the turtle spinal cord results in serotonin spillover to the axon initial segment of the motoneurones where it activates serotonin 1A (5-HT1A ) receptors and inhibits generation of action potentials. We examined whether activation of 5-HT1A receptors decreases motoneurone excitability in humans by determining the effects of a 5-HT1A receptor partial agonist, buspirone, on F waves and cervicomedullary motor evoked potentials (CMEPs). In a placebo-controlled double-blind study, 10 participants were tested on two occasions where either placebo or 20 mg of buspirone was administered orally. The ulnar nerve was stimulated supramaximally to evoke F waves in abductor digiti minimi (ADM). CMEPs and the maximal M wave were elicited in biceps brachii by cervicomedullary stimulation and brachial plexus stimulation, respectively. Following buspirone intake, F-wave area and persistence, as well as CMEP area, were significantly decreased. The mean post-pill difference in normalized F-wave areas and persistence between buspirone and placebo days was -27% (-42, -12; 95% confidence interval) and -9% (-16, -2), respectively. The mean post-pill difference in normalized CMEP area between buspirone and placebo days showed greater variation and was -31% (-60, -2). In conclusion, buspirone reduces motoneurone excitability in humans probably via activation of 5-HT1A receptors at the axon initial segment. This has implications for motor output during high drive to the motoneurones when serotonin may spill over to these inhibitory receptors and consequently inhibit motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise.

Performing post-tetanic count during rocuronium blockade has limited impact on subsequent twitch height or train-of-four responses.

BACKGROUND: Waiting five to six minutes before measuring a train-of-four (TOF) after a 50-Hz tetanic stimulation or post-tetanic count (PTC) in order to allow the facilitation of transmission to subside is commonly recommended but is based on limited evidence. The purpose of this study was to measure the TOF responses after PTC in one hand and to compare the responses with those in the contralateral (control) hand. METHODS: Twenty-two adult patients undergoing elective surgery under opioid-desflurane anesthesia were fitted with sensors to measure displacement of their thumbs in response to ulnar nerve stimulation. Rocuronium 0.6 mg·kg(-1) was administered and TOF stimulation was applied to both sides. One side was randomized to PTC (50-Hz tetanus followed by a three-second pause and 15 1-Hz stimuli) when the opposite (control) side recovered to 10% first twitch (T1) height. Train-of-four stimulation was continued bilaterally every 20 sec until 30 min after PTC. Comparisons of the T1 and TOF ratio (T4/T1) were made at two, five, ten, 20, and 30 min. RESULTS: The mean (standard deviation [SD]) T1 value in the PTC arm was 11.8 (7.1)% just before PTC. The T1 values were significantly greater in the PTC arm at two, five, and ten minutes, with mean (SD) differences of 6.3 (6.7)%, 9.4 (6.8)%, and 7.4 (3.9)%, respectively (P = 0.008). There were no significant differences in T1 values between groups at 20 and 30 min, and no statistically significant differences in T4/T1 values at any time. CONCLUSION: A small but clinically insignificant increase in T1 is seen for at least ten minutes after PTC without any detectable change in T4/T1 values. The TOF responses are reliable as early as one minute after PTC.

Peripheral afferent mechanisms underlying acupuncture inhibition of cocaine behavioral effects in rats.

Administration of cocaine increases locomotor activity by enhancing dopamine transmission. To explore the peripheral mechanisms underlying acupuncture treatment for drug addiction, we developed a novel mechanical acupuncture instrument (MAI) for objective mechanical stimulation. The aim of this study was to evaluate whether acupuncture inhibition of cocaine-induced locomotor activity is mediated through specific peripheral nerves, the afferents from superficial or deep tissues, or specific groups of nerve fibers. Mechanical stimulation of acupuncture point HT7 with MAI suppressed cocaine-induced locomotor activity in a stimulus time-dependent manner, which was blocked by severing the ulnar nerve or by local anesthesia. Suppression of cocaine-induced locomotor activity was elicited after HT7 stimulation at frequencies of either 50 (for Meissner corpuscles) or 200 (for Pacinian corpuscles) Hz and was not affected by block of C/Aδ-fibers in the ulnar nerve with resiniferatoxin, nor generated by direct stimulation of C/Aδ-fiber afferents with capsaicin. These findings suggest that HT7 inhibition of cocaine-induced locomotor activity is mediated by A-fiber activation of ulnar nerve that originates in superficial and deep tissue.

Role of activity-dependent conduction block in the diagnosis of primary demyelinating polyneuropathy.

Motor conduction block is one of the well-known neurophysiologic features of primary demyelinating polyneuropathy. In contrast, activity-dependent conduction block (motor conduction block after brief maximum voluntary contraction) is a "rare" neurophysiologic finding in primary demyelinating polyneuropathy. We are reporting the first known case of multifocal acquired demyelinating sensory and motor polyneuropathy with a well-documented activity-dependent conduction block of the ulnar nerve at the forearm segment that transformed into a typical motor response with abnormal temporal dispersion.

Occupational exposure to pesticides and nerve conduction studies among Korean farmers.

This study aimed to determine whether occupational exposure to pesticides was associated with decreased nerve conduction studies among farmers. On 2 separate occasions, the authors performed a cross-sectional study of a group of 31 male farmers who periodically applied pesticides. The study included questionnaire interviews and nerve conduction studies on the median, ulnar, posterior tibial, peroneal, and sural nerves. Although all mean values remained within laboratory normal limits, significant differences between the first and second tests were found in sensory conduction velocities on the median and sural nerves, and motor conduction velocities on the posterior tibial nerve. Lifetime days of pesticide application was negatively associated with nerve conduction velocities at most nerves after adjusting for potential confounders. These findings may reflect a link between occupational pesticide exposure and peripheral neurophysiologic abnormality that deserves further evaluation.

Oral mucosal injection of a local anesthetic solution containing epinephrine enhances muscle relaxant effects of rocuronium.

The purpose of this study was to examine how submucosal injection of a clinically relevant dose of a lidocaine hydrochloride solution containing epinephrine affects the muscle relaxant effects of rocuronium bromide. Sixteen patients scheduled for orthognathic surgery participated in this study. All patients were induced with fentanyl citrate, a target-controlled infusion of propofol and rocuronium bromide. Anesthesia was maintained by total intravenous anesthesia. After nasotracheal intubation, an infusion of rocuronium bromide was started at 7 µg/kg/min, and the infusion rate was then adjusted to maintain a train of four (TOF) ratio at 10 to 15%. The TOF ratio just prior to oral mucosal injection of a 1% lidocaine hydrochloride solution containing 10 µg/mL epinephrine (LE) was taken as the baseline. TOF ratio was observed for 20 minutes, with 1-minute intervals following the start of injection. Mean epinephrine dose was 85.6 ± 18.6 µg and mean infusion rate of rocuronium bromide was 6.3 ± 1.6 µg/kg/min. TOF ratio began to decrease 2 minutes after the injection of LE, reached the minimum value at 3.1 ± 3.6% 12 minutes after the injection, and then began to recover. We conclude that oral mucosal injection of LE enhances the muscle relaxant effects of rocuronium bromide.

Low-level mercury exposure and peripheral nerve function.

BACKGROUND: Mercury is known to be neurotoxic at high levels. There have been few studies of potential peripheral neurotoxicity among persons with exposure to elemental mercury at or near background levels. OBJECTIVES: The present study sought to examine the association between urinary mercury concentration and peripheral nerve function as assessed by sensory nerve conduction studies in a large group of dental professionals. METHODS: From 1997 through 2006 urine mercury measurements and sensory nerve conduction of the median and ulnar nerves in the dominant hand were performed, and questionnaires were completed, on the same day in a convenience sample of dental professionals who attended annual conventions of the American Dental Association. Linear regression models, including repeated measures models, were used to assess the association of urine mercury with measured nerve function. RESULTS: 3594 observations from 2656 subjects were available for analyses. Urine mercury levels in our study population were higher than, but substantially overlap with, the general population. The only stable significant positive association involved median (not ulnar) sensory peak latency, and only for the model that was based on initial observations and exclusion of subjects with imputed BMI. The present study found no significant association between median or ulnar amplitudes and urine mercury concentration. CONCLUSIONS: At levels of urine mercury that overlap with the general population we found no consistent effect of urine mercury concentration on objectively measured sensory nerve function.

Correlation between cardiac output and reversibility of rocuronium-induced moderate neuromuscular block with sugammadex.

BACKGROUND: The aim of this study was to evaluate the correlation between cardiac output (CO) and reversibility of rocuronium-induced moderate neuromuscular block with sugammadex in elderly patients. METHODS: Fifty elderly (≥ 65 years) patients were enrolled in this study. During 1.0-1.5% end-tidal sevoflurane and remifentanil anaesthesia, contraction of the adductor pollicis muscle in response to ulnar nerve stimulation was acceleromyographically quantified. All patients initially received 1 mg/kg rocuronium followed by 0.2 mg/kg whenever the second twitch T2 of the train-of-four (TOF) response reappeared. CO was measured throughout the study using a FloTrac™/Vigileo™ monitor. After completion of surgery and at the reappearance of T2, the time required for a bolus dose of 2 mg/kg sugammadex to facilitate recovery to a TOF ratio of 0.9 was recorded, and its correlation with CO was analysed. RESULTS: Adequate recovery of neuromuscular block was achieved after sugammadex in all patients. Mean CO at the time of reversal with sugammadex was 5.3 l/min (1.3), and recovery time to a TOF ratio of 0.9 was 173.4 s (54.8). A statistically significant inverse correlation was seen between the time to recovery to a TOF ratio of 0.9 and CO [reversal time (s) = -27.7·CO + 298.7, R(2) = 0.461, P < 0.0001]. CONCLUSIONS: The time to reach a TOF ratio of 0.9 following sugammadex is dependent on CO in elderly patients.

Continuous peripheral nerve block in forearm for severe hand trauma.

We studied the use of a continuous peripheral nerve block (CPNB) in the distal forearm and wrist immediately after emergent surgery for severe hand trauma in 22 hands. After emergent surgery, a 2-3 cm longitudinal incision was made at the distal forearm and an 18-gauge catheter was inserted along the peripheral nerves. All patients received postoperative analgesia by continuous infusion of 0.2% ropivacaine at 2 ml/h for seven to 21 days. Pain score remained low during postoperative period and only a small number of analgesic rescues were needed. There were no major complications related to the CPNB and one patient showed mild superficial infection at the insertion site that immediately recovered after catheter removal. This method provides good postoperative analgesia without loss of motor function in extrinsic hand muscles and should be considered as a postoperative pain management for severe hand trauma.

Effect of recombinant human growth hormone on peripheral nerve regeneration: experimental work on the ulnar nerve of the rat.

Neurotrophic factors may be used to improve the growth and repair of injured peripheral nerves. In this study we determined the effectiveness of recombinant human growth hormone on peripheral nerve injury in the Wistar rat. The ulnar nerve of the rat was sectioned and its proximal and distal ends were sutured to either end of a silastic tube, with the aim of encouraging regeneration through the tube. 32 ulnar nerve specimens were randomized into two groups: 18 nerves regenerating under the influence of recombinant growth hormone, and 14 nerves regenerating in its absence. The study was performed over a period of 8 weeks and progression of regeneration was assessed with regular surface electroneurography every 1-2 weeks after surgery. In the group receiving recombinant growth hormone, it comprised a significant improvement in the recovery of conduction velocity, and a more gradual increase in the amplitude of motor potential from the fifth week onwards was observed. Histological analysis of study specimens in the recombinant hormone group revealed an improved architecture of the regenerating nerve, a greater density of nerve fibers, and increased myelination with a lesser degree of endoneural fibrosis. Our work demonstrates the positive effect of the administration of recombinant human growth hormone in obtaining significantly improved conduction velocities, and a greater improvement in nerve regeneration from the fifth week of monitoring when compared to the control group. Histological analysis in the group receiving hormone showed acceptable degree of myelination with little granulation tissue and fibrosis.

Permanent ulnar nerve palsy after embolotherapy of arteriovenous malformation around the elbow.

Permanent nerve palsy is an extremely rare but critical complication after embolotherapy of arteriovenous malformations of the extremities. The authors present a case of permanent ulnar nerve palsy after embolotherapy of an arteriovenous malformation around the elbow, and caution that transcatheter embolotherapy of arteriovenous malformations located close to major neurovascular structures must be carefully planned and individualized.

Neurophysiological patterns of ulnar nerve neuropathy in leprosy reactions.

BACKGROUND: Leprosy neuropathy, despite being primarily demyelinating, frequently leads to axonal loss. Neurophysiological examination of the nerves during Type 1 (T1R) and Type 2 reactions (T2R) may give some insight into the pathophysiological mechanisms. METHODS: Neurophysiological examinations were performed in 28 ulnar nerves during a clinical trial of steroid treatment effectiveness, 19 patients with T1R and nine with T2R. The nerves were monitored during a period of 6 months; there were eight assessments per nerve, for a total of 224 assessments. Nine neurophysiological parameters were assessed at three sites of the ulnar nerve. The compound motor action potential amplitudes elicited at wrist, elbow and above, as well as the conduction velocity and temporal dispersion across the elbow, were chosen to focus on the changes occurring in the parameters at the elbow tunnel. RESULTS AND CONCLUSION: Neurophysiological changes indicating axonal and demyelinating processes during both T1R and T2R were detected across the elbow. Changes in demyelination, i.e. a Conduction Block, as a primary event present during T2R, occurring as an acute phenomenon, were observed regularly; in T1R Temporal Dispersion, a subacute phenomenon, was seen. During treatment remyelination occurred after both types of reactions.

Methylcobalamin, but not methylprednisolone or pleiotrophin, accelerates the recovery of rat biceps after ulnar to musculocutaneous nerve transfer.

Using ulnar nerve as donor and musculocutaneous nerve as recipient we recently demonstrated that end-to-end neurorrhaphy in young adult male Wistar rats resulted in good recovery following protracted survival. Here we explored whether anti-inflammatory drug- methylprednisolone, regeneration/myelination-enhancing agent- methylcobalamin and neurite growth-enhancing and angiogenic factor- pleiotrophin accelerated its recovery. Methylprednisolone suppressed the perineuronal microglial reaction and periaxonal ED-1 expression while pleiotrophin increased the blood vessel density and nerve fiber densities in the reconnected nerve as expected. Neither methylprednisolone nor methylcobalamin altered the expression of growth associated protein 43 in the neurons examined suggesting that they did not interfere with axonal regeneration attempt. Surprisingly methylcobalamin enhanced the recovery of compound muscle action potentials and motor end plate innervation and the performance on sticker removal grooming test and augmented the diameters and myelin thicknesses of regenerated axons dramatically while enhancing S-100 expression in Schwann cells; remarkable recovery was achieved 1 month following neurorrhaphy. Simultaneous methylcobalamin and pleiotrophin treatment resulted in quick and persistent supernumerary reinnervation but failed to enhance the recovery over that of the former alone. Methylprednisolone transiently suppressed the enumeration of regrowing axons. In conclusion, methylcobalamin may be preferred over methylprednisolone to facilitate the recovery of peripheral nerves following end-to-end neurorrhaphy. The long-term effect of this treatment however remains to be clarified.

Evaluation of a midhumeral block of the radial, ulnar, musculocutaneous and median (RUMM block) nerves for analgesia of the distal aspect of the thoracic limb in dogs.

OBJECTIVE: To evaluate a technique for midhumeral peripheral nerve blockade in the dog. STUDY DESIGN: Cadaveric technique development; in vivo placebo-controlled, prospective crossover study. ANIMALS: Canine cadavers (n=38) and 8 clinically healthy, adult hound dogs. METHODS: A technique for peripheral block of the radial, ulnar, musculocutaneous, and median nerves (RUMM block) was evaluated using cadaver limbs. Eight purpose-bred, research dogs were anesthetized; a RUMM block was performed on each thoracic limb. One limb from each dog randomly received 0.5% bupivacaine and the opposite limb was assigned to receive sterile saline solution as a control. After recovery from anesthesia, skin sensation at selected dermatomes was evaluated for 24 hours using a mechanical stimulus. Weight-bearing, conscious proprioception, and withdrawal reflex were also evaluated. One month after initial testing, each dog was reanesthetized and each limb received the opposite treatment. RESULTS: Sensory thresholds were significantly increased over baseline measurements when compared with control limbs for all nerves. Complete sensory block was achieved in radial (15/16), ulnar (3/16), musculocutaneous (8/16), and median (11/16) nerves, using a mechanical stimulus of analgesia. Complete simultaneous block of all nerves was only obtained in 1 of 16 limbs. CONCLUSION: RUMM block resulted in desensitization of the skin in the associated dermatomes for 4-10 hours. Complete sensory block of the dermatomes supplied by the radial nerve was most consistent. CLINICAL RELEVANCE: RUMM block may be an effective technique to provide adjunctive analgesia for dogs undergoing surgery of the distal aspect of the thoracic limb.

The effects of mivacurium-induced neuromuscular block on Bispectral Index and Cerebral State Index in children under propofol anesthesia - a prospective randomized clinical trial.

BACKGROUND: In adults anesthetized with propofol, muscle relaxants may decrease the Bispectral Index (BIS). The aim of this prospective randomized trial was to detect the influence of a muscle relaxant bolus on the BIS and the Cerebral State Index (CSI) in children under propofol anesthesia. METHODS: Forty pediatric patients, age 6.6 +/- 3.3 years, weight 24 +/- 9 kg, scheduled for surgical procedures requiring general anesthesia were enrolled. Two minutes after i.v. injection of 0.3 mcg.kg(-1) of sufentanil, general anesthesia was induced by an initial bolus of 3 mg.kg(-1) of propofol, followed by a continuous infusion titrated to achieve a stable BIS value of 50 +/- 5. Patients received either mivacurium 0.25 mg.kg(-1) (Group Miva) or NaCl 0.9% 0.12 ml.kg(-1) (Group Control). Mean BIS and CSI values per minute were compared between (Miva vs. Control) and within groups (Baseline vs 5 min. after study drug administration). RESULTS: The observed changes in BIS and CSI values before and after administration of study drugs revealed no differences between the study groups. Mean baseline BIS and CSI values were lower than 5 min after study drug administration. There were no intergroup differences with respect to BIS and CSI values at any time point. CONCLUSIONS: These data suggest that in pediatric patients anesthetized with propofol, administration of mivacurium has no impact on BIS and CSI values.