Prolonged Nerve Blockade Research Articles

Delivery of local anaesthetics by a self-assembled supramolecular system mimicking their interactions with a sodium channel.

Site-1 sodium channel blockers (S1SCBs) act as potent local anaesthetics, but they can cause severe systemic toxicity. Delivery systems can be used to reduce the toxicity, but the hydrophilicity of S1SCBs makes their encapsulation challenging. Here, we report a self-assembling delivery system for S1SCBs whose design is inspired by the specific interactions of S1SCBs with two peptide sequences on the sodium channel. Specifically, the peptides were modified with hydrophobic domains so that they could assemble into nanofibres that facilitated specific binding with the S1SCBs tetrodotoxin, saxitoxin and dicarbamoyl saxitoxin. Injection of S1SCB-carrying nanofibres at the sciatic nerves of rats led to prolonged nerve blockade and to reduced systemic toxicity, with benign local-tissue reaction. The strategy of mimicking a molecular binding site via supramolecular interactions may be applicable more broadly to the design of drug delivery systems for receptor-mediated drugs.

Sex-dependent prolongation of sciatic nerve blockade in diabetes patients: a prospective cohort study

IntroductionDiabetes may affect the duration of nerve block after regional anesthesia. This study aimed to compare the durations of sensory and motor block in diabetes versus non-diabetes patients after lower...

Correction for Shankarappa et al., Prolonged nerve blockade delays the onset of neuropathic pain

Correction for Shankarappa et al., Prolonged nerve blockade delays the onset of neuropathic pain

Prolonged nerve blockade delays the onset of neuropathic pain

Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain. Pharmacological blockade of that activity has been shown to mitigate the onset of associated molecular events in the nervous system. However, results in preventing onset of pain behaviors by providing prolonged nerve blockade have been mixed. Furthermore, the experimental techniques used to date to provide that blockade were limited in clinical potential in that they would require surgical implantation. To address these issues, we have used liposomes (SDLs) containing saxitoxin (STX), a site 1 sodium channel blocker, and the glucocorticoid agonist dexamethasone to provide nerve blocks lasting ~1 wk from a single injection. This formulation is easily injected percutaneously. Animals undergoing spared nerve injury (SNI) developed mechanical allodynia in 1 wk; nerve blockade with a single dose of SDLs (duration of block 6.9 ± 1.2 d) delayed the onset of allodynia by 2 d. Treatment with three sequential SDL injections resulting in a nerve block duration of 18.1 ± 3.4 d delayed the onset of allodynia by 1 mo. This very prolonged blockade decreased activation of astrocytes in the lumbar dorsal horn of the spinal cord due to SNI. Changes in expression of injury-related genes due to SNI in the dorsal root ganglia were not affected by SDLs. These findings suggest that formulations of this kind, which could be easy to apply clinically, can mitigate the development of neuropathic pain.

Prolonged nerve blockade in a patient treated with lithium

We report a case of a patient, chronically treated with oral lithium, who presented with an extremely prolonged (42-hour) duration of sensory and motor paralysis following an uneventful infraclavicular block for hand surgery that was performed under ultrasound guidance using bupivacaine and lidocaine. Due to its direct effect on nerve conduction of action potential, we propose that lithium may have had a role in the unusually prolonged duration of a peripheral nerve block.

Duration and Local Toxicity of Sciatic Nerve Blockade With Coinjected Site 1 Sodium-Channel Blockers and Quaternary Lidocaine Derivatives

Quaternary lidocaine derivatives (QLDs) have recently received much attention because of their potential application in prolonged or sensory-selective local anesthesia. However, associated tissue toxicity is an impeding factor that makes QLDs unfavorable for clinical use. Based on the proposed intracellular site of action, we hypothesized that nerve blocks obtained from lower concentrations of QLDs would be enhanced by the coapplication of extracellularly acting site 1 sodium-channel blocker, resulting in prolonged block duration but with minimal tissue toxicity. Quaternary lidocaine derivatives (QX-314 or QX-222), site 1 sodium-channel blockers (tetrodotoxin [30 μM] or saxitoxin [12.5 μM]), or both were injected in the vicinity of the sciatic nerve. Thermal nociceptive block was assessed using a modified hot plate test; motor block by a weight-bearing test. Tissue from the site of injection was harvested for histological assessment. Coapplication of 25 mM QX-314 or 100 mM QX-222 with site 1 sodium-channel blockers produced an 8- to 10- fold increase in the duration of nerve blocks (P < 0.05), compared with QLDs or site 1 blockers alone. Quaternary lidocaine derivatives elicited severe myotoxicity; this was not exacerbated by coinjection of the site 1 sodium-channel blockers. Coadministration of site 1 sodium-channel blockers and QLDs greatly prolongs the duration of peripheral nerve block without enhancing local tissue injury, but minimal myotoxicity still persists. It is not clear that the risks of QLDs are outweighed by the benefits in providing prolonged nerve blockade.

The Relationship Between Current Intensity for Nerve Stimulation and Success of Peripheral Nerve Blocks Performed in Pediatric Patients Under General Anesthesia

We evaluated the relationship between the lowest current amperage used to obtain a motor response, the success rate and the incidence of neurological complications with peripheral nerve blocks (PNB) in pediatric patients under general anesthesia. We reviewed the regional anesthesia database at The Children's Hospital of Philadelphia and included all pediatric patients who received a single-injection PNB under general anesthesia with the aid of a peripheral nerve stimulator between October 2002 and July 2006. Data analyzed included age, sex, type of block, stimulation threshold, presence of sensory and motor blockade, and neurological complications. Six-hundred sixty patients received a PNB during the study period. The average age of the patients was 13.8 yr (range = 2-18 yr). All the blocks were performed using a current ranging between 0.2 and 1 (median = 0.5 mA, interquartile range: 0.45-0.55 mA). The overall success rate was 96%. There was no difference in success rate between blocks performed using a stimulation threshold of < or =0.5 or >0.5 mA (96.3% vs 95.9%; P = 0.793). There was no correlation between the success rate and sex, type of block performed or intensity of current used. Two patients reported prolonged nerve blockade of the great toe and dorsum of the foot after a sciatic nerve block, which lasted for 72 h. No long-term sequelae were noted in our patients. In this study, a similar PNB success rate was observed with both a low (*0.5 mA) and a high stimulation threshold (>0.5 mA). Therefore, it may not be necessary to perform needle manipulations to achieve a low stimulation threshold (< or =0.5 mA), as this may increase the risk of intraneural injection.

A re-examination of tetrodotoxin for prolonged duration local anesthesia.

Highly potent toxins such as tetrodotoxin that block sodium channels with great specificity have been studied for many years and can provide prolonged blockade when coadministered with vasoconstrictors or conventional local anesthetics. Their utility has been constrained, however, by systemic toxicity. The authors examined the efficacy of tetrodotoxin with and without epinephrine or bupivacaine for producing prolonged-duration sciatic nerve blockade in the rat, and they assessed the degree of concomitant toxicity. Rats received percutaneous sciatic nerve blockade using tetrodotoxin with and without epinephrine or bupivacaine. A subset received subcutaneous injections at the nuchal midline. Nociceptive, proprioceptive, and motor blockade were quantified using contralateral leg responses as controls for systemic effects. Tetrodotoxin without epinephrine produced sciatic nerve blockade, but with considerable toxicity at most effective doses. Epinephrine reduced the median effective concentration of tetrodotoxin for nociception from 37.6 to 11.5 microM and prolonged its duration, such that reversible blocks lasting > 13 h were achieved. Epinephrine reduced measures of systemic distribution and increased the median lethal dose of tetrodotoxin from 40 to 53.6 nmole/kg, thus more than quadrupling the therapeutic index. Bupivacaine increased the local anesthetic potency of tetrodotoxin, reduced its systemic toxicity, and, when coinjected subcutaneously, increased the median lethal dose from 43.7 to 47.7 nmole/kg. The addition of epinephrine did not further improve the effectiveness of the bupivacaine-tetrodotoxin combination. Combinations of epinephrine or bupivacaine with tetrodotoxin or with other high-potency toxins active on sodium channels should be examined for the potential to provide clinically useful, prolonged nerve blockade.

Prolonged regional nerve blockade by controlled release of local anesthetic from a biodegradable polymer matrix.

Prolonged nerve blockade is potentially useful in the management of many acute and chronic pain problems. Aside from infusions via an indwelling catheter, most currently available nondestructive techniques for prolonging local anesthetic action cannot provide more than 1-2 days of blockade. Bioerodible polymer matrixes have been used to deliver a variety of drugs in patients and animals for periods lasting weeks to years. Previously, dibucaine and bupivacaine were incorporated into copolymers of 1,3 bis(p-carboxyphenoxy) propane-sebacic acid anhydride (1:4), and demonstrated sustained release in vitro following incubation of the drug-polymer matrixes in phosphate-buffered solution (pH 7.4, 37 degrees C). In the present study, cylindrical pellets made from polymer matrixes incorporated with bupivacaine-HCl were implanted surgically along the sciatic nerves of rats. Neural block was assessed by direct observation of motor skills and by leg-withdrawal latency to a hot surface. Biochemical and histologic examinations were performed 2 weeks after implantation. Sensory and motor blockade was produced for periods ranging from 2 to 6 days. Contralateral control legs receiving polymer implants without drug showed no block. Blockade was reversible, and animals appeared to recover sensory and motor function normally. Biochemical indexes of nerve and muscle function were indistinguishable from contralateral controls. This biodegradable polymer system provides a promising new alternative for the delivery of local anesthetics to peripheral nerves to produce prolonged blockade for the management of acute and chronic pain.

Terminal nerve sprouting at the frog neuromuscular junction induced by prolonged tetrodotoxin blockade of nerve conduction.

The effects of a prolonged blockade of nerve conduction by tetrodotoxin on frog motor innervation were studied in the cutaneous pectoris muscle of Rana esculenta. Prolonged nerve blockade (up to 22 days) was obtained by repeated subperineural injections of tetrodotoxin. Changes in morphological parameters of neuromuscular junctions were investigated in muscles after staining with a combined cholinesterase-silver method. In addition, changes in the incidence of polyneuronal innervation were investigated conjointly by electrophysiology and morphology. Morphometric analysis of singly innervated muscle fibres of 60 microns diameter revealed insignificant changes during the first week of tetrodotoxin-nerve blockade. After 15 days of paralysis, the mean length of synaptic contacts and the mean length of terminal arborization per synapse were significantly increased as compared to controls (contralateral muscles and citrate buffer-injected controls). After 20-22 days, differences in synaptic and aborization mean lengths were accentuated and reached 44 and 43%, respectively. At that time, the mean number of terminal branching points and of continuous synaptic contacts were also significantly increased (around 20 and 50%, respectively). No changes in the length of abandoned gutters were observed. The incidence of focal polyaxonal innervation (detected morphologically) and of polyneuronal innervation (determined electrophysiologically) was unchanged. The results show that prolonged tetrodotoxin blockade induces sprouting of the terminal arborization which results in an extension of pre-existing nerve terminals and an increase in the complexity of terminal arborization by addition of new branches. Nodal (collateral) sprouting was not changed.