Neurotoxicity of 5% lignocaine.
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Biomedical subjects
Publications and source records attributed to D H Lambert.
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BACKGROUND: Delivery of large doses of local anesthetics for spinal anesthesia by repeated injections or continuous infusion could expose the cauda equina to concentrations of drug that may be neurotoxic per se. We studied this possible neurotoxic effect by assessing recovery from conduction blockade of desheathed peripheral nerves after exposure to some of the local anesthetic solutions commonly used for spinal anesthesia. METHODS: The reversibility of conduction blockade was studied in desheathed bullfrog sciatic nerves, using the sucrose-gap method for recording compound action potentials, before and during exposure to local anesthetics and during drug washout. The nerves were exposed for 15 min to 5% or 1.5% lidocaine, with or without 7.5% dextrose; 0.5% tetracaine; or 0.75% bupivacaine (the latter two without dextrose). Some nerves were also bathed in 7.5% dextrose (without local anesthetic) or in 0.06% tetracaine, which in this preparation is equipotent to 5% lidocaine. After 15 min in the drug, the nerves were washed for 2-3 h and soaked in Ringer's solution overnight. Nerves exposed only to Ringer's solution served as controls. We also studied neuronal uptake and washout of radiolabeled lidocaine. RESULTS: Exposure of nerves to 5% lidocaine, with or without 7.5% dextrose, or to 0.5% tetracaine resulted in irreversible total conduction blockade, whereas 1.5% lidocaine or 0.75% bupivacaine caused 25-50% residual block after the 2-3 h wash. Nerves exposed to Ringer's solution, 7.5% dextrose or 0.06% tetracaine had 0-10% residual block after 2-3 h wash. The action potential of all nerves declined after overnight soak to between 30-60% of the control value, except for those nerves exposed to 5% lidocaine or 0.5% tetracaine, which showed no activity. Exposure to 5% lidocaine for periods of only 4-5 min produced total, irreversible loss of conduction. The uptake by and washout of radiolabeled lidocaine from the nerves indicate that the maximum amount of residual drug after 2-4 min of exposure to 5% lidocaine and a 3-h wash should cause at most only 50% conduction block. CONCLUSIONS: Solutions of 5% lidocaine and 0.5% tetracaine that have been associated with clinical cases of cauda equina syndrome after continuous spinal anesthesia caused irreversible conduction block in desheathed amphibian nerve. Whether these in vitro actions also occur in mammalian nerves in vivo is an important, clinically relevant question now under investigation in our laboratory.
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Forty postpartum patients with postdural puncture headache (PDPH) were randomly assigned to receive oral caffeine (300 mg) or a placebo. Intensity of headache, quantitated using a visual analogue pain scale (VAS), was assessed immediately before drug administration and 4 and 24 h later. Relief of PDPH measured as delta VAS (initial VAS - VAS at 4 h) was significantly better in the caffeine than in the placebo group (P = 0.014). Six patients (30%) whose PDPH was relieved by caffeine at 4 h had recurrence of symptoms the following day. Our study demonstrates that caffeine administered orally provides relief, albeit if sometimes transient, from PDPH with minimal side effects.
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The incidence of tourniquet pain was evaluated in 40 patients having orthopedic surgery of the lower extremities during spinal anesthesia using 15 mg of a plain solution of either 0.5% tetracaine or 0.5% bupivacaine. The drugs were administered in a randomized fashion, and measurement of the levels of sensory anesthesia to pinprick and motor blockade as well as the occurrence of tourniquet pain were made by an independent blinded observer. The onset and maximum cephalad spread of sensory anesthesia and the onset and degree of motor block were similar in both groups of patients. However, the duration of sensory anesthesia was significantly longer in patients in whom tetracaine was used. The incidence of tourniquet pain was significantly greater in patients given tetracaine (60%) than in patients given bupivacaine (25%). The occurrence of tourniquet pain was not related to the level of sensory anesthesia, because patients in the tetracaine group had a higher level of sensory anesthesia (mean T6) than did patients in the bupivacaine group (mean T10) at the onset of tourniquet pain. It is speculated that during spinal anesthesia both A and C fibers (mediating fast and slow pain, respectively) are initially equally inhibited. However, as the concentration of local anesthetic in the cerebrospinal fluid declines, C fibers may become unblocked earlier with tetracaine than A fibers, resulting in tourniquet pain in the presence of an otherwise satisfactory spinal anesthetic.
In a previous report, the incidence of tourniquet pain was found to be 25% with bupivacaine and 60% with tetracaine (P less than 0.05) spinal anesthesia. On the other hand, tetracaine is more potent than bupivacaine in abolishing the single-compound action potential in vitro in isolated nerves. These conflicting observations may be reconciled if bupivacaine produced greater frequency-dependent conduction blockade of nerve action potentials. This hypothesis was tested in C fibers of isolated, desheathed rabbit vagus nerves. The nerves were supramaximally stimulated at frequencies of 9 or 15 Hz. After a control period, the nerves were exposed to bupivacaine (0.2 mM) or tetracaine (0.02 mM) for 30 minutes. The local anesthetics were then washed out by continuous constant-rate perfusion. The decline and recovery of the first and last action potential amplitudes of the train were measured. Bupivacaine and tetracaine produced similar depression of the first action potential of the 9-Hz and 15-Hz trains. However, bupivacaine caused a delayed recovery of the last action potential of the 15-Hz train but not of the 9-Hz train. These results show that bupivacaine produces greater frequency-dependent conduction blockade of C fibers than does tetracaine. These findings offer a possible explanation as to why spinal anesthesia with bupivacaine results in a lower incidence of tourniquet pain than tetracaine.
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Bupivacaine-induced conduction blockade of A, B, and C fibers of the isolated vagus nerve was compared in fourteen pregnant and fourteen nonpregnant rabbits. After a control period in HEPES-Liley solution, the isolated nerves were exposed to bupivacaine concentrations of 0.1 mM to 1.0 mM. After 30 min exposure, the nerves were stimulated supramaximally and the percent reduction in amplitude of A, B, and C fiber compound action potentials was recorded. Linear regressions were fitted by the least squares method. The A fiber conduction blockade was consistently greater in the nerves from pregnant rabbits (P less than 0.001). The slope of the C fiber dose-response curves was also significantly greater in nerves from pregnant rabbits (P less than 0.01). The results indicate that the response of isolated nerves from pregnant animals to local anesthetic-induced conduction blockade differs from that of nerves from nonpregnant animals. However, it is not certain whether the difference is related simply to a more rapid diffusion and shorter onset of block or an enhanced sensitivity of the nerve membrane during pregnancy.
The unicellular cyanobacterium Agmenellum quadruplicatum PR-6 grows in the presence of light on agar containing 10 microM 3-(3,4 dichlorophenyl)-1,1-dimethylurea and 1 to 30 mM glycerol. A derivative strain, PR-6G2, was tolerant of 100 mM glycerol. Photoheterotrophic growth conditions had little effect on transformation competence but did decrease the viability of single cells plated onto agar, particularly cells of the parent strain.
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Pregnancy is associated with a wider dermatomal spread of local anesthetics after epidural and spinal anesthesia. This phenomenon also exists in the immediate postpartum period. The mechanism of this observation is unresolved. However, an increase in progesterone concentration in pregnancy has been implicated as one of the factors. Although plasma progesterone concentrations in humans have been well-documented, the cerebrospinal fluid (CSF) progesterone levels, which may also be important in this regard, have not been determined. Therefore, this study was undertaken to measure plasma and CSF progesterone in the nonpregnant, term parturient and in the immediate postpartum patient and also to determine the relationship between the CSF progesterone concentration and the intrathecal spread of lidocaine used for spinal anesthesia. The plasma progesterone concentrations in 12 nonpregnant, 21 term and eight postpartum patients were 2.3 +/- 61 (SEM) ng/ml, 122 +/- 8 ng/ml and 16 +/- 2.2 ng/ml, respectively. The CSF progesterone concentrations in term parturients (3 +/- 0.28 (SEM) ng/ml) and postpartum patients (1.03 +/- 0.16 ng/ml) were eight and three times greater than that of nonpregnant women (0.39 +/- 0.01 ng/ml). Significantly less lidocaine was needed (P less than 0.05) for comparable segmental levels of spinal anesthesia in term and postpartum patients than in nonpregnant individuals. These data suggest that high CSF, plasma progesterone concentrations, or both may augment the anesthetic spread of lidocaine.
The genes for the alpha- and beta-subunit apoproteins of allophycocyanin (AP) were isolated from the cyanelle genome of Cyanophora paradoxa and subjected to nucleotide sequence analysis. The AP beta-subunit apoprotein gene was localized to a 7.8-kilobase-pair Pst I restriction fragment from cyanelle DNA by hybridization with a tetradecameric oligonucleotide probe. Sequence analysis using that oligonucleotide and its complement as primers for the dideoxy chain-termination sequencing method confirmed the presence of both AP alpha- and beta-subunit genes on this restriction fragment. Additional oligonucleotide primers were synthesized as sequencing progressed and were used to determine rapidly the nucleotide sequence of a 1336-base-pair region of this cloned fragment. This strategy allowed the sequencing to be completed without a detailed restriction map and without extensive and time-consuming subcloning. The sequenced region contains two open reading frames whose deduced amino acid sequences are 81-85% homologous to cyanobacterial and red algal AP subunits whose amino acid sequences have been determined. The two open reading frames are in the same orientation and are separated by 39 base pairs. AP alpha is 5' to AP beta and both coding sequences are preceded by a polypurine, Shine-Dalgarno-type sequence. Sequences upstream from AP alpha closely resemble the Escherichia coli consensus promoter sequences and also show considerable homology to promoter sequences for several chloroplast-encoded psbA genes. A 56-base-pair palindromic sequence downstream from the AP beta gene could play a role in the termination of transcription or translation. The allophycocyanin apoprotein subunit genes are located on the large single-copy region of the cyanelle genome.
The genes for the following proteins were localized by hybridization analysis on the cyanelle genome of Cyanophora paradoxa: the alpha and beta subunits of phycocyanin (cpcA and cpcB); the alpha and beta subunits of allophycocyanin (apcA and apcB); the large and small subunits of ribulose-1,5-bisphosphate carboxylase (rbcL and rbcS); the two putative chlorophyll alpha-binding apoproteins of the photosystem I-P700 complex (psaA and psaB); four apoproteins believed to be components of the photosystem II core complex (psbA, psbB, psbC, and psbD); the two apoprotein subunits of cytochrome b-559 which is also found in the core complex of photosystem II (psbE and psbF); three subunits of the ATP synthase complex (atpA and atpBE); and the cytochrome f apoprotein (petA). Eighty-five percent of the genome was cloned as BamHI, BglII, or PstI fragments. These cloned fragments were used to construct a physical map of the cyanelle genome and to localize more precisely some of the genes listed above. The genes for phycocyanin and allophycocyanin were not clustered and were separated by about 25 kilobases. Although the rbcL gene was adjacent to the atpBE genes and the psbC and psbD genes were adjacent, the arrangement of other genes encoding various polypeptide subunits of protein complexes involved in photosynthetic functions was dissimilar to that observed for known chloroplast genomes. These results are consistent with the independent development of this cyanelle from a cyanobacterial endosymbiont.
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A study was conducted to determine the optimal interval between the administration of d-tubocurarine (dTc) and succinylcholine (SCh) with regard to onset and duration of neuromuscular block and presence of fasciculations and postoperative myalgias. Forty female patients received dTc 3 mg X 70 kg-1 prior to SCh 1.5 mg X kg-1. The interval between drugs was 0, 1, 3, 5, or 7 minutes. Transduced thumb adduction recorded block onset and recovery. Fasciculations were visually detected. Myalgias were assessed on postoperative interview. Pretreatment interval did not affect the onset or recovery of neuromuscular block. Postoperative myalgias were also independent of pretreatment timing. Fasciculations were blocked with 3, 5, or 7 minute intervals, but not with 0 or 1 minute intervals. Therefore, three minutes appear to be the optimal time interval between administration of dTc and SCh since shorter intervals do not inhibit fasciculations and longer intervals do not afford any additional advantages.