Electroencephalographic markers of brain development during sevoflurane anaesthesia in children up to 3 years old.

BACKGROUND: General anaesthetics generate spatially defined brain oscillations in the EEG that relate fundamentally to neural-circuit architecture. Few studies detailing the neural-circuit activity of general anaesthesia in children have been described. The study aim was to identify age-related changes in EEG characteristics that mirror different stages of early human brain development during sevoflurane anaesthesia. METHODS: Multichannel EEG recordings were performed in 91 children aged 0-3 yr undergoing elective surgery. We mapped spatial power and coherence over the frontal, parietal, temporal, and occipital cortices during maintenance anaesthesia. RESULTS: During sevoflurane exposure: (i) slow-delta (0.1-4 Hz) oscillations were present in all ages, (ii) theta (4-8 Hz) and alpha (8-12 Hz) oscillations emerge by ∼4 months, (iii) alpha oscillations increased in power from 4 to 10 months, (iv) frontal alpha-oscillation predominance emerged at ∼6 months, (v) frontal slow oscillations were coherent from birth until 6 months, and (vi) frontal alpha oscillations became coherent ∼10 months and persisted in older ages. CONCLUSIONS: Key developmental milestones in the maturation of the thalamo-cortical circuitry likely generate changes in EEG patterns in infants undergoing sevoflurane general anaesthesia. Characterisation of anaesthesia-induced EEG oscillations in children demonstrates the importance of developing age-dependent strategies to monitor properly the brain states of children receiving general anaesthesia. These data have the potential to guide future studies investigating neurodevelopmental pathologies involving altered excitatory-inhibitory balance, such as epilepsy or Rett syndrome.

Periaqueductal gray neuroplasticity following chronic morphine varies with age: role of oxidative stress.

The development of tolerance to the antinociceptive effects of morphine has been associated with networks within ventrolateral periaqueductal gray (vlPAG) and separately, nitric oxide signaling. Furthermore, it is known that the mechanisms that underlie tolerance differ with age. In this study, we used a rat model of antinociceptive tolerance to morphine at two ages, postnatal day (PD) 7 and adult, to determine if changes in the vlPAG related to nitric oxide signaling produced by chronic morphine exposure were age-dependent. Three pharmacological groups were analyzed: control, acute morphine, and chronic morphine group. Either morphine (10mg/kg) or equal volume of normal saline was given subcutaneously twice daily for 6½ days. Animals were analyzed for morphine dose-response using Hot Plate test. The expression of several genes associated with nitric oxide metabolism was evaluated using rtPCR. In addition, the effect of morphine exposure on immunohistochemistry for Fos, and nNOS as well as nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) reaction at the vlPAG were measured. In both age groups acute morphine activated Fos in the vlPAG, and this effect was attenuated by chronic morphine, specifically in the vlPAG at the level of the laterodorsal tegmental nucleus (LDTg). In adults, but not PD7 rats, chronic morphine administration was associated with activation of nitric oxide function. In contrast, changes in the gene expression of PD7 rats suggested superoxide and peroxide metabolisms may be engaged. These data indicate that there is supraspinal neuroplasticity following morphine administration as early as PD7. Furthermore, oxidative stress pathways associated with chronic morphine exposure appear age-specific.

Stable plasma concentrations of unbound ropivacaine during postoperative epidural infusion for 24-72 hours in children.

BACKGROUND AND OBJECTIVES: The aim of this open, non-controlled, multi-centre study was to evaluate the pharmacokinetics and safety of a 24-72 h continuous epidural ropivacaine infusion in children aged 1-9 yr. METHODS: After induction of general anaesthesia, 29 ASA I-II children, scheduled for major surgery in dermatomes below T10 had lumbar epidural catheters placed. A bolus of ropivacaine, 2 mg kg(-1), was given over 4 min, followed immediately by an infusion of 2 mg mL(-1) ropivacaine 0.4 mg kg(-1) h(-1) for the next 24-72 h. RESULTS: Plasma concentrations of total ropivacaine (mean 0.83 and 1.06 mg L(-1) at 16-31 and 59-72 h, respectively) and alpha1-acid-glucoprotein (mean 13 and 25 micromol L(-1) at baseline and 59-72 h) increased over the course of the infusion. Plasma concentrations of unbound ropivacaine were stable throughout the epidural infusion (mean 0.021 range 0.011-0.068 and mean 0.016 range 0.009-0.023 mg L(-1) at 16-31 and 59-72 h, respectively) and were well below threshold levels associated with central nervous system toxicity in adults (0.35 mg L(-1)). Apparent unbound clearance (mean 346, range 86-555 mL min(-1) kg(-1)) showed no age-dependency. No signs of systemic toxicity or cardiovascular effects were observed. All patients received additional analgesics with morphine. CONCLUSION: Following a 24-72 h epidural infusion of ropivacaine 0.4 mg kg(-1) h(-1) in 1-9-yr-old children, the plasma concentrations of unbound ropivacaine were stable over time with no age-dependency.

Effects of repeated injection of local anesthetic on sciatic nerve blocks response.

In order to examine whether repeated sciatic nerve blocks showed tachyphylaxis and continuity of sciatic nerve with spinal cord affected development of tachyphylaxis when assayed in vivo by duration of depression compound action potentials (CAP), rats were anesthetized with halothane, ventilated, monitored and supported with stable hemodynamics and temperature. Posterior tibial nerve distally and sciatic nerve in thigh were exposed, placed on bipolar silver electrodes for stimulation and recording respectively. Three sequential sciatic nerve blocks were performed between these electrodes using 0.15 ml of 3% chloroprocaine. Nine rats were chosen to observe the effects of repeated sciatic nerve blocks on CAP. In another 18 rats, a second investigator exposed the sciatic nerve near its origin at spinal cord and randomly performed nerve cut and sham (n=9), and closed the incision blinding the electrophysiologic investigator. The results showed that electrical stimulated tibial nerve induced sciatic nerve Aalpha/beta, Adelta, C fiber mediated CAP waves. CAP amplitudes were remained stable during whole experimental procedure. CAP amplitudes were decreased completely with 3% chloroprocaine blocked sciatic nerve and recovered fully. The duration of CAP depression were reduced with repeated blocks. There were no selective blocked effects on Aalpha/beta, Adelta, C fiber mediated CAP. With sciatic nerve cut proximally, there was no statistical significant tachyphylaxis with 3% chloroprocaine repeated blocked sciatic nerve, and the duration of first and third blocked Adelta fiber mediated CAP was 108+/-20 and 92+/-14 min respectively (P>0.05). In normal rats the duration of first and third blocked Adelta fiber mediated CAP was 110+/-20 and 75+/-16 min respectively (P<0.05). It was suggested that tachyphylaxis to local anesthetics can occur in rats repeated blocked sciatic nerve when assayed in vivo by duration of depression CAP. The continuity of sciatic nerve with spinal cord is one of the important factors affecting the development of tachyphylaxis.

Diagnosis and management of MNGIE syndrome in children: case report and review of the literature.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare disorder that presents in childhood; however, marked delay in diagnosis is common. We report a case and review the literature describing the typical features that should alert pediatricians to the diagnosis. We also describe a novel management strategy for providing symptomatic relief.

Glutamate-induced sensitization of rat masseter muscle fibers.

In rats, intradermal or intraarticular injection of glutamate or selective excitatory amino acid receptor agonists acting at peripheral excitatory amino acid receptors can decrease the intensity of mechanical stimulation required to evoke nocifensive behaviors, an indication of hyperalgesia. Since excitatory amino acid receptors have been found on the terminal ends of cutaneous primary afferent fibers, it has been suggested that increased tissue glutamate levels may have a direct sensitizing effect on primary afferent fibers, in particular skin nociceptors. However, less is known about the effects of glutamate on deep tissue afferent fibers. In the present study, a series of experiments were undertaken to investigate the effect of intramuscular injection of glutamate on the excitability and mechanical threshold of masseter muscle afferent fibers in anesthetized rats of both sexes. Injection of 1.0 M, but not 0.1 M glutamate evoked masseter muscle afferent activity that was significantly greater than that evoked by isotonic saline. The mechanical threshold of masseter muscle afferent fibers, which was assessed with a Von Frey hair, was reduced by approximately 50% for a period of 30 min after injection of 1.0 M glutamate, but was unaffected by injections of 0.1 M glutamate or isotonic saline. Injection of 25% dextrose, which has the same osmotic strength as 1.0 M glutamate, did not evoke significant activity in or decrease the mechanical threshold of masseter muscle afferent fibers. Magnetic resonance imaging experiments confirmed that injection of 25% dextrose and 1.0 M glutamate produced similar edema volumes in the masseter muscle tissue. Co-injection of 0.1 M kynurenate, an excitatory amino acid receptor antagonist, and 1.0 M glutamate attenuated glutamate-evoked afferent activity and prevented glutamate-induced mechanical sensitization. When male and female rats were compared, no difference in the baseline mechanical threshold or in the magnitude of glutamate-induced mechanical sensitization of masseter muscle afferent fibers was observed; however, the afferent fiber activity evoked by injection of 1.0 M glutamate into the masseter muscle was greater in female rats. The results of the present experiments show that intramuscular injection of 1.0 M glutamate excites and sensitizes rat masseter muscle afferent fibers through activation of peripheral excitatory amino acid receptors and that glutamate-evoked afferent fiber activity, but not sensitization, is greater in female than male rats.

Evidence that spinal segmental nitric oxide mediates tachyphylaxis to peripheral local anesthetic nerve block.

BACKGROUND: Tachyphylaxis to sciatic nerve blockade in rats correlates with hyperalgesia. Spinal inhibition of nitric oxide synthase with N(G)nitro-L-arginine methyl ester (L-NAME) has been shown to prevent hyperalgesia. Given systemically, L-NAME also prevents tachyphylaxis. The action of L-NAME in preventing tachyphylaxis therefore may be mediated at spinal sites. We compared systemic versus intrathecal potency of L-NAME in modulating tachyphylaxis to sciatic nerve block. METHODS: Rats were prepared with intrathecal catheters. Three sequential sciatic nerve blocks were placed. Duration of block of thermal nocifensive, proprioceptive and motor responses was recorded. We compared spinal versus systemic dose-response to L-NAME, and examined effects of intrathecal arginine on tachyphylaxis. An additional group of rats underwent testing after T10 spinal cord transection. In these rats duration of sciatic nerve block was assessed by determining the heat-induced flexion withdrawal reflex. RESULTS: L-NAME was 25-fold more potent in preventing tachyphylaxis given intrathecally than intraperitoneally. Intrathecal arginine augmented tachyphylaxis. Spinalized rats exhibited tachyphylaxis to sciatic block. CONCLUSION: The increased potency of intrathecal versus systemic L-NAME suggests a spinal site of action in inhibiting tachyphylaxis. Descending pathways are not necessary for the development of tachyphylaxis since it occurs even after T10 spinal cord transection. Thus tachyphylaxis, like hyperalgesia, is mediated at least in part by a spinal site of action.

Osmotic effects on the T2 relaxation decay of in vivo muscle.

Saline solutions are commonly employed as a vehicle for drugs administered intramuscularly. In this study, in vivo measurements of spin-spin relaxation (T2) processes by magnetic resonance imaging (MRI) were performed to investigate the distribution of water in rat masseter muscle tissue after intramuscular injection of saline solutions of varying tonicity. Prior to saline injection, image-based T2 relaxation decay of muscle was monoexponential. After injection of saline, the T2 relaxation decay became multiexponential. Non-negative least squares (NNLS) analysis of the decay curves revealed two relaxation components: a fast component (T2 = 20-40 ms) and a slow component (T2 = 150-400 ms), which are assigned to intra- and extracellular water protons, respectively. Injection of hypertonic saline solutions significantly increased the extracellular water component in muscle tissue compared to isotonic saline solutions, an effect which lasted for more than 60 min. These findings suggest that MRI techniques may be useful to investigate the effect of hyper- or hypotonic solutions on muscle tissue in vivo.

Quantitative assessment of cutaneous thermal and vibration sensation and thermal pain detection thresholds in healthy children and adolescents.

Quantitative sensory testing (QST) is a noninvasive, computer-assisted method for assessing function in peripheral small and large sensory fibers. In order to use QST for clinical neurological assessment in children, it is necessary: (1) to determine whether children can reliably perform these tests and (2) to characterize normal ranges in healthy children. Values of cold sensation, warm sensation, cold pain, heat pain, and vibration sensation detection thresholds were determined in the hand and foot with the method of limits (MLI) and method of levels (MLE) in 101 healthy children aged 6-17 years using a commercially available device. Both MLI and MLE were well-accepted by children, and there was good reproducibility between two sessions. The MLE takes longer to perform but produces lower thermal detection thresholds than the MLI. In the MLI, vibration and warm sensation showed higher thresholds in the foot than hand, whereas cold pain showed lower thresholds in the foot than hand. Based on these results, QST may be used to document and monitor the clinical course of sensory abnormalities in children with neurological disorders or neuropathic pain.

The pharmacokinetics of epidural ropivacaine in infants and young children.

UNLABELLED: The pharmacokinetic variables of ropivacaine were characterized after epidural bolus injection in pediatric patients. The subjects, 7 infants (aged 3-11 mo) and 11 young children (aged 12-48 mo), received 1.7 mg/kg of ropivacaine via a lumbar epidural catheter. Total plasma concentrations of ropivacaine measured over 24 h were assayed by high-pressure liquid chromatography, and pharmacokinetic modeling was performed by Nonlinear Mixed Effects Modeling analysis. The median peak venous plasma concentrations (C(max)) in infants and young children were 610 microg/L (interquartile range [IQR], 550-725 microg/L) and 640 microg/L (IQR, 540-750 microg/L), respectively. The median times to maximum plasma ropivacaine concentration (T(max)) were 60 min (IQR, 60-120 min) in infants and 60 min (IQR, 30-90 min) in young children. There were no statistical differences between median values of C(max) and T(max) between infants and young children. The calculated clearance (CL) in infants was 4.26 mL x min(-1) x kg(-1) (9% coefficient of variation), and in young children it was 6.15 mL x min(-1) x kg(-1) (11% coefficient of variation). The CL for infants was significantly less than the CL for young children (P < 0.01). The volume of distribution was estimated to be 2370 mL/kg (9% coefficient of variation) for both young children and infants. No systemic toxicity was observed in either group. IMPLICATIONS: This study revealed that the pharmacokinetic variables of lumbar epidural bolus ropivacaine in pediatric patients aged 3 to 48 mo are similar to those of adults, except that drug clearance was less in infants compared with older children.

High concentrations of adrenergic antagonists prolong sciatic nerve blockade by tetrodotoxin.

BACKGROUND: Millimolar-range concentrations of some adrenergic antagonists have been shown to have local anesthetic-like properties, and to stimulate GTPase activity in vitro. In this report, we investigate whether these agents can potentiate the effect of tetrodotoxin (TTX) and bupivacaine, a conventional local anesthetic, and whether GTPase activation plays a role. METHODS: Rats received sciatic nerve blockade with tetrodotoxin or bupivacaine co-injected with adrenergic antagonists and/or agonists, or pertussis toxin. Thermal nociceptive blockade was quantified with modified hotplate testing. RESULTS: Nerve block from TTX alone lasted 153 (99-223) min (median and 25th and 75th percentiles). Co-injection with 20 mM phentolamine, propranolol, and yohimbine prolonged TTX block to 856 (765-862), 486 (444-510), and 465 (413-495) min respectively (P<0.005 in all cases, compared to TTX alone). Micromolar concentrations of adrenergic antagonists (which inhibited the prolongation of TTX block by epinephrine) did not prolong TTX block. Injection of adrenergic antagonists alone did not produce specific nerve block. They did not prolong TTX block when injected at a remote subcutaneous site. Prolongation of TTX block by phentolamine was not inhibited by co-injection with pertussis toxin. Adrenergic antagonists did not prolong bupivacaine block. CONCLUSIONS: High concentrations of adrenergic antagonists markedly prolonged TTX block, but not bupivacaine block. This locally mediated action does not appear to be adrenergic-receptor-specific, or mediated by GTPase activation.

Effects of adrenergic agonists and antagonists on tetrodotoxin-induced nerve block.

BACKGROUND AND OBJECTIVES: The relative contributions of alpha(1)-, alpha(2)-, and beta-adrenergic receptors to adrenergic agonists' prolongation of nerve block by tetrodotoxin (TTX) are unknown. We investigated which receptor agonists prolong TTX block, and whether delayed injection of antagonists can interrupt prolonged blocks after coinjection of TTX and agonists. METHODS: Rats received percutaneous sciatic nerve block with 120 micromol/L TTX with and without adrenergic agonists and antagonists. Block duration was assessed by a modified hot-plate test. Functional deficits in the uninjected leg were used to assess systemic distribution of TTX. Data were expressed as medians with 25th and 75th percentiles. RESULTS: Coinjection of 5.5 micromol/L phenylephrine (alpha(1)-specific), 10 micromol/L clonidine (alpha(2)-specific), and 1.1 micromol/L epinephrine (mixed alpha- and beta-agonist) prolonged TTX nerve block, but 5.5 micromol/L isoproterenol (mixed beta-agonist) did not. Yohimbine inhibited TTX block prolongation by clonidine (median inhibitory concentrations, IC(50) = 130 nmol/L); phentolamine similarly inhibited epinephrine (IC(50) = 45 nmol/L). Adrenergic antagonists did not inhibit the prolongation of TTX block by agonists when injected 3 or 6 hours after the initial block. Subcutaneous injection of adrenergic agonists at a remote site did not prolong TTX block, except for a modest prolongation by clonidine. CONCLUSION: TTX block can be prolonged by alpha(1)- and alpha(2)-, but not beta-adrenergic agonists via locally mediated events of relatively brief duration. Delayed injection of adrenergic antagonists does not interrupt the prolonged blocks produced by coinjection of TTX and adrenergic agonists unless administered soon after block is established. Reg Anesth Pain Med 2001;26:239-245.

The local anesthetic properties and toxicity of saxitonin homologues for rat sciatic nerve block in vivo.

BACKGROUND AND OBJECTIVES: Saxitoxin and its homologues are naturally occurring compounds that block the sodium channel with high potency. They have the potential for providing prolonged duration local anesthesia when coinjected with vasoconstrictors or conventional local anesthetics and are devoid of local neurotoxicity. Here, we compare sciatic nerve block with saxitoxin to those with neosaxitoxin, decarbamoyl saxitoxin, and tetrodotoxin (TTX), in a search for even safer compounds. METHODS: Rats received percutaneous sciatic nerve block with toxins. The compounds were compared in terms of lethality, onset and duration of action for thermal analgesia (hot-plate testing), and motor block (weight-bearing). Data were expressed as medians with 25th and 75th percentiles, and median effective concentrations were determined. RESULTS: The median concentrations at which analgesia of 60 minutes duration was achieved were neosaxitoxin, 34+/-2 micromol/L; saxitoxin, 58+/-3 micromol/L; TTX, 92+/-5 micromol/L; and decarbamoyl saxitoxin, 268+/-8 micromol/L. Similar trends were observed for other measures of effectiveness (block duration of 90 minutes, maximal block), and for lethality so that the therapeutic indices were similar. No toxin had a marked predominance of sensory or motor block. The potency of TTX was intermediate between those of the saxitoxins, and its therapeutic index was slightly better. No difference was observed in time to onset of nerve blockade among the toxins. CONCLUSIONS: Substitutions on the saxitoxin nucleus result in large differences in incidence and duration of block, and toxicity. The therapeutic indices of the saxitoxins are similar; that of TTX is slightly better.

Survey of acupuncturists: practice characteristics and pediatric care.

OBJECTIVE: To describe the practice characteristics and pediatric care provided by licensed acupuncturists. DESIGN: Cross-sectional survey. SETTING: Boston metropolitan area. SUBJECTS: 227 licensed acupuncturists were surveyed; 140 (62%) responded. MAIN OUTCOME MEASURES: (1) DEMOGRAPHICS, (2) practice characteristics, (3) pediatric care, (4) recommendations of peers recognized as experts in pediatric acupuncture. RESULTS: (1) DEMOGRAPHICS: 70% Caucasian, 61% female; (2) practice characteristics: average of 39 visits weekly with an average charge of $54 for a 57-minute visit; patients were typically scheduled for follow-up once or twice weekly; only 5% of fees were covered by insurance; 80% recommended herbal remedies and 66% dispensed herbs in the office; (3) few acupuncturists treated more than one child per week; most used non-needle techniques or Japanese-style acupuncture to stimulate points in children; 85% would refer a febrile two-week-old infant immediately to a physician; (4) only 17 acupuncturists were recommended by three or more peers and saw three or more patients weekly; their practices were all in wealthy suburban areas. CONCLUSIONS: Most acupuncturists in the Boston area are Caucasian and female. Compared with physicians, they schedule patients for more frequent follow-up, allocate more time, are less likely to be reimbursed by insurance, and treat fewer children. Additional studies are needed to assess effectiveness, quality, and access to acupuncture services for adults and children.

Acupressure-acupuncture antiemetic prophylaxis in children undergoing tonsillectomy.

BACKGROUND: Acupuncture or acupressure at the Nei-Guan (P.6) point on the wrist produces antiemetic effects in awake but not anesthetized patients. The authors studied whether a combined approach using preoperative acupressure and intra- and postoperative acupuncture can prevent emesis following tonsillectomy in children. METHODS: Patients 2-12 yr of age were randomly assigned to study or placebo groups. Two Acubands with (study) and two without (placebo) spherical beads were applied bilaterally on the P.6 points; non-bead- and bead-containing Acubands, respectively, were applied on the sham points. All Acubands were applied before any drug administration. After anesthetic induction, acupuncture needles were substituted for the beads and remained in situ until the next day. All points were covered with opaque tape to prevent study group identification. A uniform anesthetic technique was used; postoperative pain was managed initially with morphine and later with acetaminophen and codeine. Emesis, defined as retching or vomiting, was assessed postoperatively. Ondansetron was administered only after two emetic episodes at least 2 min apart. Droperidol was added if emesis persisted. RESULTS: One hundred patients were enrolled in the study. There were no differences in age, weight, follow-up duration, or perioperative opioid administration between groups. Retching occurred in 26% of the study patients and in 28% of the placebo patients; 51 and 55%, respectively, vomited; and 60 and 59%, respectively, did either. There were no significant differences between the groups. Redness occurred in 8.5% of acupuncture sites. CONCLUSION: Perioperative acupressure and acupuncture did not diminish emesis in children following tonsillectomy.

Prolonged local myometrial blockade prevents preterm labor after fetal surgery in a leporine model.

BACKGROUND/PURPOSE: Postoperative premature labor remains the foremost limiting factor to the development of fetal surgery. Most attempts at controlling this complication have involved the use of drugs delivered systemically to the mother. This study assessed the effects of prolonged local anesthetic blockade of the myometrium on preterm delivery after open fetal surgery. METHODS: Eighteen New Zealand rabbits at 23 days' gestation (term, 31 to 33 days) were divided in three groups. In group I (n = 6), the most proximal fetuses of both uterine horns were submitted to open amputation of a forelimb; in a few animals, one of the uterine horns was empty, hence, only one fetus was manipulated. In groups II (n = 5) and III (n = 7), an identical surgical procedure was performed. In group II, immediately before hysterotomy, the myometrium was injected with 0.5 mL of 0.5% bupivacaine along the incision line. In group III, only saline was injected. In group II, before uterine closure, the incised area of the myometrium was injected with 1.5 mL of a novel suspension of biodegradable polylactic-co-glycolic acid microspheres loaded with 75% w/w bupivacaine and 0.05% w/w dexamethasone. This suspension previously has been shown to provide peripheral nerve blockade for approximately 5 days. In group III, microspheres without any drug were injected. RESULTS: Abortion rates were significantly different among the groups: 83.3% (five of six) for the does in group I, zero in group II, and 71.4% (five of seven) in group III (P < .05). The absence of abortions observed in group II occurred despite the fact that the fetal mortality rate was significantly higher in this group (87.5%, seven of eight fetuses) than in groups I (0) and III (33.3%, 4 of 12 fetuses, P < .05). CONCLUSIONS: Prolonged local blockade of the myometrium with bupivacaine inhibits preterm labor after fetal surgery in rabbits. The high fetal mortality rate observed in this study may be caused by "transplacental" transfer of the local anesthetic to the fetus. Notably, the abortifacient effect of a dead fetus was completely suppressed by the local blockade. Studies using microspheres with local anesthetics that do not cross the placenta, in animal models with longer gestational periods, are warranted.

Vanilloid receptor agonists potentiate the in vivo local anesthetic activity of percutaneously injected site 1 sodium channel blockers.

BACKGROUND: Capsaicin, the pungent ingredient in chili peppers, is a vanilloid with noxious and analgesic effects that inhibits tetrodotoxin-resistant sodium currents. Because tetrodotoxin-resistant currents are found primarily in small-diameter nociceptor afferents of the peripheral nerves, their inhibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 sodium channel blocker, and capsaicin on nerve blockade in vivo. METHODS: Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 microM tetrodotoxin, or both were administered to male Sprague-Dawley rats. Thermal nociceptive and motor blockade were measured. Data were expressed as medians with 25th and 75th percentiles. RESULTS: Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsaicin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that rats achieved maximal block shown by isobolographic analysis. The combination of tetrodotoxin and capsaicin showed less motor predominance than tetrodotoxin did alone. Similar interactions were found between tetrodotoxin and resiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (another site 1 sodium channel blocker), but much less so between bupivacaine and capsaicin. CONCLUSIONS: Site 1 sodium channel blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions may be useful in developing prolonged local anesthetics and elucidating mechanisms of functionally selective nerve blockade.

Sciatic nerve blockade in infant, adolescent, and adult rats: a comparison of ropivacaine with bupivacaine.

BACKGROUND: Ropivacaine is a newly introduced local anesthetic. No data are available regarding its safety, efficacy, or sensory-selectivity in children. The sciatic block duration and systemic toxicity of bupivacaine and ropivacaine were compared among infant, adolescent, and adult rats. METHODS: Infant, adolescent, and adult rats received blocks with ropivacaine or bupivacaine. Nociceptive, proprioceptive, and motor blockade were assessed. Systemic effects (contralateral leg analgesia, seizures, respiratory distress, apnea) were quantified. Plasma local anesthetic concentrations were measured at terminal apnea. RESULTS: Nerve blockade for a given absolute dose lasted longer in infants than in older rats for both drugs. Block duration from ropivacaine generally was the same as or slightly shorter than bupivacaine. There was no difference in sensory-selectivity between the drugs. Doses required to induce all systemic toxicity indices were inversely related to age (e.g., the lethal dose in 50% of animals [LD50] of ropivacaine in infants is 155 mg/kg; in adults it is 54 mg/kg). All indices of toxicity occurred at higher doses per kilogram for ropivacaine than bupivacaine, at all ages (e.g., the LD50 of bupivacaine in infants is 92 mg/kg; in adults it is 30 mg/kg). Plasma concentrations at terminal apnea were higher for ropivacaine than for bupivacaine at all ages, and were higher in infants than in older rats. CONCLUSIONS: Ropivacaine resembles bupivacaine in its local anesthetic effects but has a greater margin of safety. For a given absolute dose, sciatic blockade in infant rats lasts longer than in adolescents or adults. Although the doses (in milligrams per kilogram) causing toxicity were much higher in infants than in adults, this probably does not correspond to a wider therapeutic index.

Prolonged intercostal nerve blockade in sheep using controlled-release of bupivacaine and dexamethasone from polymer microspheres.

BACKGROUND: Previous work from the authors' group characterized a prolonged percutaneous blockade of the sciatic nerve in rats using bupivacaine-dexamethasone microspheres. The goals of the current study are to examine the (1) efficacy of bupivacaine microspheres with and without dexamethasone for intercostal blockade in sheep; (2) scaling of dose and duration with a 100-fold increase in body size from rats to sheep; (3) local toxicity and adverse systemic reactions to bupivacaine microspheres with and without dexamethasone. METHODS: Intercostal blocks were performed percutaneously in sedated sheep. Sensory blockade was measured at repeated time points by absent flinch response to skin pinch. Plasma bupivacaine concentrations were measured using high performance liquid chromatography. Chest wall specimens were examined by light microscopy. RESULTS: The duration of intercostal blockade increased with bupivacaine dose for animals receiving from 8 to 80 mg/kg of microspheres with and without dexamethasone. At each dose, microspheres containing dexamethasone had a longer duration of block than microspheres without dexamethasone. From 8 to 80 mg/kg, the mean duration of block with bupivacaine-dexamethasone microspheres increased from 4 to 13 days. Plasma concentrations of bupivacaine remained 10-fold below the convulsive EC50 concentration for sheep. Chest wall histology showed a significant granulomatous reaction around bupivacaine microspheres but not around bupivacaine-dexamethasone microspheres. CONCLUSIONS: A single administration of bupivacaine-dexamethasone microspheres produces an effective chest wall analgesia of several days' duration. This may prove useful clinically for thoracic surgery or trauma.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.