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Concept: Local anesthetic

169

General anesthetics are used during medical and surgical procedures to reversibly induce a state of total unconsciousness in patients. Here, we investigate, from a dynamic network perspective, how the cortical and cardiovascular systems behave during anesthesia by applying nonparametric spectral techniques to cortical electroencephalography, electrocardiogram and respiratory signals recorded from anesthetized rats under two drugs, ketamine-xylazine (KX) and pentobarbital (PB). We find that the patterns of low-frequency cortico-cardio-respiratory network interactions may undergo significant changes in network activity strengths and in number of network links at different depths of anesthesia dependent upon anesthetics used.

Concepts: Pharmacology, Surgery, Anesthesia, General anaesthesia, Chloroform, Local anesthetic, Anesthetic, EEG measures during anesthesia

168

Lubeluzole, which acts on various targets in vitro, including voltage-gated sodium channels (NaChs), was initially proposed as neuroprotectant. Lubeluzole structure contains a benzothiazole moiety (R-like) related to riluzole and a phenoxy-propranol-amine moiety (A-core) recalling propranolol. Both riluzole and propranolol are efficient NaCh blockers. We studied in detail the effects of lubeluzole (racemic mixture and single isomers), aforementioned lubeluzole moieties, and riluzole on NaChs to increase our knowledge about drug-channel molecular interactions. Compounds were tested on hNav1.4 NaChs, and F1586C or Y1593C mutants functionally expressed in HEK293 cells, using patch-clamp. Lubeluzole blocked NaChs with a remarkable effectiveness. No stereoselectivity was found. Compared to mexiletine, dissociation constant for inactivated channels was ≈600 times lower (≈11 nM), conferring to lubeluzole a huge use-dependence of great therapeutic value. The F1586C mutation impaired use-dependent block only partially, suggesting that additional amino acids are critically involved in high-affinity binding. Lubeluzole moieties were modest NaCh blockers. Riluzole blocked NaChs efficiently but lacked use-dependence, similarly to R-like. F1586C fully abolished A-core use-dependence, suggesting that A-core binds to the local anesthetic receptor. Thus lubeluzole likely binds to the local anesthetic receptor through its phenoxy-propranol-amine moiety, with consequent use-dependent behavior. Nevertheless, compared to other known NaCh blockers, lubeluzole adds a third pharmacophoric point through its benzothiazole moiety, that greatly enhances high-affinity binding and use-dependent block. If sufficient isoform specificity can be attained, the huge use-dependent block may help in the development of new NaCh inhibitors to provide pharmacotherapy for membrane excitability disorders, such as myotonia, epilepsy, or chronic pain.

Concepts: Protein, Acid, Amine, Functional group, Ion channel, Local anesthetic, Racemic mixture, Adderall

136

Local anesthetic agents such as bupivacaine and lidocaine are commonly used after surgery for pain control. The aim of this prospective study was to evaluate the safety of a mixture of bupivacaine and lidocaine in children who underwent urologic inguinal and scrotal surgery.

Concepts: Anesthesia, Local anesthetic, Local anesthetics

46

Randomised, controlled trials have been retracted after publication because of data fabrication and inadequate ethical approval. Fabricated data have included baseline variables, for instance, age, height or weight. Statistical tests can determine the probability of the distribution of means, given their standard deviation and the number of participants in each group. Randomised, controlled trials have been retracted after the data distributions have been calculated as improbable. Most retracted trials have been written by anaesthetists and published by specialist anaesthetic journals. I wanted to explore whether the distribution of baseline data in trials was consistent with the expected distribution. I wanted to determine whether trials retracted after publication had distributions different to trials that have not been retracted. I wanted to determine whether data distributions in trials published in specialist anaesthetic journals have been different to distributions in non-specialist medical journals. I analysed the distribution of 72,261 means of 29,789 variables in 5087 randomised, controlled trials published in eight journals between January 2000 and December 2015: Anaesthesia (399); Anesthesia and Analgesia (1288); Anesthesiology (541); British Journal of Anaesthesia (618); Canadian Journal of Anesthesia (384); European Journal of Anaesthesiology (404); Journal of the American Medical Association (518) and New England Journal of Medicine (935). I chose these journals as I had electronic access to the full text. Trial p values were distorted by an excess of baseline means that were similar and an excess that were dissimilar: 763/5015 (15.2%) trials that had not been retracted from publication had p values that were within 0.05 of 0 or 1 (expected 10%), that is, a 5.2% excess, p = 1.2 × 10(-7) . The p values of 31/72 (43%) trials that had been retracted after publication were within 0.05 of 0 or 1, a rate different to that for unretracted trials, p = 1.03 × 10(-10) . The difference between the distributions of these two subgroups was confirmed by comparison of their overall distributions, p = 5.3 × 10(-15) . Each journal exhibited the same abnormal distribution of baseline means. There was no difference in distributions of baseline means for 1453 trials in non-anaesthetic journals and 3634 trials in anaesthetic journals, p = 0.30. The rate of retractions from JAMA and NEJM, 6/1453 or 1 in 242, was one-quarter the rate from the six anaesthetic journals, 66/3634 or 1 in 55, relative risk (99%CI) 0.23 (0.08-0.68), p = 0.00022. A probability threshold of 1 in 10,000 identified 8/72 (11%) retracted trials (7 by Fujii et al.) and 82/5015 (1.6%) unretracted trials. Some p values were so extreme that the baseline data could not be correct: for instance, for 43/5015 unretracted trials the probability was less than 1 in 10(15) (equivalent to one drop of water in 20,000 Olympic-sized swimming pools). A probability threshold of 1 in 100 for two or more trials by the same author identified three authors of retracted trials (Boldt, Fujii and Reuben) and 21 first or corresponding authors of 65 unretracted trials. Fraud, unintentional error, correlation, stratified allocation and poor methodology might have contributed to the excess of randomised, controlled trials with similar or dissimilar means, a pattern that was common to all the surveyed journals. It is likely that this work will lead to the identification, correction and retraction of hitherto unretracted randomised, controlled trials.

Concepts: Surgery, Anesthesia, Anesthesiologist, Local anesthetic, Retraction, Journal of the American Medical Association, American Medical Association, Twilight anesthesia

43

The neurophysiological mechanisms by which anesthetic drugs cause loss of consciousness are poorly understood. Anesthetic actions at the molecular, cellular, and systems levels have been studied in detail at steady states of deep general anesthesia. However, little is known about how anesthetics alter neural activity during the transition into unconsciousness. We recorded simultaneous multiscale neural activity from human cortex, including ensembles of single neurons, local field potentials, and intracranial electrocorticograms, during induction of general anesthesia. We analyzed local and global neuronal network changes that occurred simultaneously with loss of consciousness. We show that propofol-induced unconsciousness occurs within seconds of the abrupt onset of a slow (<1 Hz) oscillation in the local field potential. This oscillation marks a state in which cortical neurons maintain local patterns of network activity, but this activity is fragmented across both time and space. Local (<4 mm) neuronal populations maintain the millisecond-scale connectivity patterns observed in the awake state, and spike rates fluctuate and can reach baseline levels. However, neuronal spiking occurs only within a limited slow oscillation-phase window and is silent otherwise, fragmenting the time course of neural activity. Unexpectedly, we found that these slow oscillations occur asynchronously across cortex, disrupting functional connectivity between cortical areas. We conclude that the onset of slow oscillations is a neural correlate of propofol-induced loss of consciousness, marking a shift to cortical dynamics in which local neuronal networks remain intact but become functionally isolated in time and space.

Concepts: Nervous system, Neuron, Brain, Cognition, Cerebral cortex, Anesthesia, Local anesthetic, Anesthetic

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BACKGROUND:Between 1992 and 2011, 373 Canadian individuals with adverse anesthetic reaction were referred to the Malignant Hyperthermia Unit in Toronto, Ontario, Canada for malignant hyperthermia (MH) diagnostic testing. We analyzed the epidemiologic characteristics of the index adverse anesthetics for those probands who were confirmed to be MH susceptible.METHODS:One hundred twenty-nine proband survivors of adverse anesthetic reactions, whose MH susceptible status was confirmed by caffeine-halothane contracture testing were selected. Individuals were excluded if the index anesthetic record was not available for review. Data regarding demographics, clinical signs, laboratory findings, treatment, and complications were retrospectively compiled and analyzed. A Fisher exact test and χ(2) test were applied to compare categorical variables. The Wilcoxon rank-sum test was applied with continuous variables.RESULTS:Young males (61.2%) dominated among selected patients. Seventeen of 129 (13.2%) patients had prior unremarkable anesthesia. Anesthetic triggers were volatile-only (n = 58), succinylcholine-only (n = 20), or both volatile and succinylcholine (n = 51). Eight (6.2%) cases occurred in the postanesthetic care unit. There were no reactions after discharge from the postanesthetic care unit. The most frequent clinical signs were hyperthermia (66.7%), sinus tachycardia (62.0%), and hypercarbia (51.9%). Complications occurred in 20.1% of patients, the most common complication being renal dysfunction. When 20 or more minutes between the first adverse sign and dantrolene treatment elapsed, complication rates increased to ≥30%.CONCLUSIONS:This is the first Canadian study in 3 decades to report nationwide data on MH epidemiology. Features that differ from earlier reports include a 15.5% incidence of reactions triggered by succinylcholine alone and lower complication rates. In agreement with previously published studies, we confirmed in this independent dataset that increased complication rates were associated with an increased time interval between the first adverse clinical sign and dantrolene treatment. This underscores the need for early diagnosis and rapid dantrolene access and administration in anesthetizing locations using either succinylcholine or volatile anesthetic drugs.

Concepts: Statistical tests, Anesthesia, Malignant hyperthermia, Fever, Ketamine, Local anesthetic, Anesthetic, Anesthetics

28

Venipuncture and intravenous cannulation are the most common painful procedures performed on children. The most widely used topical anesthetic is eutectic mixture of local anesthetics (EMLA). EMLA use is associated with a transient cutaneous vasoconstriction which can make it difficult to identify veins. We assessed with a prospective, multicenter, observational study whether EMLA interferes with venipuncture and intravenous cannulation. The primary study outcome was a success at first attempt in the course of venipuncture or venous cannulation. The study enrolled 388 children; 255 of them received EMLA and 133 did not. Eighty-six percent of procedures were successful at the first attempt in the EMLA group and 76.7 % in the no EMLA group. Conclusion: In this study, EMLA use did not interfere with the success of venipuncture or venous cannulation in children.

Concepts: Anesthesia, Topical anesthetic, Local anesthetic, Lidocaine, Local anesthetics, Prilocaine, Lidocaine/prilocaine

28

Profound pulpal anesthesia in posterior mandibular teeth with irreversible pulpitis usually requires administering an inferior alveolar nerve block (IANB) plus other supplemental injections. The purpose of this prospective, randomized, double-blind study was to compare the anesthetic success rate of buccal infiltration injections of articaine and lidocaine when supplemented with an IANB.

Concepts: Cranial nerves, Mandibular nerve, Local anesthetic, Inferior alveolar nerve, Mandibular canal

28

We hypothesize that isoflurane and ketamine impact ventilatory pattern variability (VPV) differently. Adult Sprague-Dawley rats were recorded in a whole-body plethysmograph before, during and after deep anesthesia. VPV was quantified from 60-s epochs using a complementary set of analytic techniques that included constructing surrogate data sets that preserved the linear structure but disrupted nonlinear deterministic properties of the original data. Even though isoflurane decreased and ketamine increased respiratory rate, VPV as quantified by the coefficient of variation decreased for both anesthetics. Further, mutual information increased and sample entropy decreased and the nonlinear complexity index (NLCI) increased during anesthesia despite qualitative differences in the shape and period of the waveform. Surprisingly mutual information and sample entropy did not change in the surrogate sets constructed from isoflurane data, but in those constructed from ketamine data, mutual information increased and sample entropy decreased significantly in the surrogate segments constructed from anesthetized relative to unanesthetized epochs. These data suggest that separate mechanisms modulate linear and nonlinear variability of breathing.

Concepts: Fundamental physics concepts, Anesthesia, Randomness, Surrogate, Information theory, Ketamine, Local anesthetic, Anesthetic

28

BACKGROUND: Interscalene nerve blocks provide adequate analgesia, but there are no objective criteria for early assessment of correct catheter placement. In the present study, pulse oximetry technology was used to evaluate changes in the perfusion index (PI) in both blocked and unblocked arms, and changes in the plethysmographic variability index (PVI) were evaluated once mechanical ventilation was instituted. METHODS: The PI and PVI values were assessed using a Radical-7™ finger pulse oximetry device (Masimo Corp., Irvine, CA, USA) in both arms of 30 orthopedic patients who received an interscalene catheter at least 25 min before induction of general anesthesia. Data were evaluated at baseline, on application of local anesthetics; five, ten, and 15 min after onset of interscalene nerve blocks; after induction of general anesthesia; before and after a 500 mL colloid fluid challenge; and five minutes thereafter. RESULTS: In the 25 patients with successful blocks, the difference between the PI values in the blocked arm and the PI values in the contralateral arm increased within five minutes of the application of the local anesthetics (P < 0.05) and increased progressively until 15 min. After induction of general anesthesia, the PI increased in the unblocked arm while it remained relatively constant in the blocked arm, thus reducing the difference in the PI. A fluid challenge resulted in a decrease in PVI values in both arms. CONCLUSION: The perfusion index increases after successful interscalene nerve blockade and may be used as an indicator for successful block placement in awake patients. The PVI values before and after a fluid challenge can be useful to detect changes in preload, and this can be performed in both blocked and unblocked arms. (ClinicalTrials.gov number: NCT 01389011).

Concepts: Anesthesia, Local anesthesia, Catheter, Pulse oximetry, Local anesthetic, Block, Blocking, Masimo