Michael G. Byas-Smith

Functional connectivity changes with concentration of sevoflurane anesthesia

Low-frequency oscillations (<0.08 Hz) have been detected in functional magnetic resonance imaging studies, and appear to be synchronized between functionally related areas. The effect of anesthetic agents on cortical activity is not completely characterized. This study assessed the effect of anesthesia on the temporal relations in activity in the motor cortices. Resting-state magnetic resonance data were acquired on six volunteers under different anesthetic states (using 0.0%, 2.0% and 1.0% stable end-tidal sevoflurane). Across all volunteers, the number of significant voxels (p<2.5×10−5) in the functional connectivity maps was reduced by 78% for light anesthesia and by 98% for deep anesthesia, compared with the awake state. Additionally, significant correlations in the connectivity maps were bilateral in the awake state but unilateral in the light anesthesia state.

Intrathecal Ziconotide in the Treatment of Chronic Nonmalignant Pain: A Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial

Objective.  The safety and efficacy of intrathecal (IT) ziconotide was studied in a randomized, double‐blind, placebo‐controlled trial.

Interaction of Isoflurane with the Dopamine Transporter

Background Isoflurane administration is known to increase extracellular dopamine (DA) concentration. Because the dopamine transporter (DAT) is a key regulator of DA, it is likely affected by isoflurane. This study investigates the hypothesis that isoflurane inhibits DA reuptake by causing DAT to be trafficked into the cell. Methods Rhesus monkeys were scanned with positron emission tomography (PET) using [18F]FECNT (a highly specific DAT ligand) while anesthetized with 1% isoflurane. The isoflurane was increased to 2%, and the animals were rescanned. Uptake was analyzed with the tissue reference method using the cerebellum as the reference tissue to determine the binding potential in the putamen. Immunohistochemistry and Western blot analyses were performed in vivo in rats to determine if isoflurane administration would change the total amount of DAT. Rats breathed air plus 2% isoflurane for 30 min, and then striatal DAT assays were rapidly performed. In vitro immunocytochemistry experiments were performed using human embryonic kidney (HEK) cells stably transfected with human DAT. The cells were exposed to 4% isoflurane for 1 h while the location of DAT was observed with fluorescent confocal microscopy. Results The [18F]FECNT binding potential in rhesus monkeys decreased by 63 ± 6% (SEM, n = 5) when isoflurane was increased from 1 to 2% as compared with no significant change (0.7 ± 2.5%; SEM, n = 5) when the isoflurane concentration was not changed (P < 0.001). No difference in DAT staining between isoflurane-treated and control rats was apparent from visual inspection, and quantitative Western blot analyses showed no significant change in total DAT protein. After isoflurane treatment, focal puncta of intense fluorescence was visible inside the HEK cells. Conclusions The in vitro experiments indicate that DAT is trafficked into the cell by isoflurane without changing the total amount of DAT in the striatum. The PET data are consistent with this finding, provided that intracellular DAT acquires a conformation that has low affinity for [18F]FECNT. Thus, [18F]FECNT appears to be an excellent agent for measuring plasma membrane-expressed DAT and evaluating DAT trafficking in vivo.

Attenuated Brain Response to Auditory Word Stimulation with Sevoflurane A Functional Magnetic Resonance Imaging Study in Humans

Background:Functional magnetic resonance imaging offers a compelling, new perspective on altered brain function but is sparsely used in studies of anesthetic effect. To examine effects on verbal memory encoding, the authors imaged human brain response to auditory word stimulation using functional magnetic resonance imaging at different concentrations of an agent not previously studied, and tested memory after recovery. Methods:Six male volunteers were studied breathing 0.0, 2.0, and 1.0% end-tidal sevoflurane (awake, deep, and light states, respectively) via laryngeal mask. In each condition, they heard 15 two-syllable English nouns via closed headphones. Each word was repeated 15 times (1/s), followed by 15 s of rest. Blood oxygenation level–dependent brain activations during blocks of stimulation versus rest were assessed with a 3-T Siemens Trio scanner and a 20-voxel spatial extent threshold. Memory was tested approximately 1.5 h after recovery with an auditory recognition task (chance performance = 33% correct). Results:Scans showed widespread activations (P < 0.005, uncorrected) in the awake state, including bilateral superior temporal, frontal, and parietal cortex, right occipital cortex, bilateral thalamus, striatum, hippocampus, and cerebellum; more limited activations in the light state (bilateral superior temporal gyrus, right thalamus, bilateral parietal cortex, left frontal cortex, and right occipital cortex); and no significant auditory-related activation in the deep state. During recognition testing, subjects correctly selected 77 ± 12% of words presented while they were awake as “old,” versus 32 ± 15 and 42 ± 8% (P < 0.01) correct for the light and deep stages, respectively. Conclusions:Sevoflurane induces dose-dependent suppression of auditory blood oxygenation level–dependent signals, which likely limits the ability of words to be processed during anesthesia and compromises memory.

Isoflurane alters the amount of dopamine transporter expressed on the plasma membrane in humans.

Background:Isoflurane increases extracellular dopamine concentration and causes trafficking of the dopamine transporter (DAT) in transfected cells. Also, the binding potentials of highly specific positron-emitting DAT ligands are altered by isoflurane in rhesus monkeys. The purpose of this study was to determine the dose–response curve for isoflurane altering the binding potential of one of these ligands ([F-18]FECNT) in humans. Methods:Twenty human volunteers underwent positron emission tomography using [F-18]FECNT. All subjects were scanned while awake and then again after assignment to one of four groups (n = 5 each): awake-control, propofol-control, or light or deep isoflurane anesthesia as defined by Bispectral Index monitoring. Bispectral Index values in the light anesthesia group were 40 ± 7 (end-tidal isoflurane, 1.02 ± 0.08) versus 27 ± 10 (end-tidal isoflurane, 1.6 ± 0.3) in the deep anesthesia group. The within-subject percent change in putamen binding potential between the awake and second scans was determined for each subject, averaged within groups, and compared across groups. Results:The [F-18]FECNT binding potential exhibited a biphasic shape as a function of anesthetic dose. The binding potential for the second scan in the awake-control and propofol-control groups was significantly less than the initial scan; for the light anesthesia group, the binding potential was significantly increased during anesthesia, and no change was detected between the two scans in the deeper anesthesia group. Conclusion:Isoflurane causes a dose-dependent change in the [F-18]FECNT binding potential for DAT consistent with isoflurane causing trafficking of the DAT between the plasma membrane and the cell interior. Concentrations of isoflurane below minimum alveolar concentration causes DAT to be trafficked to the plasma membrane from the cell interior, but no net trafficking occurs at higher concentrations. The data are most easily explained if isoflurane alters the amount of functionally expressed DAT through an indirect pathway. This phenomena should be more fully explored to help make the next generation of anesthetics more mechanistically specific and to reduce undesired side effects.

Tourniquet constriction exacerbates hyperalgesia-related pain induced by intradermal capsaicin injection

BACKGROUND When capsaicin is injected intradermally, hyperalgesia develops around the injection site. The authors observed that volunteers report painful sensations in the skin remote from the injection site during tourniquet constriction of the affected extremity. METHODS Each volunteer received an intradermal injection of capsaicin on the volar forearm, followed by intermittent tourniquet constriction of the extremity. In some participants, the tourniquet position was rotated between different sites on the upper extremities. Laser Doppler measurements were made in the skin to measure capillary blood flow during pain magnification. RESULTS Hyperalgesia developed in the volunteers who were tested after the capsaicin injection. Blood flow increased three times in the dermal capillaries remote from the injection site after capsaicin injection. The tourniquet-induced pain reached peak intensity soon after tourniquet inflation. Tourniquet constriction of the arm on the affected side reliably induced painful exacerbation in each person tested. The quality of the sensation was described as burning and extended across the arm in most volunteers. Only when pinprick hyperalgesia was detectable did the volunteers experience the diffuse, immediate pain sensation. The pain initiated by the tourniquet constriction likely is related to changes in skin capillary blood flow. CONCLUSIONS Low cutaneous blood perfusion is related to the intensity of ongoing, spontaneous pain when secondary hyperalgesia is present. The specific trigger(s) have yet to be identified.

Phenylephrine and norepinephrine increase dopamine transporter ligand binding in striatum

PURPOSE 8-(2-[18F]fluoroethyl)-2 beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane ([18F]FECNT) is a radiotracer for positron emission tomography (PET) used to trace the location and binding potential (BP) of the dopamine transporter (DAT). We tested the hypothesis that adrenergic receptor agonists increase the BP of [18F]FECNT for the DAT. PROCEDURES Anesthetized monkeys were scanned twice to determine the ligand BP at baseline and during administration of phenylephrine (3-6 microg/kg/min) or norepinephrine (0.5-1 microg/kg/min). Standard immunohistochemistry and immunoblot analyses were performed in rats to determine if the quantity of DAT changed with phenylephrine. [18F]FECNT uptake in human embryonic kidney (HEK) cells, stably transfected with DAT cDNA, was measured by gamma scintillation counting during phenylephrine. RESULTS The PET measured BP of [18F]FECNT increased by 50% and 45% during the phenylephrine and norepinephrine infusion, respectively. The immunohistochemistry and immunoblot analyses did not show a difference in total DAT. CONCLUSION Adrenergic agonists increase the BP of [18F]FECNT in monkey striatum.

Ultrasound-guided esophageal occlusion during rapid sequence induction.

To the Editor, In 1961, Dr. B.A. Sellick demonstrated cricoid pressure (CP), a technique used for esophageal occlusion to prevent gastric regurgitation during tracheal intubation. The ‘‘Sellick Maneuver’’ has since become common practice during induction of anesthesia when risk of regurgitation is suspected. Recent investigations refute the presumed benefits of this maneuver. Magnetic resonance imaging and computerized axial tomography scanning show that esophageal occlusion with CP may be unreliable. While the Sellick technique may be unreliable, the threat of oral pharyngeal aspiration cannot be ignored in patients undergoing rapid sequence induction. Hence, it is clinically important to ascertain more reliable methods to reduce the risk of this complication. We present a four-step ultrasound (US)-guided method that has the potential to occlude the esophagus reliably during rapid sequence induction The following steps are required to perform this technique: Step 1: Identify surface landmarks, cervical cartilages, and muscles. Step 2: Identify the position of the esophagus relative to the surrounding anatomy via standard US probing. The esophagus may be located either to the left or to the right of the trachea (most commonly on the left), typically at four or seven o’clock in the crosssectional view. Step 3: Apply the standard Sellick maneuver to occlude the esophagus or to serve as a backstop to prevent medial migration of the esophagus if pressure is applied laterally. Step 4: If there is inadequate compression of the esophageal lumen, apply gentle pressure with the US probe to maintain CP and to compress the esophagus lateralmedially until the internal lumen is occluded. The images in the Figure (panels A and B) show how this clinical end point is accomplished with a thumb-shaped transducer (SonoSite S-nerve, C11x/8-5 MHz Transducer, Sonosite, Seattle, WA, USA). This four-step technique allows for verification of esophageal orientation and occlusion during rapid sequence induction via the standard Sellick maneuver or by using US assistance. In addition to real-time evaluation of esophageal occlusion, inadvertent collapse of the trachea can be detected at the point when pressure is applied. This approach could supplant the blind technique currently practiced, since the esophagus is easy to identify using standard US equipment and the procedure is easy to apply. In our practice, foreknowledge of the position of the esophagus prior to rapid sequence induction is useful to predict the likelihood of effective esophageal occlusion with a standard CP application and also to recognize when lateral compression is necessary to occlude the esophageal lumen. Our anecdotal experience suggests that most patients have no vital tissues lying between the skin and the esophagus when the esophagus deviates laterally to the cartilage either at or below the level of the C6 vertebra. We recognize that the efficacy of the standard Sellick maneuver and our modified approach may be compromised in patients with large goiter formation or thickened esophageal musculature or when the esophagus is deep to the surface anatomy. Observational studies are warranted to confirm the efficacy of this technique.