James W. Ibinson

Neurotoxicity of Adjuvants Used in Perineural Anesthesia and Analgesia in Comparison With Ropivacaine

Background and Objectives: Clonidine, buprenorphine, dexamethasone, and midazolam (C, B, D, M) have been used to prolong perineural local anesthesia in the absence of data on the influence of these adjuvants on local anesthetic-induced neurotoxicity. Therefore, the impact of these adjuvants on ropivacaine (R)-induced death of isolated sensory neurons was assessed. Methods: The trypan blue exclusion assay was used to assess death of sensory neurons isolated from adult male Sprague-Dawley rats. Drugs were applied, alone or in combination, for 2 or 24 hrs at 37°C. Results: Neuronal viability was halved by 24-hr exposure to R (2.5 mg/mL), far exceeding the neurotoxicity of C, B, D, or M (at 2-100 times estimated clinical concentrations). Plain M at twice the estimated clinical concentration produced a small but significant increase in neurotoxicity at 24 hrs. After 2-hr exposure, high concentrations of B, C, and M increased the neurotoxicity of R; the combination of R + M killed more than 90% of neurons. Estimated clinical concentrations of C + B (plus 66 &mgr;g/mL D) had no influence on (i) R-induced neurotoxicity, (ii) the increased neurotoxicity associated with the combination of R + M, or (iii) the neurotoxicity associated with estimated clinical concentrations of M. There was increased neurotoxicity with 133 &mgr;g/mL D combined with R + C + B. Conclusions: Results with R reaffirm the need to identify ways to mitigate local anesthetic-induced neurotoxicity. While having no protective effect on R-induced neurotoxicity in vitro, future research with adjuvants should address if the C + B + D combination can enable reducing R concentrations needed to achieve equianalgesia (and/or provide equal or superior duration, in preclinical in vivo models).

Eliminating arterial injury during central venous catheterization using manometry.

BACKGROUND: Unintended arterial puncture occurs in 2%-4.5% of central venous catheterizations, resulting in arterial injury in 0.1%-0.5% of patients. Routine performance of manometry during catheterization may successfully identify unintended arterial puncture and avoid arterial cannulation and injury. METHODS: We conducted a retrospective review of all cases of central venous catheter placement during a 15-yr period after implementation of a safety program requiring mandatory use of manometry to verify venous access. Arterial injuries were defined as unintended arterial cannulations with a 7-French or larger catheter or dilator. Arterial punctures were defined as the unintended placement of an 18-gauge catheter or needle into the artery. Data were reviewed for all arterial injuries during the entire 15-yr period. In addition, data on both arterial puncture and subsequent arterial injury were evaluated during the final year of analysis. RESULTS: A total of 9348 central venous catheters were placed during the observation period. During the full 15 yr of observation, there were no cases of arterial injury. During the final year of assessment, 511 central venous catheters were placed, with arterial punctures in 28 patients (5%). Arterial puncture was recognized without manometry in 24 cases. Arterial puncture was identified only with manometry in 4 cases, with no incidents of arterial injury. CONCLUSIONS: Consistent use of manometry, to verify venous placement, during central venous catheterization effectively eliminated arterial injury from unintended arterial cannulation during the 15-yr assessment.

Aprepitant plus ondansetron compared with ondansetron alone in reducing postoperative nausea and vomiting in ambulatory patients undergoing plastic surgery.

Background: Postoperative nausea and vomiting is a major challenge in the perioperative setting. The incidence can be as high as 80 percent, and the majority of the symptoms among outpatients occur after discharge. This study evaluated the efficacy of a neurokinin-1 receptor antagonist (aprepitant) in reducing postoperative symptoms for up to 48 hours in patients undergoing outpatient plastic surgery. Methods: A prospective, double-blinded, randomized, two-arm evaluation of 150 ambulatory plastic surgery patients receiving a standardized general anesthetic, including postoperative nausea and vomiting prophylaxis with ondansetron and either aprepitant or placebo, was performed. The main outcome measures were the occurrence of vomiting and the severity of nausea for up to 48 hours postoperatively. Results: Overall, 9.3 percent of patients who received aprepitant versus 29.7 percent in group B had vomiting, with the majority of vomiting episodes occurring after hospital discharge. The Kaplan-Meier plot of the hazards of vomiting revealed an increased incidence of emesis in patients receiving ondansetron alone compared with the combination of ondansetron and aprepitant (p = 0.006). The incidence of nausea was not significantly different in the two groups. Severity of nausea, however, was significantly higher in those receiving ondansetron alone compared with those receiving ondansetron and aprepitant, as measured by a peak nausea score (p = 0.014) and by multivariate analysis of variance results comparing repeated verbal rating scale scores over 48 hours after surgery (p = 0.024). Conclusion: In patients undergoing plastic surgery, the addition of aprepitant to ondansetron significantly decreases postoperative vomiting rates and nausea severity for up to 48 hours postoperatively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Functional magnetic resonance imaging studies of pain: an investigation of signal decay during and across sessions.

Background:Several investigations into brain activation caused by pain have suggested that the multiple painful stimulations used in typical block designs may cause attenuation over time of the signal within activated areas. The effect this may have on pain investigations using multiple tasks has not been investigated. The signal decay across a task of four repeating pain stimulations and between two serial pain tasks separated by a 4-min interval was examined to determine whether signal attenuation may significantly confound pain investigations. Methods:The characteristics of the brain activation of six subjects were determined using whole brain blood oxygenation level–dependent functional magnetic resonance imaging on a 1.5-T scanner. Tasks included both tingling and pain induced by transcutaneous electrical stimulation of the median nerve. The average group maps were analyzed by general linear modeling with corrected cluster P values of less than 0.05. The time courses of individual voxels were further investigated by analysis of variance with P values of less than 0.05. Results:Significant differences between pain and tingling were found in the ipsilateral cerebellum, contralateral thalamus, secondary somatosensory cortex, primary somatosensory cortex, and anterior cingulate cortex. Highly significant signal decay was found to exist across each single pain task, but the signal was found to be restored after a 4-min rest period. Conclusions:This work shows that serial pain tasks can be used for functional magnetic resonance imaging studies using electrical nerve stimulation as a stimulus, as long as sufficient time is allowed between the two tasks.

An fMRI study of semantic priming: modulation of brain activity by varying semantic distances.

Research into the acute treatment of central nervous system (CNS) injury has become a national priority, and recent progress has been remarkable. Unfortunately, this progress has not carried over to the less acute sequelae of CNS injury, which often include serious cognitive and motor disability. One particular CNS disease, stroke, is the primary cause of serious disability in adults yet treatment for the enduring effects of stroke lags significantly behind treatment for the acute illness. Such efforts often focus on work-arounds or compensation, for deficits, rather than their remediation, because this produces rapid ‘‘functional improvement.’’ We believe that understanding remediation will ultimately require a neurobiologic theory of neural circuit reorganization (remodeling), the networklevel correlate of regeneration and repair. Neural remodeling relies on powerful interconnections among and within brain regions. Successful remediation might result from appropriate manipulation of the intensity and diversity of the regional inputs and outputs that exercise these interconnections. Many neural systems provide convergent inputs to facilitate human movement. In the presence of a motor system lesion, enhanced motor, sensory, or limbic inputs converging on the motor system may partially overcome the deficit and/or evoke pathways that bypass the lesion and facilitate motor execution and motor system remodeling. In a special issue of Cognitive and Behavioral Neurology that appeared last March, from which this editorial was inadvertently omitted, we collected a number of articles on novel, neurobiologically oriented approaches for the recovery of hand movement. We hoped that in pulling together these papers, the reader could gain perspective on current efforts underway to develop rehabilitation strategies for the patient with chronic stroke that are based on neurobiologic principles. The contributions in this special issue of cognitive and behavioral neurology fell into 3 broad categories: (1) Key neurobiologic concepts associated with motor recovery after stroke: Along these lines, Floel and Cohen reviewed both the important neurobiologic underpinnings of brain plasticity and existing methodologic approaches to assess brain plasticity after stroke. Further, they discussed the problems associated with translating the key basic scientific concepts into rehabilitative strategies. (2) Plausible (theoretical) mechanisms associated with motor recovery after stroke: The neurobiologic mechanisms of motor behavior in the healthy adult and in persons with motor system stroke are represented in this volume by several contributions. Bhimani et al described the results of an investigation into the neural mechanisms producing skilled motor behavior, using tasks originally elaborated by the esteemed 20th century neuropsychologist Aleksandr Luria. Fregni and Pascual-Leone provided an account of the neural mechanisms of recovery as seen through a process of motor relearning. Hlustik and Mayer highlighted the role of motor learning as a part of the motor recovery process after stroke, focussed on the critical yet understudied topic of (possibly) maladaptive motor learning. (3) Neurobiologically oriented therapies: The final section of the issue focused on the discussion on novel rehabilitative therapies that have been developed on the basis of data from neurobiologic studies and interpretations of those data in the context of neurologic rehabilitation.ObjectiveOur purpose was to study the effect of semantic priming at varying semantic distances on brain activation during a lexical decision experiment, using functional magnetic resonance imaging (fMRI). BackgroundNeuroimaging studies have demonstrated decreased brain activation for primed versus unprimed stimuli in language areas due to semantic priming, suggesting facilitated semantic retrieval. However, the effect of varying semantic distances on brain activation has not been studied. Therefore we examined direct and indirect priming effects on cerebral activation to provide information regarding spread of activation in the semantic network. MethodsParticipants were presented with closely, distantly, and unrelated word pairs during fMRI, and asked to make a lexical decision on the second word. ResultsBehavioral measurements demonstrated significant priming effects for all semantic distances. Imaging results showed modulation of brain activation due to different semantic relationships in the left inferior frontal gyrus, bilateral middle frontal gyrus and anterior temporal lobe, and consisted of decreased magnitude of activation when primed stimuli were processed compared with unprimed stimuli, with the greatest effect observed for closely related words. ConclusionsThis study demonstrates graduated effects of semantic priming on fMRI in semantic but not attentional brain regions, contributing to explain how semantic knowledge is organized and retrieved. These findings support the network model for organization of the semantic lexicon.

Research Priorities Regarding Multimodal Peripheral Nerve Blocks for Postoperative Analgesia and Anesthesia Based on Hospital Quality Data Extracted from Over 1,300 Cases (2011–2014)

The use of additives with local anesthetics for peripheral nerve blocks has received considerable attention [1] due to the patient-centered goals of prolonging analgesic duration and possibly reducing local anesthetic-related toxicity. Applying such additives to single-injection nerve blocks also has the potential to reduce overhead [2] and disposables [3] costs, when compared with the costs related to continuous perineural infusions. Furthermore, recent research has elucidated in vivo animal sciatic nerve safety of the preservative-free combination of clonidine, buprenorphine, and dexamethasone (CBD) with the local anesthetic bupivacaine (BPV) [4]. Ropivacaine–CBD was previously demonstrated to be no more neurotoxic than plain ropivacaine to cultured primary sensory neurons harvested from rat dorsal root ganglia in vitro [5]. In our institution (Veterans Affairs Pittsburgh Healthcare System [VAPHS]), the lead author was in charged with creating a regional anesthesia (RA) and analgesia program for patients eligible for peripheral nerve blocks. For this new program, hospital administration was unable to budget resources for a perineural catheter-based acute pain service. Instead, the Medical Executive Board approved the lead authors recommendation to routinely use BPV–CBD off-label. These single-injection nerve block procedures are typically placed before surgery to provide postoperative analgesia and intraoperative anesthesia when feasible, and thus avoiding general endotracheal anesthesia (GETA). The Medical Executive Board tasked the lead author with per-patient quality assurance/quality improvement (QA/QI) data collection to evaluate comparative effectiveness (against historical controls) and outcomes (block duration and rebound pain [6,7], perineural complications, etc.). In accordance with Veterans Health Administration Handbook 1058.05, this manuscript was processed for authentication of nonresearch status of the activities prior to submission to this journal. Our institutional review board declared these clinical operations as “not research” at the time of program initiation (mid-2011) and annually since then during required reviews. The objective is to describe the patient outcomes …

Local anesthetics in diabetic rats (and patients): shifting from a known slippery slope toward a potentially better multimodal perineural paradigm?

Despite the calls for focused research on diabetes mellitus (DM) and peripheral nerve blockade, and the resulting studies on this topic, there remain important research opportunities to explore perineural analgesia options that are less reliant upon neurotoxic (in vitro) local anesthetics. In this issue of the Regional Anesthesia and Pain Medicine, Kroin et al and Lirk et al report their investigations on the effect of hyperglycemia in 2 different rodent models of diabetes: the traditional streptozotocin (STZ)Yinduced diabetic state with peripheral neuropathy (a model more similar to type 1 or insulin-dependent DM) and the Zucker diabetic fatty (ZDF) model of type 2 DM. These studies, considered together, illustrate a ‘‘slippery slope’’ when only local anesthetics are used for peripheral nerve blocks in diabetic rodents. How this ‘‘slippery slope’’ could adversely affect our patients with subclinical diabetic neuropathy remains unknown. Using the STZ model, Kroin et al showed that (i) local anesthetic nerve block duration was prolonged in the chronic hyperglycemic state, and (ii) block duration does not depend on the presence of coinciding acute tissue hyperglycemia. Only with sustained glycemic control over time (2 weeks) was there a return of nerve block duration to the nondiabetic baseline after the use of local anesthetics. Kroin et al did not evaluate tissue toxicity in this study related to the perineural injections (having already performed elegant histological analysis in previous work), instead only reporting that there were no gait abnormalities in any of the diabetic rats after the nerve block effects dissipated. Lirk et al examined local anesthetic block duration using ZDF rats as a model of type 2 DM. As with the STZ model of Kroin et al, block duration was increased from baseline in ZDF diabetic rats with chronic hyperglycemia, even though the ZDF rats showed only subclinical neuropathy. This is an important inaugural study of local anestheticYinduced neurotoxicity in a ZDF model and represents a major step forward for clinicians who should be concerned about the long-term effect of peripheral nerve blocks with local anesthetics on DM-induced peripheral neuropathy, primarily because the ZDF rat appears to more accurately represent the most common DM clinical condition from an epidemiological standpoint. As our knowledge currently stands, the local anesthetics (eg, lidocaine, ropivacaine, etc) that are approved by the US Food and Drug Administration are notably neurotoxic in vitro. Lirk et al further illustrate this, finding that a hyperglycemic environment did not alter the toxicity of lidocaine to primary sensory neurons in culture, but that lidocaine was slightly more neurotoxic in diabetic rats. Again, the acute hyperglycemic milieu does not seem to matter; it is the neuronal changes that occur over the long term that put diabetic neurons (and nerves) at risk. In the opinion of Lirk et al, the neurotoxicity difference between treatment groups was small. However, we believe that ‘‘small’’ does not equal ‘‘clinically insignificant.’’ We acknowledge that morphologic changes in the nerve do not always correlate to function, but observing transient analgesia/anesthesia in a laboratory rodent that then resolves to ‘‘no change from baseline’’does not rule out that there was some nerve fiber degeneration, as the nervous system has considerable redundancy to ‘‘clinically’’ compensate (personal communication, M. T. Butt, DVM, ACVP, Frederick, Maryland). Evolving bench evidence of the subtle perineural deficits created by prototypical local anesthetics in the diabetic model, including the prolonged block duration and neurotoxicity described in the aforementioned studies, continues to alert our subspecialty to the need to consider other perineural mechanisms of analgesia. EDITORIAL

Clinical Benchmarks Regarding Multimodal Peripheral Nerve Blocks for Postoperative Analgesia: Observations Regarding Combined Perineural Midazolam-Clonidine-Buprenorphine-Dexamethasone

In a separate commentary [1], we reported on potential clinical research priorities with respect to multimodal perineural anesthesia and analgesia (MMPNA). This was based on our groups review of institutional quality assurance/improvement (QA/QI) data routinely using this technique for over 1,300 patients from late 2011 to the present at the Veterans Affairs Pittsburgh Healthcare System. This previous commentary addressed the four-drug combination of bupivacaine, clonidine, buprenorphine, and dexamethasone (BPV-CBD) used for postoperative perineural analgesia (e.g., combined with intraoperative spinal anesthesia), or for the dual role of intraoperative perineural anesthesia and postoperative analgesia. The average block duration (block insertion time until peak rebound pain score on a 0 to 10 scale) in this previous commentary was 33 to 37 hours, depending on the context. We believe that this clinical observation warrants high-priority research for the specialty, especially in the context of the effects of buprenorphine dose response and the parameters of block duration and rebound pain. In this current commentary, we will direct separate attention toward the four-drug combination of midazolam (MDZ) with CBD used for specific contexts of motor-sparing perineural analgesia. Both BPV-CBD and MDZ-CBD four-drug nerve block combinations were shown to be safe in vivo, as reported in a separate manuscript [2] in this issue of Pain Medicine . Based on the previously reported in vitro safety of MDZ-CBD [3], we used MDZ-CBD blocks in selected cases where the risk of motor block (and subsequent falls) was deemed as high as the potential short- and long-term risks of escalating systemic opioid analgesia (and/or intraoperative conversion to general endotracheal anesthesia [GETA]). All patients were fully informed before the use of MDZ-CBD as an “off-label” good-faith effort to 1) avoid motor block (i.e., routinely resulting from perineural bupivacaine use with or without perineural CBD use); 2) avoid GETA; and …

GlideScope Use improves intubation success rates: an observational study using propensity score matching.

BackgroundRigid video laryngoscopes are popular alternatives to direct laryngoscopy for intubation, but further large scale prospective studies comparing these devices to direct laryngoscopy in routine anesthesiology practice are needed. We hypothesized that the first pass success rate with one particular video laryngoscope, the GlideScope, would be higher than the success rate with direct laryngoscopy.Methods3831 total intubation attempts were tracked in an observational study comparing first-pass success rate using a Macintosh or Miller-style laryngoscope with the GlideScope. Propensity scoring was then used to select 626 subjects matched between the two groups based on their morphologic traits.ResultsComparing the GlideScope and direct laryngoscopy groups suggested that intubation would be more difficult in the GlideScope group based on the Mallampati class, cervical range of motion, mouth opening, dentition, weight, and past intubation history. Thus, a propensity score based on these factors was used to balance the groups into two 313 patient cohorts. Direct laryngoscopy was successful in 80.8% on the first-pass intubation attempt, while the GlideScope was successful in 93.6% (p <0.001; risk difference of 0.128 with a 95% CI of 0.0771 – 0.181).ConclusionA greater first-attempt success rate was found when using the GlideScope versus direct laryngoscopy. In addition, the GlideScope was found to be 99% successful for intubation after initial failure of direct laryngoscopy, helping to reduce the incidence of failed intubation.

A first look at the Accreditation Council for Graduate Medical Education anesthesiology milestones: implementation of self-evaluation in a large residency program ☆

STUDY OBJECTIVE The objective was to determine if there is a correlation between resident postgraduate year (PGY) of training and self-evaluation of performance using the Accreditation Council for Graduate Medical Education milestones. DESIGN Survey. SETTING Residency program at a large academic center. PATIENTS Residents and Faculty Clinical Competency Committee (CCC). INTERVENTIONS None. MEASUREMENTS Resident and CCC milestone scores. MAIN RESULTS Correlation coefficients for average score for each milestone vs PGY level ranged from 0.80 for receiving and giving feedback to 0.95 for anesthetic choice and conduct. All milestones showed a relatively linear relationship with PGY of training, and none were found to be consistently reached very late or very early in training. When examining variation across the scores for the individual residents, the distributions for PGY-2 and -3 appeared to be wider than those for PGY-1 and -4. The intraclass correlation coefficients ranged from 0.718 to 0.928. CONCLUSIONS There was a remarkable degree of consistency in the relationship between level of training and resident self-assessment score for every milestone, as well as strong agreement between the resident and CCC faculty scores. Examination of the variance in the scores, when interpreted in light of our particular training programs characteristics, suggests that the milestones accurately reflect the progression in skill across the residency. In addition, given the concordance between the self-evaluation scores and the CCC faculty scores, self-evaluation may be a reasonable starting point as programs begin the daunting task of determining scores for each of the 25 milestones as part of the biannual evaluation process.