Effects of prolonged peri-neural bupivacaine infusion in rat sciatic nerves (axon and myelin).

BACKGROUND/OBJECTIVE: Peripheral-nerve blocks (PNBs) using continuous-infusion of local anesthetics are used to provide perioperative analgesia. Yet little research exists to characterize the histopathological effects of continuous long-duration PNBs. Herein we test the hypothesis that continuous peri-neural bupivacaine infusion (3-day vs. 7-day infusion) contributes to histologic injury in a duration-dependent manner using an in vivo model of rat sciatic nerves. METHODS: We placed indwelling catheters in 22 rats for infusion with low-dose (0.5mg/kg/hr) bupivacaine or normal saline proximal to the right sciatic nerves for 3 or 7 consecutive days. Hind-limb analgesia was measured using Von-Frey nociceptive testing. At infusion end, rats were sacrificed, bilateral nerves were sectioned and stained with hematoxylin and eosin and CD68 for evaluation of inflammatory response, and eriochrome to assess damage to myelin. RESULTS: Animals receiving continuous infusion of bupivacaine maintained analgesia as demonstrated by significant decrease (50% on average) in nociceptive response in bupivacaine-infused limbs across time points. Both 7-day saline and bupivacaine-infused sciatic nerves showed significantly-increased inflammation by H&E staining compared to untreated native nerve controls (P = 0.0001, P < 0.0001). Extent of inflammation did not vary significantly based on infusate (7-day saline vs. 7-day bupivacaine P > 0.99) or duration (3-day bupivacaine vs 7-day bupivacaine P > 0.99). No significant change in sciatic nerve myelin was found in bupivacaine-infused animals compared to saline-infused controls, regardless of duration. CONCLUSIONS: Long-duration (7-day) bupivacaine infusion provided durable post-operative analgesia, yet contributed to equivalent neural inflammation as short duration (3-day) infusion of bupivacaine or saline with no evidence of demyelination.

Agreement Between the Mini-Cog in the Preoperative Clinic and on the Day of Surgery and Association With Postanesthesia Care Unit Delirium: A Cohort Study of Cognitive Screening in Older Adults.

BACKGROUND: Cognitive impairment is common in older surgical patients and is associated with postoperative delirium. However, cognitive function is inconsistently assessed preoperatively, leading to missed opportunities to recognize vulnerable patients. We designed a prospective cohort study to assess the agreement of the Mini-Cog screening tool administered in the preoperative clinic (clinic-day test) or immediately before surgery (surgery-day test) and to determine whether a positive screening for cognitive dysfunction in the surgery-day test is associated with postoperative delirium in the postanesthesia care unit (PACU). METHODS: This was a cohort study of patients aged 65-89 years, scheduled for elective, inpatient surgery under general anesthesia between June 20, 2018 and August 3, 2018. Mini-Cog test scores were obtained during a clinic-day test and surgery-day test. The Short Confusion Assessment Method was performed in the PACU. Agreement between Mini-Cog clinic-day and surgery-day test scores was estimated using an ordinally weighted kappa statistic, κ. Multivariable logistic regression was used to determine whether there was an association between a positive screen for cognitive impairment and PACU delirium. Odds ratio analysis was performed to determine whether the Mini-Cog score was associated with PACU delirium. RESULTS: Of 128 patients meeting eligibility criteria, 80 patients were enrolled. Ten had cognitive impairment based on the Mini-Cog clinic-day test score, while 70 did not. Age, sex, race, education level, subjective memory impairment, and American Society of Anesthesiologists (ASA) physical status were equivalent in the 2 groups. The mean number of days between the clinic-day score and the surgery-day score was 8.4 days (standard deviation [SD] = 6.9). Mini-Cog clinic-day and surgery-day scores had high agreement (κ = 0.78; 95% confidence interval [CI], 0.69-0.87; P < .001), and both scores were highly predictive of PACU delirium. Patients with Mini-Cog surgery-day scores compatible with cognitive impairment (Mini-Cog scores ≤2) had an estimated 12.8 times higher odds of PACU delirium compared to patients with normal cognitive function or Mini-Cog scores >2 (odds ratio [OR] = 12.8; 95% CI, 2.6-63.8, P = .002). Similarly, patients with Mini-Cog clinic-day test scores compatible with cognitive impairment had an estimated 29 times higher odds of PACU delirium compared to patients with normal cognitive function (OR = 29.0; 95% CI, 2.6-63.8, P < .001). CONCLUSIONS: These data support the approach of using the Mini-Cog on the day of surgery to screen for cognitive impairment in older patients. Importantly, Mini-Cog surgery-day test scores compatible with cognitive impairment (≤2) were strongly associated with PACU delirium.

Oropharyngeal Oxygen Concentration Is Dependent on the Oxygen Mask System and Sampling Location.

BACKGROUND: Numerous oxygen delivery systems are used to treat hypoxemia. It is unknown if FIO2 at the lips predicts oropharyngeal FIO2 for various oxygen mask systems. We tested whether FIO2 measurements differed between the lips and oropharynx, and whether this difference depends on the mask system. METHODS: Ten healthy volunteers had one sampling catheter positioned at the lips and another catheter in the oropharynx. FIO2 was sampled at each location while the subjects breathed normal tidal volumes with oxygen at 15 L/min via 4 delivery devices: a simple mask, a non-rebreather mask, a face mask with a diffuser that concentrates and directs O2 toward the mouth and nose (mask with diffuser), and a closed mask with a Jackson-Rees circuit. Data were analyzed by using a linear mixed model to account for subject crossover in the repeated measures design. RESULTS: FIO2 levels differed significantly for the 4 delivery mask systems (P < .001) and by sampling catheter location (P < .001). Differences in mean FIO2 between the lips and the oropharynx were observed for the mask with diffuser (difference 0.30, 95% CI 0.25-0.36; P < .001), and non-rebreather mask (difference 0.09, 95% CI 0.04-0.15; P = .001). The mean FIO2 at the oropharynx was highest for the closed mask (0.97, 95% CI 0.92-1.00), followed by the non-rebreather mask (0.76, 95% CI 0.72-0.81), simple mask (0.62, 95% CI 0.58-0.67), and the mask with diffuser (0.51, 95% CI 0.46-0.56). At the lips, the mean FIO2 was highest for the closed mask (0.97, 95% CI 0.92-1.00), followed by the non-rebreather mask (0.86, 95% CI 0.81- 0.90), OxyMask (0.81, 95% CI 0.76-0.86), and simple mask (0.67, 95% CI 0.62-0.71). CONCLUSIONS: With high oxygen flows and normal tidal volume breathing, FIO2 measurements obtained at the oropharynx or at the lips depended on the device used, with the mask with diffuser showing the most significant discrepancies. FIO2 measures at the oropharynx and the lips were only consistent for the closed mask system. (ClinicalTrials.gov registration NCT02523586.).

Does Participation in Written Guided Reflective Practice Exercises Affect Readiness for Self-Directed Learning in a Sample of US Anesthesiology Residents?

BACKGROUND: Reflective practice has been identified as one way to increase participation in self-directed lifelong learning so that physicians maintain a level of current and relevant medical knowledge for their practice. This study sought to determine if reflective practice affected the readiness for self-directed learning in a sample of anesthesiology residents in the United States. METHODS: An experimental design was used to employ quantitative methods to investigate the effects of a self-guided 8-week reflective practice exercise on readiness for self-directed learning as measured by Guglielmino's Self-Directed Learning Readiness Scale/Learning Preference Assessment (SDLRS/LPA). Participants were randomly assigned into an experimental group or control group. RESULTS: Fifty-one anesthesiology residents in 3 residency programs completed this study. No significant difference was found between the posttest SDLRS/LPA scores of the control (median = 227) and experimental group (median = 225; U = 294; z = -.584; P = .559; r = 41.18) as well as the pretest and posttest scores (z = -.65; P = .518; r = -.129) of the experimental group. CONCLUSIONS: We should continue to explore ways to train physicians to engage in practices that promote self-directed lifelong learning.

Effects of anesthesia on cerebral blood flow, metabolism, and neuroprotection.

Administration of anesthetic agents fundamentally shifts the responsibility for maintenance of homeostasis from the patient and their intrinsic physiological regulatory mechanisms to the anesthesiologist. Continuous delivery of oxygen and nutrients to the brain is necessary to prevent irreversible injury and arises from a complex series of regulatory mechanisms that ensure uninterrupted cerebral blood flow. Our understanding of these regulatory mechanisms and the effects of anesthetics on them has been driven by the tireless work of pioneers in the field. It is of paramount importance that the anesthesiologist shares this understanding. Herein, we will review the physiological determinants of cerebral blood flow and how delivery of anesthesia impacts these processes.

Lean Strategies in the Operating Room.

Lean strategies can be readily applied to health care in general and operating rooms specifically. The emphasis is on the patient as the customer, respect and engagement of all providers, and leadership from management. The strategy of lean is to use continuous improvement to eliminate waste from the care process, leaving only value-added activities. This iterative process progressively adds the steps of identifying the 7 common forms of waste (transportation, inventory, motion, waiting, overproduction, overprocessing, and defects), 5S (sort, simplify, sweep, standardize, sustain), visual controls, just-in-time processing, level-loaded work, and built-in quality to achieve the highest quality of patient care.

Assessing the Academic Productivity of Foundation for Anesthesia Education and Research (FAER) Resident Scholars.

BACKGROUND: The Foundation for Anesthesia Education and Research Resident Scholar Program (RSP) supports academically promising anesthesiology residents to attend mentoring seminars at the American Society of Anesthesiologists annual meeting. The objective of this study was to describe the career paths of RSP participants. METHODS: Prior RSP participants were surveyed regarding their academic productivity and their evaluation of the RSP experience. Univariate statistics were used to characterize the survey results. RESULTS: A total of 882 RSP participants were surveyed. The response rate was 26%. Seventy-two percent of respondents had worked in an academic institution, and 45% (95% CI: 38%-51%) were currently at an academic institution, which is higher than the national average of 18% (P<0.001). CONCLUSIONS: This program may be a model for supporting the development of future academic anesthesiologists.

Barrier protection capacity of flip-top pharmaceutical vials.

STUDY OBJECTIVE: To test the sterility of medication vial tops after removal of the dust cover, and to survey anesthesia providers for their perceptions surrounding medication vials and sterility. DESIGN: Experimental design and survey instrument. SETTING: Ambulatory and hospital care setting. PARTICIPANTS: Anesthesia providers in the United States. MEASUREMENTS: A two-question survey was distributed to anesthesia providers in the U.S. An experimental model was conducted on a total of 42 medication vials. The access diaphragms of medication vials were sampled after routine handling, after exposure to aerosolized contamination with the dust cover on, and after submersion into a bacterial medium with the dust cover on. MAIN RESULTS: 878 responses to Question 1 and 876 responses to Question 2 were received. Fifty-two percent of respondents declared that the access diaphragm was sterile in routine conditions, and 43% felt that (or were unsure if) the dust cover would prevent contamination when exposed to a contaminated environment. Two of the 12 vials sampled in the routine handling model had microbial contaminants on the access diaphragm. No growth was found on any of the 15 vials exposed to aerosolized E. coli. Seven of the 15 vials in the submersion model were contaminated. CONCLUSIONS: Anesthesia providers in the U.S. possess contradictory opinions of, and unclear knowledge about, the sterility of rubber stoppers used to access medications, and also the barrier capacity of a vial's dust cover. Standard anesthetic medication vial dust covers do not offer barrier protection against the growth of pathogens.

Anesthetic neurotoxicity.

Concerns for toxic effects of anesthesia to the brains of the young and the elderly are mounting. While experimental evidence for such effects in the developing brain is strong, the underlying mechanisms are less well understood and debate continues as to whether young humans are at risk for anesthetic neurotoxicity. The phenomenon of postoperative cognitive deterioration in the elderly remains controversial. Time course, severity, and whether or not it persists long term are under debate. For both patient groups, today's evidence is not sufficient to guide change in clinical practice. Well-designed research is therefore imperative to tackle this critical issue.

Local anesthetic Schwann cell toxicity is time and concentration dependent.

BACKGROUND: Peripheral nerve blocks with local anesthetics (LAs) are commonly performed to provide surgical anesthesia or postoperative analgesia. Nerve injury resulting in persistent numbness or weakness is a potentially serious complication. Local anesthetics have previously been shown to damage neuronal and Schwann cells via several mechanisms. We sought to test the hypothesis that LAs are toxic to Schwann cells and that the degree of toxicity is directly related to the concentration of LA and duration of exposure. Intraneural injection of LAs has been shown to produce nerve injury. We sought to test the hypothesis that a prolonged extraneural infusion of LA can also produce injury. METHODS: Schwann cells cultured from neonatal rat sciatic nerves were incubated with LAs at different concentrations (10, 100, 500, and 1000 µM), and each concentration was assessed for toxicity after 4, 24, 48 and 72 hours of exposure. Local anesthetics tested were lidocaine, mepivacaine, chloroprocaine, ropivacaine, and bupivacaine. Cell death was assessed by lactate dehydrogenase release measured by optical density.In a separate experiment, a microcatheter was placed along the sciatic nerves of Sprague-Dawley rats. Rats were randomly assigned to receive either 0.9% saline (n = 8) or bupivacaine (0.5%, n = 4; 0.75%, n = 4) via the perineural catheters for 72 hours. The rats were then killed, and their nerves sectioned and stained for analysis. Sections were stained for myelin and with an antimacrophage (CD68) antibody. RESULTS: None of the LAs tested produced significant Schwann cell death at very low concentrations (10 µM, or 0.0003%) even after prolonged exposure. With prolonged exposure (48 or 72 hrs) to high concentrations (1000 µM, or 0.03%), all of the LAs tested produced significant Schwann cell death (increased lactate dehydrogenase release relative to control as measured by optical density, 0.384-0.974; all P values < 0.001). Only bupivacaine produced significant cell death (0.482, P < 0.001) after prolonged exposure to low concentrations (100 µM, or 0.003%). At intermediate concentrations (500 µM, or 0.015%), cell death was more widespread with bupivacaine (0.768, P < 0.001) and ropivacaine (0.675, P < 0.001) than the other agents (0.204-0.368; all P values < 0.001). Prolonged extraneural exposure of rat sciatic nerves to bupivacaine caused significant demyelination and infiltration of nerves with inflammatory cells. CONCLUSIONS: Local anesthetics induce Schwann cell death in a time- and concentration-dependent manner. Bupivacaine and ropivacaine have greater toxicity at intermediate concentrations, and prolonged exposure to bupivacaine produces significant toxicity even at low concentrations. Brief exposure to high concentrations of bupivacaine damages Schwann cells. Prolonged extraneural infusion of bupivacaine results in nerve injury.

Training intensivists and clinician-scientists for the 21st century: the Oregon scholars program.

BACKGROUND: Innovation is important for the development and advancement of any medical specialty. Leaders in anesthesiology have emphasized the need for more training in critical care and additional research to advance our specialty. INTERVENTION: To help address this need, Oregon Health & Science University (OHSU) developed an innovative training program that combines a critical care medicine (CCM) or research fellowship with traditional clinical anesthesia training. This article outlines the program structure, challenges, and successes of this innovative approach to training anesthesiology clinicians and scientists. FINDINGS: Since the program began in 2006, we have filled all available positions and currently have 9 scholars in the anesthesiology/CCM track and 3 in the anesthesiology/research track at the postgraduate year-2 to postgraduate year-5 levels. Our first class of scholars graduated in the summer of 2010. The Oregon Scholars Program (OSP) scholars and faculty have confronted challenges, including the transition from resident in the operating rooms to fellow in the critical care units. In 2007, our residents acknowledged the OSP/CCM scholars' expertise in CCM and have looked to them as teachers and advocates for their education during their CCM rotations. In July 2007, OHSU received a National Institutes of Health T32 training grant to support the research component of the OSP. OSP scholars' research productivity has resulted in 11 publications, 3 abstracts, 3 presentations, 3 research grants, and 1 resident research award. Several other anesthesiology programs have recently instituted similar programs to address the need for anesthesiologists trained as intensivists and clinician-scientists.

Video laryngoscopy with the macintosh video laryngoscope in simulated prehospital scenarios by paramedic students.

OBJECTIVE: To investigate the effectiveness of the Karl Storz BERCI DCI Macintosh video laryngoscope (MVL) via the TELE PACK system for facilitating intubation by novice paramedic students in a simulation environment. We assessed the laryngeal view, measured by percentage of glottic opening (POGO), when intubating the SimMan manikin airway in different settings. The primary endpoint was the best POGO achieved by the student. Secondary endpoints included intubation times and success rate. METHOD: We enrolled 25 novice paramedic students to intubate SimMan manikins. Students were randomized to use either a conventional Macintosh 3 (Mac3) blade alone or the MVL with a Mac3 blade. Students attempted their first intubation with the manikin on a stretcher in a normal neck position and reattempted intubation with the manikin's neck stiffened. The groups then crossed over using the alternate device to repeat the attempts in the manikin with a normal neck and with a stiffened neck. The students then attempted the same sequence of four intubations with the manikin on the floor. RESULTS: The MVL significantly improved POGO in all scenarios (p < 0.05). The MVL improved mean POGO 16% +/- 6% in the manikin with a normal neck position on a stretcher and 33% +/- 7% in the manikin with a stiff neck on the floor. The improvement was significantly greater in simulated difficult scenarios. The intubation success rate (94%) was equal in the two groups, and the POGO was significantly worse in the failures. In some subgroups, intubation times were longer with the MVL. CONCLUSION: The MVL improves the laryngeal view for novice laryngoscopists in a simulated setting, and this improvement is greatest in simulated difficult scenarios.

Cyclic adenosine monophosphate response element-binding protein phosphorylation and neuroprotection by 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP).

BACKGROUND: Previous studies show that the potent, prototypical sigma(1)-receptor agonist 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) prevents cell death after oxygen-glucose deprivation (OGD) in primary cortical neuronal cultures. We tested the hypothesis that PPBP protects neurons by a mechanism involving activation of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB). METHODS: Primary cultured cortical neurons were exposed to 2 h of OGD and allowed to recover for 24 h, and PPBP treatment was initiated 15 min before the insult in the presence and absence of the sigma(1)-receptor antagonist rimcazole and inhibitors against protein kinases known to activate signal transduction cascades that result in CREB phosphorylation, such as H89 (protein kinase A inhibitor), LY294002 (PI3K inhibitor), U0126 (MEK1/2 inhibitor), or KN62 calmodulin kinase II inhibitor). Neuronal cell death was assayed by lactate dehydrogenase measurement 24 h after OGD. CREB phosphorylation was measured by immunoblot analysis at 30 min, 1 h, and 3 h of reoxygenation. Blots were quantitatively analyzed using Quantity One image analysis software. RESULTS: PPBP increased CREB phosphorylation at 1 h after recovery from OGD, which was abolished by rimcazole (1.7 +/- 0.2 in PPBP and 0.8 +/- 0.1 in PPBP plus rimcazole with OGD compared with 0.9 +/- 0.1 in OGD alone, p-CREB/CREB). The PPBP-induced increase in CREB phosphorylation was blocked by H89 (0.5 +/- 0.07) but not U0126, KN62, or LY294002. PPBP treatment prevented OGD-induced cell death and pretreatment with H89 blocked this protection (0.18 +/- 0.02 in PPBP and 0.27 +/- 0.03 in PPBP plus H89 with OGD compared with 0.33 +/- 0.02 in OGD alone, lactate dehydrogenase assay). Pretreatment with LY294002, UO126, or KN62 had no effect on neuronal protection by PPBP. CONCLUSIONS: These data suggest that the mechanism of neuroprotection by PPBP may be linked to CREB phosphorylation.

Can gender differences be evaluated in a rhesus macaque (Macaca mulatta) model of focal cerebral ischemia?

Gender differences, sex steroid effects, and sex-specific candidate therapeutics in ischemic stroke have been studied in rodents but not in nonhuman primates. In this feasibility study (n = 3 per group), we developed a model of transient focal cerebral ischemia in adult male and female rhesus macaques that consistently includes white matter injury. The animals also were used to determine whether gender-linked differences in histopathologic outcomes could be evaluated in this model in future, larger preclinical trials. Histologic brain pathology was evaluated at 4 d after 90 min of reversible occlusion of the middle cerebral artery (MCA). MCA occlusion was accomplished by using a transorbital approach and temporary placement of an aneurysm clip. Male and female rhesus macaques 7 to 11 y of age were studied. Baseline and intraischemic blood glucose, systolic blood pressure, heart rate, oxygen saturation, end-tidal CO2, and rectal temperatures were not different among groups. The variability in injury volume was comparable to that observed in human focal cerebrovascular ischemia and in other nonhuman primate models using proximal MCA occlusion. In this small sample, the volume of injury was not different between male and female subjects, but observed variability was higher in female caudate nucleus, putamen, and hemisphere. This report is the first to compare cerebral ischemic outcomes in female and male rhesus macaques. The female rhesus macaque ischemic stroke model could be used after rodent studies to provide preclinical data for clinical trials in women.