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Objective: Hyperinflation of the laryngeal mask airway (LMA) cuff is thought to be the etiology underlying many of the complications associated with the use of this device. Until now, there has not been a clinically acceptable method (besides direct measurement) to assure that the cuff pressure is maintained less than the recommended maximum value of 44 mm Hg (60 cm H(2)O).Methods: We inflated sizes #2 and #5 LMAs with air to 40, 60, or 120 mm Hg starting pressures, using 30- and 60-ml BD™ and B Braun™ syringes; we then allowed the syringe plungers to recoil to equilibrium before removing the syringe from the LMA inflation port. Residual LMA cuff pressures following complete passive recoil were measured and recorded.Results: A number of combinations of syringes (30 and 60 ml) and starting pressures (40, 60, 120 mm Hg) resulted in safe residual (#2 and #5 LMA) cuff pressures of <44 mm Hg.Conclusion: When using specific combinations of syringes, LMA sizes and inflation pressures, these data demonstrate an efficient, practical and easy method to achieve an initial equilibrium recoil LMA cuff pressure that is less than, or very near to, the recommended upper safe limit of 44 mm Hg. [ABSTRACT FROM AUTHOR]

Introduction: A study using unblinded block performance and subjective outcome measurements suggested that "opening the space" surrounding the femoral nerve with 10 mL dextrose 5% in water (D5W) before catheter placement facilitated placement and improved the quality of the nerve block. We conducted a double-blind, prospectively randomized study to evaluate this suggestion by adding objective measurements to the original subjective measurements.Methods: A Tuohy needle was directed toward the femoral nerve under ultrasound and nerve stimulator guidance. A quadriceps femoris motor response was identified by cephalad patellar movements with a maximum nerve stimulator output of 0.5 mA. The primary anesthesiologist either injected D5W or made no injection through the needle, depending on patient randomization. A second anesthesiologist, unaware of randomization, placed the stimulating perineural catheter. The primary measurement was the procedure time (in seconds) for threading the catheter. Additional measurements included total nerve block time (in minutes), number of attempts passing the catheter, subjective ease of placement by the second anesthesiologist, depth of needle and catheter, minimum stimulating current through needle and catheter, and the quality of the nerve block.Results: Two groups of 35 patients were enrolled. Statistically significant differences were found in the median (5th-95th confidence intervals) catheter threading time (21.0 [9.6-118] and 33.0 [13.4-193] secs in the control and D5W groups, respectively; P = 0.03). Significant difference was also found in the number of attempts at passing the catheter (1 [1-2] and 2 [1-4] in the control and D5W groups, respectively; P = 0.03).Conclusions: The findings of this study do not support the concept that opening the space surrounding the femoral nerve with D5W before femoral catheter placement adds value to perineural catheter placement. [ABSTRACT FROM AUTHOR]

Objective: Documented falls after lower-extremity-nerve blocks are rare. We believe this paucity of documented falls is the result of underreporting and the lack of serious complications resulting from these falls. In addition, the mechanism(s) for falls after lower-extremity-nerve blocks has not been elucidated.Case Reports: These reports highlight the mechanism of fall in a patient with a femoral-nerve block (FNB) and in a patient with a femoral-nerve and sciatic-nerve block (FNB/SNB). In addition, we report our findings when volunteers underwent FNB, sciatic-nerve block (SNB) and FNB/SNB and were studied in a gait-analysis laboratory.Conclusions: Lower-extremity-nerve blocks result in decreased leg stiffness and lateral instability, which may lead to difficulty with pivoting maneuvers. [ABSTRACT FROM AUTHOR]

We have proposed a novel hypothesis regarding the potential role of occupational or second-hand exposure in physician substance use, abuse, and addiction. While only 5.6% of licensed physicians in Florida are anesthesiologists, nearly 25% of physicians followed for substance abuse/dependence are anesthesiologists. When we sort by drug of choice, anesthesiologists have more opioid abuse and dependence than other physicians and appropriate controls. Abuse of one opioid, fentanyl, appears to be increasing and has been noted among the State of Florida's causes of opioid deaths. Fentanyl and sufentanyl are commonly administered highly potent opioid analgesics, as much as 80-800 times as potent as morphine. We have recent data from the State of Florida impaired physicians database, which has allowed us to categorize all fentanyl abusing and/ or dependent physicians. Just knowing that a physician abuses fentanyl gives you a good clue as to their specialty; 75% are anesthesiologists! While drug abuse researchers, oncologists and others who handle drugs of abuse everyday, have no greater incidence of opioid abuse or dependence, anesthesiologists are at the top of every list. Can this be due to just access and stress? We have proposed an alternative hypothesis of second hand exposure. To test this hypothesis, we developed a sensitive LC/MS/MS assay to measure the intravenous anesthetic and analgesic agents, propofol and fentanyl in air. Not only did we detect propofol and fentanyl in cardiovascular surgery operating room air, we also found the highest concentrations were close to the patient's mouth where anesthesiologists work for hours. Like tobacco, second hand opioid exposure can sensitize and change the brain making abuse, dependence and behavioral disorders more likely. Thus environmental exposure and sensitization may be an important risk factor in physician addiction. Second hand exposure may affect treatment outcome and explain anesthesiologist's inability to return to work in the operating room. We are developing an animal model for second hand exposure and additional studies of the operating room and cardiac anesthesiologists are underway. [ABSTRACT FROM AUTHOR]

Background and Objectives: Although a continuous interscalene nerve block (CISB) has been shown to provide potent analgesia after major shoulder surgery, its potential effects on postoperative rehabilitation remain uninvestigated. Therefore, this retrospective case-control study was undertaken to determine the association between CISB and joint range-of-motion after total shoulder arthroplasty (TSA).Methods: The medical records for patients who underwent TSA at our institution in the previous 3 years were examined. Each patient with a CISB (cases) was matched with a patient without a CISB (controls) for the following variables: age, gender, and TSA type (primary v revision). Data collected included maximum shoulder elevation and external rotation (primary endpoints), along with pre- and postoperative pain scores.Results: Of 134 charts reviewed, 25 cases were matched with an equal number of controls. On postoperative day 1, patients with or without a CISB achieved a median (5th-95th percentiles) of 85% (51-100) and 33% (11-56) of their surgeon-defined goal for elevation (P = .048), respectively, and attained 100% (33-100) and 17% (-81-68) for external rotation (P < .001), respectively. The median numeric rating pain score (NRS) during shoulder movement for patients with CISB was 2.0 (0.0-8.7) versus 8.5 (1.8-10.0) for patients without CISB (P < .001). Least, median, and highest resting NRS for the 24 hours after surgery were 0.0 (0.0-5.8), 1.0 (0.0-6.4), and 3.0 (0.0-9.0) for patients with CISB, respectively, versus 2.0 (0.0-7.7), 6.0 (0.3-9.6), and 8.0 (0.0-10.0) for patients without CISB (P = .030, P < .001, and P < .001 between groups, respectively).Conclusions: The day after TSA, a CISB is associated with increased shoulder range of motion, most likely resulting from the potent analgesia these nerve blocks provide. [ABSTRACT FROM AUTHOR]

Children of parents with traumatic brain injury (TBI) are more likely to develop psychiatric disorders. This association is usually attributed to TBI-induced changes in parents' personality and families' social environment. We tested the hypothesis that offspring of young adult male rats with TBI develop neurodevelopmental abnormalities in the absence of direct social contact with sires. Male Sprague-Dawley rats (F0 generation) in the TBI group underwent moderate TBI via a midline fluid percussion injury that involved craniectomy under sevoflurane (SEVO) anesthesia for 40 min on post-natal Day 60 (P60), while F0 rats in the control group were placed in a new cage, one per cage, for the equivalent time duration. A subset of F0 rats was sacrificed on P66 to assess acute changes in hypothalamic-pituitary-adrenal (HPA) axis and inflammation markers. The remaining F0 males were mated with naive females on P90 to generate offspring (F1 generation). The F0 males and F1 males and females were sequentially evaluated in the elevated plus maze, for pre-pulse inhibition of acoustic startle, in the Morris water maze, and for resting and stress levels of serum corticosterone starting on ∼P105 (F0) and ∼P60 (F1), followed by tissue collection for further analyses. Acutely, the F0 TBI males had messenger RNA (mRNA) transcripts altered to support an increased hypothalamic and hippocampal Na + -K + -Cl - ( Slc12a2 ) Cl - importer / K + -2Cl - ( Slc12a5 ) Cl - exporter ratio and decreased hippocampal glucocorticoid receptors ( Nr3c1 ), as well as increased serum levels of corticosterone, interleukin-1β (IL-1β), and biomarkers of activated hippocampal microglia and astrocytes. Long-term, F0 TBI rats exhibited increased corticosterone concentrations at rest and under stress, anxiety-like behavior, impaired sensory-motor gating, and impaired spatial memory. These abnormalities were underpinned by reduced mRNA levels of hypothalamic and hippocampal mineralocorticoid receptors ( Nr3c2 ), hippocampal Nr3c1, and hypothalamic brain-derived neurotrophic factor (Bdnf), as well as elevated serum levels of IL-1β, and biomarkers of activated hippocampal microglia and astrocytes. F1 male offspring of TBI sires exhibited abnormalities in all behavioral tests, while their F1 female counterparts had abnormal pre-pulse inhibition responses only. F1 male offspring of TBI sires also had reduced mRNA levels of hippocampal Nr3c1 and Nr3c2 , as well as hypothalamic and hippocampal Bdnf, whereas increases in inflammatory markers were more profound in F1 females. These findings suggest that offspring of sires with a history of a moderate TBI that involved craniectomy under SEVO anesthesia for 40 min, develop sex-dependent neurobehavioral abnormalities in the absence of direct social interaction between the sire and the offspring.

Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors' own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).

Background: The authors tested the hypothesis that the effects of traumatic brain injury, surgery, and sevoflurane interact to induce neurobehavioral abnormalities in adult male rats and in their offspring (an animal model of intergenerational perioperative neurocognitive disorder)., Methods: Sprague-Dawley male rats (assigned generation F0) underwent a traumatic brain injury on postnatal day 60 that involved craniectomy (surgery) under 3% sevoflurane for 40 min followed by 2.1% sevoflurane for 3 h on postnatal days 62, 64, and 66 (injury group). The surgery group had craniectomy without traumatic brain injury, whereas the sevoflurane group had sevoflurane only. On postnatal day 90, F0 males and control females were mated to generate offspring (assigned generation F1)., Results: Acutely, F0 injury rats exhibited the greatest increases in serum corticosterone and interleukin-1β and -6, and activation of the hippocampal microglia. Long-term, compared to controls, F0 injury rats had the most exacerbated corticosterone levels at rest (mean ± SD, 2.21 ± 0.64 vs. 7.28 ± 1.95 ng/ml, n = 7 - 8; P < 0.001) and 10 min after restraint (133.12 ± 33.98 vs. 232.83 ± 40.71 ng/ml, n = 7 - 8; P < 0.001), increased interleukin-1β and -6, and reduced expression of hippocampal glucocorticoid receptor (Nr3c1; 0.53 ± 0.08 fold change relative to control, P < 0.001, n = 6) and brain-derived neurotrophic factor genes. They also exhibited greater behavioral deficiencies. Similar abnormalities were evident in their male offspring, whereas F1 females were not affected. The reduced Nr3c1 expression in F1 male, but not female, hippocampus was accompanied by corresponding Nr3c1 promoter hypermethylated CpG sites in F0 spermatozoa and F1 male, but not female, hippocampus., Conclusions: These findings in rats suggest that young adult males with traumatic brain injury are at an increased risk of developing perioperative neurocognitive disorder, as are their unexposed male but not female offspring., (Copyright © 2023, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats., Methods: Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus., Results: Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities., Conclusions: This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Neonatal exposure to sevoflurane induces neurobehavioral and neuroendocrine abnormalities in exposed male rats (generation F0) and neurobehavioral, but not neuroendocrine, abnormalities in their male, but not female, offspring (generation F1). These effects of sevoflurane are accompanied by a hypermethylated neuron-specific K-2Cl (Kcc2) Cl exporter gene in the F0 spermatozoa and the F1 male hypothalamus, while the gene's expression is reduced in the F0 and F1 hypothalamus. We investigated whether inhibition of deoxyribonucleic acid methyltransferases (DNMTs) before paternal sevoflurane exposure could alleviate the anesthetic's F0 and F1 effects., Methods: Sprague-Dawley male rats were anesthetized with 2.1% sevoflurane for 5 hours on postnatal day (P) 5 and mated with control females on P90 to generate offspring. The nonselective DNMT inhibitor decitabine (0.5 mg/kg, intraperitoneally) was administered 30 minutes before sevoflurane exposure. The F0 and F1 male rats were evaluated in in vivo and in vitro tests in adulthood., Results: Paternal exposure to sevoflurane induced impaired prepulse inhibition of the acoustic startle response and exacerbated corticosterone responses to stress in F0 males and impaired prepulse inhibition of the startle responses in F1 males. These effects were accompanied in both generations by reduced and increased expressions of hypothalamic Kcc2 and Dnmt3a/b, respectively. Decitabine deterred the effects of paternal exposure to sevoflurane in F0 and F1 males., Conclusions: These results suggest that similar decitabine-sensitive mechanisms regulating expression of multiple genes are involved in the mediation of neurobehavioral abnormalities in sires neonatally exposed to sevoflurane and in their future unexposed male offspring.

Testosterone (T), predominantly acting through its derivative 17β-estradiol (E2), regulates the brain's sexual differentiation in rodents during the perinatal sensitive period, which mirrors the window of vulnerability to the adverse effects of general anesthetics. The mechanisms of anesthesia's adverse effects are poorly understood. We investigated whether sevoflurane alters T and E2 levels and whether they contribute to sevoflurane's acute adverse effects in postnatal day 5 Sprague-Dawley rats. The rats underwent electroencephalography recordings for 2 h of baseline activity or for 1 h before and another hour during 2.1% sevoflurane exposure, followed by collection of trunk blood and brain tissue. Pharmacological agents, including the GABA type A receptor inhibitor bicuculline and the aromatase inhibitor formestane, were administered 30 min before sevoflurane anesthesia. Sevoflurane increased serum T levels in males only. All other effects of sevoflurane were similar in both sexes, including increases in serum levels of E2, hypothalamic mRNA levels of aromatase, estrogen receptor α ( Er α) [not estrogen receptor β ( Erβ) ], Na + -K + -Cl - cotransporter ( Nkcc1 )/K + -Cl - cotransporter ( Kcc2 ) mRNA ratio, electroencephalography-detectable seizures, and stress-like corticosterone secretion. Bicuculline and formestane alleviated these effects, except the T level increases. The ERα antagonist MPP, but not the ERβ antagonist PHTPP, reduced electroencephalography-detectable seizures and normalized the Nkcc1/Kcc2 mRNA ratio. Collectively, sevoflurane exacerbates levels of T in males and E2 in both sexes during the period of their organizational effects in rodents. Sevoflurane acts through GABA A R-mediated, systemic T-independent elevation of E2 to cause electroencephalography-detectable seizures, stress-like corticosterone secretion, and changes in the expression of genes critical for brain development., (Copyright © 2020 Li, Xu, Lin, Lei, Ju, Morey, Gravenstein, Zhang and Martynyuk.)

Background: Deficiencies in neurocognitive function have been found in late childhood or adolescence in patients who had prolonged and/or repeated early-life general anesthesia. Animal studies suggest that anesthetic-induced impairment in the neuron-specific K + -2Cl - (Kcc2) Cl - exporter expression, which regulates developmental maturation of GABA type A receptor (GABA A R) signaling from excitatory to inhibitory, may play a mediating role. We tested whether the DNA methyltransferase (DNMT) inhibitor decitabine ameliorates the anesthetic's adverse effects., Methods: Sprague-Dawley male rats were injected with vehicle or decitabine 30 min before 2.1 % sevoflurane exposure for 5 h on postnatal day 5 (P5). On P19, P20, or P21, electroencephalography-detectable seizures were measured during 1 h of sevoflurane exposure, followed by collection of the trunk blood and brain tissue samples. Other rats were evaluated for changes in hippocampal CA1 dendrite morphology and gene expressions on ≥ P120., Results: Rats in the vehicle plus sevoflurane group responded to sevoflurane exposure on P19, P20 or P21 with electroencephalography-detectable seizures and stress-like corticosterone secretion and had altered hippocampal dendrite morphology in adulthood. These rats had expressions of Kcc2 and Dnmt genes downregulated and upregulated, respectively, in the P19 - P21 cortex and hypothalamus and the ≥ P120 hippocampus. All measured parameters in the sevoflurane-exposed rats that were pretreated with decitabine were not different from those in the control group., Conclusions: Neonatal exposure to sevoflurane sensitizes rats to adverse effects of repeated exposure to the anesthetic. The anesthetic-caused changes in the decitabine-sensitive mechanisms may play a mediating role in the developmental effects of early-life anesthesia., (Copyright © 2020. Published by Elsevier B.V.)

The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves., Methods: Sprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring., Results: Adult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050)., Conclusions: Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprogramming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.

Early life stressors, including general anesthesia, can have adverse effects on adult neural and behavioral outcomes, such as disruptions in inhibitory signaling, stress responsivity and increased risk of psychiatric disorders. Here we used a rat model to determine the effects of combined exposure to etomidate (ET) neonatal anesthesia and maternal separation on adult amygdala expression of genes for corticotropin-releasing hormone (Crh) and the chloride co-transporters Nkcc1 and Kcc2, as well as ethanol intake. Male and female Sprague-Dawley rats were subjected to 2 h of ET anesthesia on postnatal days (P) 4, 5, or 6 followed by maternal separation for 3 h on P10 (ET + SEP). During the P91-P120 period rats had daily 2 h access to three 0.05% saccharin solutions containing 0%, 5%, or 10% ethanol, followed by gene expression analyses. The ET + SEP group had increased Crh mRNA levels and Nkcc1/Kcc2 mRNA ratios in the amygdala, with greater increases in Nkcc1/Kcc2 mRNA ratios in males. A moderate increase in 5% ethanol intake was evident in the ET + SEP males, but not females, after calculation of the ratio of alcohol intake between the last week and first week of exposure. In contrast, control males tended to decrease alcohol consumption during the same period. A brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala Crh, Nkcc1 and Kcc2 with greater changes in the Cl - transporter expression in males. The possibility of increased alcohol intake in the exposed males requires further confirmation using different alcohol intake paradigms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K + -2Cl - Cl - exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats., Methods: Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations., Results: Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups., Conclusions: Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Tracheal intubation via laryngeal exposure has evolved over the past 150 years and has greatly expanded in the last decade with the introduction and development of newer, more sophisticated optical airway devices. The introduction of indirect and video-assisted laryngoscopes has significantly impacted airway management as evidenced by the presence of these devices in the majority of published difficult airway algorithms. However, it is quite possible that many airway managers do not have a thorough comprehension of how these devices actually function, an understanding that is vital not only for their use but also for assessing the devices' limitations. This article discusses the development of video laryngoscopy, how the video laryngoscope works, and the impact of video laryngoscopy on difficult airway management.

Background: Overinflation of the laryngeal mask airway (LMA) cuff may cause many of the complications associated with the use of the LMA. There is no clinically acceptable (cost effective and practical) method to ensure cuff pressure is maintained below the manufacturer's recommended maximum value of 60 cm H 2 O (44 mmHg). We studied the use of the intrinsic recoil of the LMA inflating syringe as an effective and practical way to limit cuff pressures at or below the manufacturer's recommended values., Methods: We enrolled 332 patients into three separate groups: LMAs inserted and inflated per standard practice at the institution with only manual palpation of the pilot balloon; LMA cuff pressures measured by a pressure transducer and reduced to < 60 cm H 2 O (44 mmHg); and LMA intra-cuff pressure managed by the intrinsic recoil of the syringe., Results: There were no statistically significant differences between the pressure transducer group and the syringe recoil group for initial cuff pressure or cuff pressure 1 hour after surgery. Both the syringe recoil group and pressure transducer group were less likely than the standard practice group to have sore throat and dysphagia 1 hour after surgery. These differences remained 24 hours after surgery., Conclusions: Syringe recoil provides an efficient and reproducible method similar to manometry in preventing overinflation of the LMA cuff and decreasing the incidence of postoperative laryngopharyngeal complications., Competing Interests: Conflict of interest Nothing to declare

Background: The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure., Methods: Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na + -K + -2Cl - (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3h at P10. 3-7days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K + -2Cl - (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects., Conclusions: Post-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Modern clinical research commonly uses complex designs with multiple related outcomes, including repeated-measures designs. While multiple comparison corrections and effect size calculations are needed to more accurately assess an intervention's significance and impact, understanding the limitations of these methods in the case of dependency and correlation is important. In this review, we outline methods for multiple comparison corrections and effect size calculations and considerations in cases of correlation and summarize relevant simulation studies to illustrate these concepts.

Background: The nasal ala is an attractive site for pulse oximetry because of perfusion by branches of the external and internal carotid arteries. We evaluated the accuracy of a novel pulse oximetry sensor custom designed for the nasal ala., Methods: After IRB approval, healthy non-smoking subjects [n=12; aged 28 (23-41) yr; 6M/6F] breathed hypoxic mixtures of fresh gas by a facemask to achieve oxyhaemoglobin saturations of 70-100% measured by traditional co-oximetry from radial artery samples. Concurrent alar and finger pulse oximetry values were measured using probes designed for these sites. Data were analysed using the Bland-Altman method for multiple observations per subject., Results: Bias, precision, and accuracy root mean square error (ARMS) over a range of 70-100% were significantly better for the alar probe compared with a standard finger probe. The mean bias for the alar and finger probes was 0.73% and 1.90% (P<0.001), respectively, with corresponding precision values of 1.65 and 1.83 (P=0.015) and ARMS values of 1.78% and 2.72% (P=0.047). The coefficients of determination were 0.96 and 0.96 for the alar and finger probes, respectively. The within/between-subject variation for the alar and finger probes were 1.14/1.57% and 1.87/1.47%, respectively. The limits of agreement were 3.96/-2.50% and 5.48/-1.68% for the alar and finger probes, respectively., Conclusions: Nasal alar pulse oximetry is feasible and demonstrates accurate pulse oximetry values over a range of 70-100%. The alar probe demonstrated greater accuracy compared with a conventional finger pulse oximeter., (© The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Contamination of a central venous catheter may occur through use of conventional open-lumen stopcock devices (COLDs), or disinfectable, needleless, closed connectors (DNCCs). We investigated the effectiveness of a new universal IV access cleaning device (Site-Scrub) compared with 70% isopropyl alcohol prep pads for sanitizing COLDs or DNCCs inoculated with common catheter-associated pathogens., Methods: Site-Scrub was compared with 70% alcohol prep pads for sanitizing contaminated female Luer lock COLD or DNCC filled with sterile saline or propofol and 2 common bacterial central venous catheter contaminants (Staphylococcus epidermidis or Pseudomonas aeruginosa). Devices were contaminated using a glove touch (COLD and DNCC) or syringe tip (COLD). The primary end point of the study was colony-forming units (CFU) after 24 hours., Results: The use of glove touch contamination, the contaminants, S epidermidis and P aeruginosa, produced CFU in saline-filled COLDs treated with the Site-Scrub, but not in those treated with alcohol pads (P < 0.001). Similar results were observed with propofol-filled COLDs (P < 0.001). For DNCCs filled with saline or propofol, both alcohol and Site-Scrub effectively reduced CFU growth compared with contaminated controls (P < 0.001). When COLDs were contaminated by treated syringe tips, there was no significant evidence of reduction in CFU growth by using either alcohol pads or Site-Scrub compared with contaminated controls., Conclusions: These data suggest that when the inner surface of the COLD is contaminated, both alcohol pads and Site-Scrub were not significantly effective in decontaminating the COLD. When the COLD rim is contaminated, however, alcohol pads outperform Site-Scrub. DNCCs were uniformly decontaminated with either treatment. Future work should focus on better access systems because current COLDs are difficult to decontaminate.

Background: It is generally accepted that when an ignition source is used the inspired oxygen concentration (FIO2) should be <30% in the breathing circuit to help prevent airway fires. The time and conditions required to reduce a high O2% in the breathing circuit to <30% has not yet been systematically studied., Methods: We evaluated the inspired and expired circuit oxygen concentration response times of an Aestiva Avance S/5 anesthesia machine to reach an FIO2 of <30% from a starting FIO2 of 100% and 60% after reducing the FIO2 to 21%. The circuit was connected to a human patient simulator which has a functional residual capacity of 2 L, total lung capacity of 2.8 L, an oxygen consumption of 200 mL/min, and respiratory quotient of 0.8. Fresh gas flow (FGF) inputs of 2 L/min and 5 L/min were chosen to represent a spectrum of typical clinical FGF rates. Minute ventilation was set at 4 L/min. Determining the requisite median time to reach an O2 concentration of <30% in the breathing circuit was the primary aim of the study., Results: The median times (1st-99th percent confidence interval) required to achieve inspiratory and expiratory oxygen concentrations of <30% with the extended circuit configuration when starting at 60% for 5 L FGFs were 35 (32-36) and 104 (88-122) seconds, respectively. With 2 L FGF, these median times increased to 303 (291-313) and 255 (232-278) seconds, respectively. A shortened circuit configuration (P = 0.006) and higher FGF flow rate (P < 0.0001) were noted to be factors decreasing the median time required to achieve an oxygen concentration of <30%., Conclusions: Both inspired and expired circuit oxygen concentration may take minutes to decrease to <30% depending on circuit length, FGF rate, and starting circuit oxygen concentration. During the reduction in FIO2, the expiratory oxygen concentration may be >30% for a considerable time after the FIO2 is in a "safe" range. An increased expired oxygen concentration should also be considered an airway fire risk, and patient care protocols may need to be modified based on future studies.

Evaluating the accuracy of medical devices has traditionally been a blend of statistical analyses, at times without contextualizing the clinical application. There have been a number of recent publications on the accuracy of a continuous noninvasive hemoglobin measurement device, the Masimo Radical-7 Pulse Co-oximeter, focusing on the traditional statistical metrics of bias and precision. In this review, which contains material presented at the Innovations and Applications of Monitoring Perfusion, Oxygenation, and Ventilation (IAMPOV) Symposium at Yale University in 2012, we critically investigated these metrics as applied to the new technology, exploring what is required of a noninvasive hemoglobin monitor and whether the conventional statistics adequately answer our questions about clinical accuracy. We discuss the glucose error grid, well known in the glucose monitoring literature, and describe an analogous version for hemoglobin monitoring. This hemoglobin error grid can be used to evaluate the required clinical accuracy (±g/dL) of a hemoglobin measurement device to provide more conclusive evidence on whether to transfuse an individual patient. The important decision to transfuse a patient usually requires both an accurate hemoglobin measurement and a physiologic reason to elect transfusion. It is our opinion that the published accuracy data of the Masimo Radical-7 is not good enough to make the transfusion decision.

We assessed the feasibility of a breath test to detect women's single or concurrent use of vaginal products by adding ester taggants to vaginal gel and condom lubricant. Healthy non-pregnant women were enrolled into a two-day cohort (N = 13) and a single-day cohort (N = 12) in San Francisco. Within each cohort, women were randomized (5:1) to tagged or untagged products, and inserted in a clinical setting: 4 mL of tenofovir placebo gel (ten tagged with 15 mg 2-pentyl acetate; three untagged), and an artificial phallus with a lubricated condom (11 tagged with 15 mg 2-butyl acetate; two untagged), on two separate days (two-day cohort) or concurrently (single-day cohort). Using a portable mini-gas chromatograph, the presence/absence of taggants was determined in breath specimens collected prior to, and at timed intervals following product exposure. Demographic, clinical and product use experience data were collected by structured interview. All participants completed all visits and inserted their assigned products. At 5 min post-insertion, the breath test was 100% accurate in identifying insertion of the tagged (or untagged) gel and/or condom. The half-life in breath of the two esters tested was <1 h with large variability between individuals, taggants and cohorts. Overall, among those receiving tagged product, six mild and two moderate product-related AEs were reported. All were transient and resolved spontaneously. Additional sensations included taste in mouth (N = 4) and scent (N = 5). The tagged products were well tolerated. This breath test has the potential to accurately and objectively monitor adherence to vaginal gel and condom used separately or concurrently.

The practice of medicine to care for injured patients after an earthquake can challenge physicians. The great need requires an open mind to develop anesthetic plans around locally available resources. A focus on monitored anesthetic care and regional anesthesia is frequently practiced and beneficial to patients. Anesthesiologists will serve as leaders to organize perioperative surgical services and provide input into the ethical triage of patients. The physicians should be mentally and physically prepared to enter into service in this disorganized zone of service to provide care., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Adherence to microbicide gel use is critical to optimizing effectiveness in preventing human immunodeficiency virus transmission. The authors hypothesized that ester taggants added to vaginal gels would generate exhaled alcohol and ketone metabolites and provide a "breath test" for vaginal gel use. This 2-arm (vaginal and dermal), randomized, participant-blinded, pilot study tested this hypothesis. On 8 visits, healthy women (n = 8) received intravaginal taggant (2-butyl acetate, 2-pentyl acetate, isopropyl butyrate, or 2-pentyl butyrate; 30 mg) formulated in hydroxyethylcellulose or tenofovir placebo gel. A second group (n = 4) of women received the same formulations administered dermally on the forearm to determine if skin administration might confound the system. Breath samples were collected using bags before and after taggant administration for 1 hour. Samples were measured using a miniature gas chromatograph and/or gas chromatography-mass spectroscopy for ester taggant, alcohol, and ketone concentrations. After vaginal administration, 2-butyl acetate, 2-pentyl acetate, and metabolites were observed in breath, whereas isopropyl butyrate, 2-pentyl butyrate, and metabolites were not. Some women reported self-resolving, mild burning (24/64 visits) with vaginal administration or a "bubblegum" taste (7/64 visits). No taggants or metabolites were detected following dermal application. A "breath test" for adherence to antiretroviral vaginal gel application appears physiologically and technically feasible., (© 2012 The Author(s).)

A breath-based adherence system to document ingestion of oral medications (e.g., HAART) was investigated. Specifically, the food additive 2-butanol, which can be easily packaged with a drug, is converted via alcohol dehydrogenase to the volatile metabolite 2-butanone that rapidly appears in breath, indicating adherence. In healthy adults using a portable sensor and GC-MS, the following experiments were performed: yield of 2-butanone in breath following ingestion of 2-butanol, adherence system accuracy, and potential interference of the adherence system by food or misplacement of 2-butanol on the tongue. During feasibility testing, every subject exhaled 2-butanone with 6.6 ± 1.5 min to peak concentrations of 548 ± 235 ppb following ingestion of 2-butanol (40 mg). ROC areas at 5 and 10 min were 0.95 (0.86-1.00) and 1.00 (1.00-1.00). Food did not interfere. Tongue application resulted in large concentrations of 2-butanol, but not 2-butanone. A breath test to provide definitive evidence of oral medication adherence appears technically feasible.

Adverse drug reactions, including severe patient bleeding, may occur following the administration of anticoagulant drugs. Bivalirudin is a synthetic anticoagulant drug sometimes employed as a substitute for heparin, a commonly used anticoagulant that can cause a condition called heparin-induced thrombocytopenia (HIT). Although bivalrudin has the advantage of not causing HIT, a major concern is lack of an antidote for this drug. In contrast, medical professionals can quickly reverse the effects of heparin using protamine. This report details the selection of an aptamer to bivalirudin that functions as an antidote in buffer. This was accomplished by immobilizing the drug on a monolithic column to partition binding sequences from nonbinding sequences using a low-pressure chromatography system and salt gradient elution. The elution profile of binding sequences was compared to that of a blank column (no drug), and fractions with a chromatographic difference were analyzed via real-time PCR (polymerase chain reaction) and used for further selection. Sequences were identified by 454 sequencing and demonstrated low micromolar dissociation constants through fluorescence anisotropy after only two rounds of selection. One aptamer, JPB5, displayed a dose-dependent reduction of the clotting time in buffer, with a 20 µM aptamer achieving a nearly complete antidote effect. This work is expected to result in a superior safety profile for bivalirudin, resulting in enhanced patient care.

Background: Point-of-care (POC) devices measuring hematocrit rely on determination of electrical conductivity of whole blood. We hypothesized that some frequently administered IV fluids independently alter blood conductivity and confound hematocrit determination., Methods: Whole human blood was diluted to predetermined hematocrit values with normal saline, lactated Ringer solution, hetastarch, or plasma. Electrical conductivity and hematocrit (i-STAT® and spun methods) were measured at each dilution. In separate experiments, the effects of propofol and heparin were noted on these variables., Results: Greater dilution significantly increased conductivity irrespective of diluent type. The magnitude of the conductivity slopes increased in order for plasma, hetastarch, lactated Ringer solution, and normal saline dilution. Moreover, each slope varied from every other slope (all P < 0.0001), and 94.2% of hematocrit values measured by i-STAT (n = 211 of 224) were less than those for the spun method. Dilution with plasma, normal saline, lactated Ringer solution, and hetastarch caused bias (Bland-Altman limits of agreement) of -2.7% (-6.9/1.4), -4.6% (-7.3/-2.0), -4.8% (-7.8/-1.7), and -2.0% (-5.6/1.9), respectively. The Cohen κ agreement values (5th-95th confidence interval) for a transfusion trigger of 30% were 0.90 (all values, 0.85-0.95), 0.25 (hematocrit <30%, 0.02-0.48), and 0.21 (hematocrit 18%-30%, 0.01-0.42). Clinically relevant concentrations of propofol and heparin had minimal effects on electrical conductivity or hematocrit determination., Conclusions: Dilution of blood with frequently used IV solutions affects whole blood conductivity determinations and thereby decreases hematocrits measured by a POC device relying on this method as compared with spun hematocrit. Conductivity-based hematocrit POC devices should be cautiously interpreted when hemodilution is present.