Intergenerational Perioperative Neurocognitive Disorder in Young Adult Male Rats with Traumatic Brain Injury.

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-1ß 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-1ß 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.

Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats.

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.

The potential role of stress and sex steroids in heritable effects of sevoflurane†.

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.

Coronavirus disease 2019 pandemic: staged management of surgical services for gynecology and obstetrics.

The coronavirus disease 2019 pandemic warrants an unprecedented global healthcare response requiring maintenance of existing hospital-based services while simultaneously preparing for high-acuity care for infected and sick individuals. Hospitals must protect patients and the diverse healthcare workforce by conserving personal protective equipment and redeployment of facility resources. While each hospital or health system must evaluate their own capabilities and surge capacity, we present principles of management of surgical services during a health emergency and provide specific guidance to help with decision making. We review the limited evidence from past hospital and community responses to various health emergencies and focus on systematic methods for adjusting surgical services to create capacity, addressing the specific risks of coronavirus disease 2019. Successful strategies for tiered reduction of surgical cases involve multidisciplinary engagement of the entire healthcare system and use of a structured risk-assessment categorization scheme that can be applied across the institution. Our institution developed and operationalized this approach over 3 working days, indicating that immediate implementation is feasible in response to an unforeseen healthcare emergency.

A Methyltransferase Inhibitor (Decitabine) Alleviates Intergenerational Effects of Paternal Neonatal Exposure to Anesthesia With Sevoflurane.

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.

Intergenerational Effects of Sevoflurane in Young Adult Rats.

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.

The Technology of Video Laryngoscopy.

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.

Limitations of Significance Testing in Clinical Research: A Review of Multiple Comparison Corrections and Effect Size Calculations with Correlated Measures.

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.

Universal intravenous access cleaning device fails to sterilize stopcocks.

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.

Neurobehavioral Abnormalities in Offspring of Young Adult Male Rats With a History of Traumatic Brain Injury.

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-1ß (IL-1ß), 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-1ß, 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.

A novel breath test to directly measure use of vaginal gel and condoms.

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.

Oral adherence monitoring using a breath test to supplement highly active antiretroviral therapy.

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.

Noninvasive hemoglobin monitoring: how accurate is enough?

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.

Prevention of airway fires: do not overlook the expired oxygen concentration.

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.

Intergenerational Perioperative Neurocognitive Disorder.

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).