Combined effects of mild hypothermia and nitrous-oxide-induced narcosis on manual and cognitive performance.

Divers are at enhanced risk of suffering from acute cognitive deterioration because of the low ambient temperatures and the narcotic action of inert gases inspired at high pressures. Yet, the behavioral effects of cold and inert gas narcosis have commonly been assessed in isolation and during short-term provocations. We therefore evaluated the interactive influence of mild hypothermia and narcosis engendered by a subanesthetic dose of nitrous oxide (N2O; a normobaric intervention analog of hyperbaric nitrogen) on cognitive function during prolonged iterative exposure. Fourteen men partook in two ∼12-h sessions (separated by ≥4 days), wherein they performed sequentially three 120-min cold (20°C) water immersions (CWIs), while inhaling, in a single-blinded manner, either normal air or a normoxic gas mixture containing 30% N2O. CWIs were separated by a 120-min rewarming in room-air breathing conditions. Before the first CWI and during each CWI, subjects performed a finger dexterity test, and the Spaceflight Cognitive Assessment Tool for Windows (WinSCAT) test assessing aspects of attention, memory, learning, and visuospatial ability. Rectal and skin temperatures were, on average, reduced by ∼1.2 °C and ∼8 °C, respectively (P < 0.001). Cooling per se impaired (P ≤ 0.01) only short-term memory (∼37%) and learning (∼18%); the impairments were limited to the first CWI. N2O also attenuated (P ≤ 0.02) short-term memory (∼37%) and learning (∼35%), but the reductions occurred in all CWIs. Furthermore, N2O invariably compromised finger dexterity, attention, concentration, working memory, and spatial processing (P < 0.05). The present results demonstrate that inert gas narcosis aggravates, in a persistent manner, basic and higher-order cognitive abilities during protracted cold exposure.

Orbital infarction during drug abuse: tissues of the globe do not appear to recover function.

AIM: To describe the features of an orbital infarction syndrome arising after prolonged orbital pressure during drug-induced stupor in young people. PATIENTS AND METHODS: The clinical presentation and course for drug-induced orbital infarction is described, based on a retrospective review of clinical notes and imaging. RESULTS: Two cases of orbital infarction syndrome, due to prolonged orbital compression caused by sleeping with pressure on the orbit during drug-induced stupor, are described. Both patients presented with very poor vision and mydriasis, marked periorbital swelling with some pain, and complete external ophthalmoplegia. Whilst the orbital changes and eye movements recovered, the affected eyes had persistent wide mydriasis, and remained blind with marked optic atrophy. CONCLUSION: With a mechanism analogous to prolonged orbital pressure due to improper head positioning during neurosurgical procedures, drug-users appear to risk developing an orbital infarction syndrome if they rest with prolonged pressure on the orbit during a drug-induced stupor.

Clinical assessment and short-term mortality prediction of older adults with altered mental status using RASS and 4AT tools.

BACKGROUND: Altered mental status (AMS) in older adults is a common reason for admission to emergency departments (EDs) and usually results from delirium, stupor, or coma. It is important to proficiently identify underlying factors and anticipate clinical outcomes for those patients. AIM: The primary objective of this study was to reveal and compare the clinical outcomes and etiologic factors of older patients with delirium, stupor, and coma. The secondary objective was to identify the 30-day mortality risk for those patients. METHOD: The study was conducted as prospective and observational research. We included patients aged 65 years and older who presented with new-onset neurological and cognitive symptoms or worsening in baseline mental status. Patients who presented no change in their baseline mental status within 48 h and those who needed urgent interventions were excluded. Selected patients were assessed using RASS and 4AT tools and classified into three groups: stupor/coma, delirium, and no stupor/coma or delirium (no-SCD). Appropriate statistical tests were applied to compare these 3 groups. The 30-day mortality risks were identified by Cox survival analysis and Kaplan-Meier curve. RESULTS: A total of 236 patients were eligible for the study. Based on their RASS and 4AT test scores: 56 (23.7%), 94 (40.6%), and 86 (36.4%) patients formed the stupor/coma, delirium and no-SCD groups, respectively. There was no statistical difference in the three groups for gender, mean age, and medical comorbidities. Neurological (34.7%), infectious (19.4%), and respiratory (19.0%) diseases were the leading factors for AMS. Post-hoc tests showed that CCI scores of the delirium (6, IQR = 3) and stupor/coma (7, IQR = 3) groups were not significantly different. The 30-day mortality rates of stupor/coma, delirium, and no-SCD groups were 42.%, 15.9%, and 12.8%, respectively (p < 0.005). The hazard ratio of the stupor/coma group was 2.79 (CI: 95%, 1.36-5.47, p = 0.005). CONCLUSION: AMS remains a significant clinical challenge in EDs. Using the RASS and 4AT tests provides benefits and advantages for emergency medicine physicians. Neurological, infectious, and respiratory diseases can lead to life-threatening mental deterioration. Our study revealed that long-term mortality predictor CCI scores were quite similar among patients with delirium, stupor, or coma. However, the short-term mortality was significantly increased in the stupor/coma patients and they had 2.8 times higher 30-day mortality risk than others.

Rapture of the deep: gas narcosis may impair decision-making in scuba divers.

Introduction: While gas narcosis is familiar to most divers conducting deep (> 30 metres) dives, its effects are often considered minuscule or subtle at 30 metres. However, previous studies have shown that narcosis may affect divers at depths usually considered safe from its influence, but little knowledge exists on the effects of gas narcosis on higher cognitive functions such as decision-making in relatively shallow water at 30 metres. Impaired decision-making could be a significant safety issue for a multitasking diver. Methods: We conducted a study exploring the effects of gas narcosis on decision-making in divers breathing compressed air underwater. The divers (n = 22) were evenly divided into 5-metre and 30-metre groups. In the water, we used underwater tablets equipped with the Iowa Gambling Task (IGT), a well-known psychological task used to evaluate impairment in decision-making. Results: The divers at 30 metres achieved a lower score (mean 1,584.5, standard deviation 436.7) in the IGT than the divers at 5 metres (mean 2,062.5, standard deviation 584.1). Age, body mass index, gender, or the number of previous dives did not affect performance in the IGT. Conclusions: Our results suggest that gas narcosis may affect decision-making in scuba divers at 30 metres depth. This supports previous studies showing that gas narcosis is present at relatively shallow depths and shows that it may affect higher cognitive functions.

External Compressive Ischemic Orbitopathy: A Rising Clinical Entity.

PURPOSE: Saturday night retinopathy, the term coined by Jayam et al . in 1974, is a rare condition in which external compression of the orbit during a drug and alcohol stupor causes a unilateral orbitopathy with ophthalmoplegia and ischemic retinopathy. This condition has been increasingly reported in the last decade, correlating with an increasing burden of substance use. This condition mirrors a similar entity typically reported in patients following spinal surgery, where a headrest supporting the patient's face compresses the orbit. The current authors combine these 2 entities, entitled external compressive ischemic orbitopathy, and present a comprehensive literature review describing this entity. METHODS: A systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All related publications of vision loss in the setting of orbital compression were reviewed. Data collected included patient demographics, precipitating circumstances of vision loss, presenting ocular symptoms, outcomes, and ancillary imaging. RESULTS: In total 31 articles were selected for inclusion, yielding 46 patients. A total of 10 patients suffered orbitopathy in the setting of a drug stupor, and 36 following prone-positioned surgery. However, 79% of patients presented with visual acuity of light perception or worse. Also, 86% of patients presented with ophthalmoplegia, 92% with proptosis and orbital edema, and 86% with varying degrees of retinal ischemia. When compared with iatrogenic cases, self-induced stuporous cases demonstrated worse presenting visual acuity, ophthalmoplegia, retinal and choroidal filling, and worse final outcomes. CONCLUSION: External compressive ischemic orbitopathy is a severe vision-threatening condition that has been increasingly reported in the last decade.

Nitrous oxide consistently attenuates thermogenic and thermoperceptual responses to repetitive cold stress in humans.

Divers are at enhanced risk of hypothermia, due to the independent action of the inspired inert gases on thermoregulation. Thus, narcosis induced by acute (≤2 h) exposure to either hyperbaric nitrogen or normobaric nitrous oxide (N2O) impairs shivering thermogenesis and accelerates body core cooling. Animal-based studies, however, have indicated that repeated and sustained N2O administration may prevent N2O-evoked hypometabolism. We, therefore, examined the effects of prolonged intermittent exposure to 30% N2O on human thermoeffector plasticity in response to moderate cold. Fourteen men participated in two ∼12-h sessions, during which they performed sequentially three 120-min cold-water immersions (CWIs) in 20°C water, separated by 120-min rewarming. During CWIs, subjects were breathing either normal air or a normoxic gas mixture containing 30% N2O. Rectal and skin temperatures, metabolic heat production (via indirect calorimetry), finger and forearm cutaneous vascular conductance (CVC; laser-Doppler fluxmetry/mean arterial pressure), and thermal sensation and comfort were monitored. N2O aggravated the drop in rectal temperature (P = 0.01), especially during the first (by ∼0.3°C) and third (by ∼0.4°C) CWIs. N2O invariably blunted the cold-induced elevation of metabolic heat production by ∼22%-25% (P < 0.001). During the initial ∼30 min of the first and second CWIs, N2O attenuated the cold-induced drop in finger (P ≤ 0.001), but not in forearm CVC. N2O alleviated the sensation of coldness and thermal discomfort throughout (P < 0.001). Thus, the present results demonstrate that, regardless of the cumulative duration of gas exposure, a subanesthetic dose of N2O depresses human thermoregulatory functions and precipitates the development of hypothermia.NEW & NOTEWORTHY Human thermoeffector plasticity was evaluated in response to prolonged iterative exposure to 30% N2O and moderate cold stress. Regardless of the duration of gas exposure, N2O-induced narcosis impaired in a persistent manner shivering thermogenesis and thermoperception.

Possible causes of narcosis-like symptoms in freedivers.

During deep-sea freediving, many freedivers describe symptoms fairly similar to what has been related to inert gas narcosis in scuba divers. This manuscript aims to present the potential mechanisms underlying these symptoms. First, known mechanisms of narcosis are summarized while scuba diving. Then, potential underlying mechanisms involving the toxicity of gases (nitrogen, carbon dioxide and oxygen) are presented in freedivers. As the symptoms are felt during ascent, nitrogen is likely not the only gas involved. Since freedivers are frequently exposed to hypercapnic hypoxia toward the end of the dive, it is proposed that carbon dioxide and oxygen gases both play a major role. Finally, a new "hemodynamic hypothesis" based on the diving reflex is proposed in freedivers. The underlying mechanisms are undoubtedly multifactorial and therefore require further research and a new descriptive name. We propose a new term for these types of symptoms: freediving transient cognitive impairment.

"The eyes are the windows of the soul": Portable automated pupillometry to monitor autonomic nervous activity in CO2 narcosis: A case report.

RATIONALE: Altered autonomic responses can be observed in patients in the intensive care unit (ICU), and these changes in abnormal autonomic responses are known to be associated with patient prognosis. Therefore, it is important to monitor autonomic nervous system activity in these critically ill patients. While the utility of monitoring critically ill patients using heart rate (HR) variability measurements has been reported, portable automated pupillometers are small, lightweight, and easy-to-operate medical devices that may be more easily evaluated for autonomic nervous system function. PATIENT CONCERNS: An unconscious 80-year-old female patient with chronic obstructive pulmonary disease was brought to the medical emergency department after a call from her caregiver. DIAGNOSIS: On arrival, the patient's Glasgow coma scale score was 7, her blood pressure was 140/80 mm Hg, her HR was 114 bpm, and her respiratory rate was 27 breaths/minutes with increased breathing effort. Oxygen saturation was 90% on a venturi mask (3 L of supplemental oxygen). The arterial blood gas analysis showed a pH of 7.196, a partial pressure of carbon dioxide (CO2) of 89.6 mm Hg, a partial pressure of oxygen of 87.5 mm Hg, and a bicarbonate level of 29.4 mmol/L. Other than CO2 narcosis, there were no abnormal findings to induce impaired consciousness. The patient did not respond to support with a bag-valve mask and was intubated. One hour after intubation, her impaired consciousness improved. The patient was extubated 20 hours later and discharged on Day 3. INTERVENTIONS: The patient was admitted to the ICU after being intubated, where vital signs and blood gas analysis were monitored every 2 hours, and consciousness was assessed using the Glasgow coma scale. Using a portable automated pupillometer (NeurOptics NPi™-200, Neuroptics Inc., Irvine, CA), pupillary responses, including pupil size or light reflex, were measured every 2 hours during ICU stay. OUTCOMES: Changes in respiratory rate and partial pressure of CO2 values correlated with pupil size and constriction velocity, but HR changes were contrary. LESSONS: Pupillary responses exhibited by automated pupillometers observed in patients with CO2 narcosis may be linked to vital signs and allow for autonomic evaluation.

Catatonia associated with prolonged stupor after general anesthesia in a patient with multiple neuropsychiatric disorders -a case report.

BACKGROUND: Delayed emergence after general anesthesia may significantly affect a patient's condition. We present the case of a patient who experienced prolonged delayed recovery of consciousness, language, and motor response due to catatonia after eight hours of total elbow arthroplasty under general anesthesia. CASE: A 68-year-old woman with neuropsychiatric disorders and Parkinson's disease did not respond adequately during recovery after more than eight hours of general anesthesia. Following the operation, the patient was semi-comatose and appeared to have nonconvulsive status epilepticus upon awakening from anesthesia. However, subsequent examinations did not reveal any organic causes. The patient was subsequently diagnosed with catatonia, treated, and discharged following gradual improvement. CONCLUSIONS: Although rare, patients taking psychiatric drugs for an extended period may experience delayed emergence after prolonged general anesthesia without identifiable causes. Catatonia should be considered in the differential diagnoses of these patients.

Medetomidine/midazolam/fentanyl narcosis alters cardiac autonomic tone leading to conduction disorders and arrhythmias in mice.

Arrhythmias are critical contributors to cardiovascular morbidity and mortality. Therapies are mainly symptomatic and often insufficient, emphasizing the need for basic research to unveil the mechanisms underlying arrhythmias and to enable better and ideally causal therapies. In translational approaches, mice are commonly used to study arrhythmia mechanisms in vivo. Experimental electrophysiology studies in mice are performed under anesthesia with medetomidine/midazolam/fentanyl (MMF) and isoflurane/fentanyl (IF) as commonly used regimens. Despite evidence of adverse effects of individual components on cardiac function, few data are available regarding the specific effects of these regimens on cardiac electrophysiology in mice. Here we present a study investigating the effects of MMF and IF narcosis on cardiac electrophysiology in vivo in C57BL/6N wild-type mice. Telemetry transmitters were implanted in a group of mice, which served as controls for baseline parameters without narcosis. In two other groups of mice, electrocardiogram and invasive electrophysiology studies were performed under narcosis (with either MMF or IF). Basic electrocardiogram parameters, heart rate variability parameters, sinus node and atrioventricular node function, and susceptibility to arrhythmias were assessed. Experimental data suggest a remarkable influence of MMF on cardiac electrophysiology compared with IF and awake animals. While IF only moderately reduced heart rate, MMF led to significant bradycardia, spontaneous arrhythmias, heart rate variability alterations as well as sinus and AV node dysfunction, and increased inducibility of ventricular arrhythmias. On the basis of these observed effects, we suggest avoiding MMF in mice, specifically when studying cardiac electrophysiology, but also whenever a regular heartbeat is required for reliable results, such as in heart failure or imaging research.

Using membrane-water partition coefficients in a critical membrane burden approach to aid the identification of neutral and ionizable chemicals that induce acute toxicity below narcosis levels.

The risk assessment of thousands of chemicals used in our society benefits from adequate grouping of chemicals based on the mode and mechanism of toxic action (MoA). We measure the phospholipid membrane-water distribution ratio (DMLW) using a chromatographic assay (IAM-HPLC) for 121 neutral and ionized organic chemicals and screen other methods to derive DMLW. We use IAM-HPLC based DMLW as a chemical property to distinguish between baseline narcosis and specific MoA, for reported acute toxicity endpoints on two separate sets of chemicals. The first set comprised 94 chemicals of US EPA's acute fish toxicity database: 47 categorized as narcosis MoA, 27 with specific MoA, and 20 predominantly ionic chemicals with mostly unknown MoA. The narcosis MoA chemicals clustered around the median narcosis critical membrane burden (CMBnarc) of 140 mmol kg-1 lipid, with a lower limit of 14 mmol kg-1 lipid, including all chemicals labelled Narcosis_I and Narcosis_II. This maximum 'toxic ratio' (TR) between CMBnarc and the lower limit narcosis endpoint is thus 10. For 23/28 specific MoA chemicals a TR >10 was derived, indicative of a specific adverse effect pathway related to acute toxicity. For 10/12 cations categorized as "unsure amines", the TR <10 suggests that these affect fish via narcosis MoA. The second set comprised 29 herbicides, including 17 dissociated acids, and evaluated the TR for acute toxic effect concentrations to likely sensitive aquatic plant species (green algae and macrophytes Lemna and Myriophyllum), and non-target animal species (invertebrates and fish). For 21/29 herbicides, a TR >10 indicated a specific toxic mode of action other than narcosis for at least one of these aquatic primary producers. Fish and invertebrate TRs were mostly <10, particularly for neutral herbicides, but for acidic herbicides a TR >10 indicated specific adverse effects in non-target animals. The established critical membrane approach to derive the TR provides for useful contribution to the weight of evidence to bin a chemical as having a narcosis MoA or less likely to have acute toxicity caused by a more specific adverse effect pathway. After proper calibration, the chromatographic assay provides consistent and efficient experimental input for both neutral and ionizable chemicals to this approach.

Baseline Narcosis for the Glass-Vial 96-h Growth Inhibition of the Nematode C. elegans and Its Use for Identifying Electrophilic and Pro-Electrophilic Toxicity.

The nematode Caenorhabditis elegans has been widely used as a model organism for assessing chemical toxicity. So far, however, a respective baseline narcosis reference has been lacking to predict narcosis-level toxicity and to identify excess-toxic compounds and associated mechanisms of action. Employing 22 organic narcotics that cover 7.2 units of their log Kow (octanol/water partition coefficient) from -1.20 to 6.03, a baseline narcosis model has been derived for a glass-vial 96-h growth inhibition test with C. elegans, both without and with correction for compound loss through volatilization and sorption. The resultant effective concentrations yielding 50% growth inhibition, EC50, vary by 6.4 log units from 5.04 · 10-1 to 1.90 · 10-7 mol/L (exposure-corrected). Application of the new model is illustrated through sensing the toxicity enhancement (Te) of four Michael-acceptor carbonyls driven by their reactive mode of action. Moreover, narcosis-level predicted vs experimental EC50 of two α,ß-unsaturated alcohols demonstrate the biotransformation capability of C. elegans regarding ADH (alcohol dehydrogenase). The discussion includes narcosis-level and excess-toxicity doses (critical body burdens) as well as chemical activities A50 (at the EC50) as compared to fish, daphnids, ciliates, bacteria, zebrafish embryo, and cell lines. Overall, the presently introduced model for predicting C. elegans baseline narcosis enables generating respective pre-test expectations, enriches experimental results by mechanistic information, and may complement 3Rs (reduce, refine, replace) test batteries through its ADH metabolic capacity.

Dopamine/BDNF loss underscores narcosis cognitive impairment in divers: a proof of concept in a dry condition.

PURPOSE: Divers can experience cognitive impairment due to inert gas narcosis (IGN) at depth. Brain-derived neurotrophic factor (BDNF) rules neuronal connectivity/metabolism to maintain cognitive function and protect tissues against oxidative stress (OxS). Dopamine and glutamate enhance BDNF bioavailability. Thus, we hypothesized that lower circulating BDNF levels (via lessened dopamine and/or glutamate release) underpin IGN in divers, while testing if BDNF loss is associated with increased OxS. METHODS: To mimic IGN, we administered a deep narcosis test via a dry dive test (DDT) at 48 msw in a multiplace hyperbaric chamber to six well-trained divers. We collected: (1) saliva samples before DDT (T0), 25 msw (descending, T1), 48 msw (depth, T2), 25 msw (ascending, T3), 10 min after decompression (T4) to dopamine and/or reactive oxygen species (ROS) levels; (2) blood and urine samples at T0 and T4 for OxS too. We administered cognitive tests at T0, T2, and re-evaluated the divers at T4. RESULTS: At 48 msw, all subjects experienced IGN, as revealed by the cognitive test failure. Dopamine and total antioxidant capacity (TAC) reached a nadir at T2 when ROS emission was maximal. At decompression (T4), a marked drop of BDNF/glutamate content was evidenced, coinciding with a persisting decline in dopamine and cognitive capacity. CONCLUSIONS: Divers encounter IGN at - 48 msw, exhibiting a marked loss in circulating dopamine levels, likely accounting for BDNF-dependent impairment of mental capacity and heightened OxS. The decline in dopamine and BDNF appears to persist at decompression; thus, boosting dopamine/BDNF signaling via pharmacological or other intervention types might attenuate IGN in deep dives.

Impacts and mechanisms of CO2 narcosis in bumble bees: narcosis depends on dose, caste and mating status and is not induced by anoxia.

Carbon dioxide (CO2) is commonly used to immobilize insects and to induce reproduction in bees. However, despite its wide use and potential off-target impacts, its underlying mechanisms are not fully understood. Here, we used Bombus impatiens to examine whether CO2 impacts are mediated by anoxia and whether these mechanisms differ between female castes or following mating in queens. We examined the behavior, physiology and gene expression of workers, mated queens and virgin queens following exposure to anoxia, hypoxia, full and partial hypercapnia, and controls. Hypercapnia and anoxia caused immobilization, but only hypercapnia resulted in behavioral, physiological and molecular impacts in bees. Recovery from hypercapnia resulted in increased abdominal contractions and took longer in queens. Additionally, hypercapnia activated the ovaries of queens, but inhibited those of workers in a dose-dependent manner and caused a depletion of fat-body lipids in both castes. All responses to hypercapnia were weaker following mating in queens. Analysis of gene expression related to hypoxia and hypercapnia supported the physiological findings in queens, demonstrating that the overall impacts of CO2, excluding virgin queen ovaries, were unique and were not induced by anoxia. This study contributes to our understanding of the impacts and the mechanistic basis of CO2 narcosis in insects and its impacts on bee physiology. This article has an associated ECR Spotlight interview with Anna Cressman.

CO2 narcosis induces a metabolic shift mediated via juvenile hormone in Bombus impatiens gynes.

Carbon dioxide (CO2) has pleiotropic effects on insect physiology and behavior. Although diverse, many impacts are related to changes in metabolism and reallocation of macronutrients. Here we examined the metabolic shift induced by CO2 and its regulation using Bombus impatiens. CO2 applied to bumble bee gynes induces bypass of diapause and transition into reproduction. We analyzed ovary activation and macronutrient amounts in four tissues/body parts (fat body, thorax, ovaries, and crop) at three timepoints following CO2 administration. To tease apart the effects of CO2 on reproduction and metabolism, we monitored the metabolic changes in gynes following ovary removal and CO2 narcosis. We also explored the role of juvenile hormone in mediating CO2 impact by feeding queens with a JH antagonist (Precocene). Gynes ovary activation was increased following CO2 treatment. Additionally, CO2-treated gynes showed lower lipid amount in the fat body and higher glycogen and protein amount in the ovary ten days after the treatment. CO2 treatment following ovary removal also resulted in decreased fat body lipids, suggesting that CO2 operates by inducing a metabolic shift independent of reproduction. Lastly, gynes fed with precocence did not show a metabolic shift following CO2, suggesting CO2 impact is mediated via juvenile hormone. Overall, these data suggest that CO2 induces transfer of macronutrients and utilization of stored reserved by accelerating metabolism. The proposed mechanism of CO2 may explain many of the pleiotropic effects of CO2 across species and can aid in understanding how this common anastatic influences insect physiology.

Changes in Intraocular Pressure following Narcosis With Medetomidine, Midazolam, and Fentanyl in Association With Initial Intraocular Pressure in Mice.

PURPOSE: This article describes the development of decreased intraocular pressure (IOP) under general anesthesia with medetomidine, midazolam, and fentanyl in mice with normal and elevated IOP. METHODS: IOP was measured using the iCare Tonolab rebound tonometer. Twelve 3-4 months-old male and female C57BL/6J mice were randomized to a control group with physiological IOP and a high IOP group with experimentally induced ocular hypertension using tarsal injections of dexamethasone-21-acetate. For anesthesia, medetomidine and midazolam were used, subgroups additionally received fentanyl. IOP was measured every 2.5 min for 30 min. RESULTS: Control group differed with 14.89 mmHg (SEM: 0.58) significantly (p = 0.0002) from the high IOP group with initial 20.44 mmHg (SEM: 0.75). All groups showed a significant (p < 0.05) decrease in IOP under general anesthesia. There was no significant difference in IOP development and decrease between the group additionally receiving fentanyl and the group without fentanyl. The decrease in IOP was highly dependent on the initial value, with the high IOP group showing a greater decrease. After 10 min, no significant difference in IOP could be detected between the high IOP and control group. CONCLUSIONS: In mice, general anesthesia with medetomidine and midazolam leads to a declining IOP over time. Adding fentanyl to the anesthesia did not alter these effects. The decline is time-dependent and IOP-dependent.

Data-driven learning of narcosis mode of action identifies a CNS transcriptional signature shared between whole organism Caenorhabditis elegans and a fish gill cell line.

With the large numbers of man-made chemicals produced and released in the environment, there is a need to provide assessments on their potential effects on environmental safety and human health. Current regulatory frameworks rely on a mix of both hazard and risk-based approaches to make safety decisions, but the large number of chemicals in commerce combined with an increased need to conduct assessments in the absence of animal testing makes this increasingly challenging. This challenge is catalysing the use of more mechanistic knowledge in safety assessment from both in silico and in vitro approaches in the hope that this will increase confidence in being able to identify modes of action (MoA) for the chemicals in question. Here we approach this challenge by testing whether a functional genomics approach in C. elegans and in a fish cell line can identify molecular mechanisms underlying the effects of narcotics, and the effects of more specific acting toxicants. We show that narcosis affects the expression of neuronal genes associated with CNS function in C. elegans and in a fish cell line. Overall, we believe that our study provides an important step in developing mechanistically relevant biomarkers which can be used to screen for hazards, and which prevent the need for repeated animal or cross-species comparisons for each new chemical.

Does hyperbaric oxygen cause narcosis or hyperexcitability? A quantitative EEG analysis.

Divers breathe higher partial pressures of oxygen at depth than at the surface. The literature and diving community are divided on whether or not oxygen is narcotic. Conversely, hyperbaric oxygen may induce dose-dependent cerebral hyperexcitability. This study evaluated whether hyperbaric oxygen causes similar narcotic effects to nitrogen, and investigated oxygen's hyperexcitability effect. Twelve human participants breathed "normobaric" air and 100% oxygen, and "hyperbaric" 100% oxygen at 142 and 284 kPa, while psychometric performance, electroencephalography (EEG), and task load perception were measured. EEG was analyzed with functional connectivity and temporal complexity algorithms. The spatial functional connectivity, estimated using mutual information, was summarized with the global efficiency network measure. Temporal complexity was calculated with a "default-mode-network (DMN) complexity" algorithm. Hyperbaric oxygen-breathing caused no change in EEG global efficiency or in the psychometric test. However, oxygen caused a significant reduction of DMN complexity and a reduction in task load perception. Hyperbaric oxygen did not cause the same changes in EEG global efficiency seen with hyperbaric air, which likely related to a narcotic effect of nitrogen. Hyperbaric oxygen seemed to disturb the time evolution of EEG patterns that could be taken as evidence of early oxygen-induced cortical hyperexcitability. These findings suggest that hyperbaric oxygen is not narcotic and will help inform divers' decisions on suitable gas mixtures.