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Nitrous oxide (N 2 O), also known as laughing gas, has a euphoric effect and is becoming increasingly popular as a recreational inhalant drug. Deaths caused by recreational nitrous oxide abuse are rare, but may still occur. Although some methods for the quantification of N 2 O by GC-MS have been reported, elimination of carbon dioxide interference and the choice of a suitable internal standard remain current limitations to accurate N 2 O quantification. Here, a validated method using headspace-gas chromatography-mass spectrometry (HS-GC-MS) is described that allows the quantification of N 2 O in human blood samples: sodium hydroxide is used to remove carbon dioxide, and n-pentane is chosen as a suitable internal standard. Collectively, the validation results show a good linear relationship of N 2 O in blood within the concentration range of 0.02 ∼ 0.5 mL/mL and an LOD of 0.005 mL/mL. Subsequent application of the validated method to two real mortality cases due to N 2 O intoxication provided reference values for blood concentrations in forensic cases. Other biological specimens (gaseous samples and tissues) of the deceased were also analyzed to demonstrate that the deaths were caused by asphyxia due to the inhalation of N 2 O., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recent evidence suggests that 1α,25-dihydroxyvitamin D3 (VD3), the active form of vitamin D, inhibits microbial proliferation. Previously, we used in vivo murine models to investigate the antimalarial activity of VD3 and confirmed potent antimalarial activity in the acute phase. This study aimed to clarify the mechanisms underlying the antimalarial activity of VD3 in vivo, particularly extensive inhibition of parasitemia in the acute phase, focusing on nitric oxide (NO), a potent antimalarial molecule. VD3 is a good NO inducer. When most Plasmodium chabaudi AS (PcAS)-infected mice treated with VD3 survived, NO was present in blood samples obtained from VD3-treated mice at a significantly higher rate at 2 and/or 3 days post-infection than that in vehicle-treated control mice. To verify the involvement of NO in the antimalarial activity of VD3, we used aminoguanidine (AG), an inducible NO synthase (iNOS) inhibitor, to abrogate the antimalarial activity of VD3. However, despite AG-induced reductions in NO levels, parasitemia remained inhibited during the acute phase, even in the presence of AG, and the antiplasmodial faculty of VD3 was not ablated. VD3-mediated antimalarial activity irrelevant of NO compelled us to consider another candidate. In a pilot experiment, we used cathelicidin (CAMP), an antimicrobial peptide, since it is known that VD3 induces CAMP synthesis. Serum CAMP levels increased on days 4 or 5 post-infection with or without VD3 administration, but experiments using exogenous CAMP did not display curative effects in PcAS-infected mice. The present study using VD3 to target the malarial parasite thus suggests a potential novel approach to treat malarial infections., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Hazelnut and cocoa spread is an Italian product containing cocoa and hazelnut. Several epidemiological studies suggest that cocoa and hazelnuts cocoa exert beneficial cardiovascular effects. To investigate whether in smokers, hazelnut and cocoa spread elicits artery dilatation via down-regulation of oxidative stress. Flow-mediated dilatation (FMD), oxidative stress (as assessed by serum isoprostanes excretion, Nox2 activation and NO bioavailability) and antioxidant status [as assessed by vitamin E levels, plasma total polyphenols and H 2 O 2 breaking down activity (HBA)] were studied in 20 smokers in a crossover, single-blind study. Patients were randomly allocated to 60 g of Hazelnut and cocoa spread or 60 g of milk chocolate (≤ 35% cocoa). FMD, serum isoprostanes, Nox2 activation, NOx, vitamin E, HBA and total polyphenols were assessed at baseline and 2 h after chocolate ingestion. After Hazelnut and cocoa spread intake, FMD and NOx significantly increased (from 4.3 ± 2.8 to 8.0 ± 3.2%, p < 0.001 and from 23.1 ± 5.5 to 32.0 ± 12.6 µM, p = 0.016, respectively); conversely, serum isoprostanes and Nox2 activation significantly decreased (from 302.8 ± 59.8 to 240.7 ± 90.8 pmol/l, p = 0.03 and from 25 ± 4.4 to 22.6 ± 3.2, p = 0.03, respectively). After Hazelnut and cocoa spread intake, serum total polyphenols, vitamin E and HBA significantly increased (from 133.8 ± 49.7 to 202.5 ± 69.5 mg/l GAE, p = 0.001; from 3.56 ± 1.4 to 4.5 ± 1.0 μmol/mmol cholesterol, p = 0.002 and from 63.3 ± 13.2 to 74.2 ± 12.4%, p = 0.003, respectively). No changes in the above variables were observed after milk chocolate intake. A linear correlation analysis shows that Δ (expressed by difference of values between before and after chocolate intake) of FMD correlates with Δ of total polyphenols and Δ of vitamin E. This study shows that Hazelnut and cocoa spread improves FMD with a mechanism potentially involving downregulation of oxidative stress and eventually increased NO generation in smokers.

Background: Observational studies suggest a potentially protective role of the Mediterranean diet (MD) in allergic diseases, including asthma. Large scale randomised controlled trials (RCTs) are needed to test the hypothesised allergy-prevention benefits of a MD during pregnancy. The present two-arm pilot RCT in pregnant women at high-risk of having a child who would develop allergic disease investigated maternal recruitment, retention and acceptability of an MD dietary intervention in the UK. The trial also assessed the effect of the intervention on MD adherence scores at 12 and at 24 weeks post-randomisation., Methods: Thirty women were recruited at around 12 weeks of gestation. Retention was high (28 out of 30; 93%). The intervention was acceptable to participants. Mean (SD) adherence to the MD at baseline was 12.4 (2.9) in the intervention arm (n = 14) and 13.0 (1.9) in the control arm (n = 16), where 24 represents maximal adherence. There was a favourable short-term change in MD score: the adjusted mean difference (intervention - control) in the change in MD score from baseline to 12 weeks post-randomisation was 2.4 (95% confidence interval = 0.6-4.2, P = 0.012)., Conclusions: The trial provides important insights into recruitment, retention and sustaining the dietary intervention, which will be used in the design of a large RCT., (© 2017 The British Dietetic Association Ltd.)

Sapropterin, a synthetic form of tetrahydrobiopterin (BH4), has been reported to improve symptoms in children with autism spectrum disorder (ASD). However, as BH4 is involved in multiple metabolic pathway that have been found to be dysregulated in ASD, including redox, pterin, monoamine neurotransmitter, nitric oxide (NO) and immune metabolism, the metabolic pathway by which sapropterin exerts its therapeutic effect in ASD effect remains unclear. This study investigated which metabolic pathways were associated with symptomatic improvement during sapropterin treatment. Ten participants (ages 2-6 years old) with current social and/or language delays, ASD and a central BH4 concentration 30 nM l(-1) were treated with a daily morning 20 mg kg(-1) dose of sapropterin for 16 weeks in an open-label fashion. At baseline, 8 weeks and 16 weeks after starting the treatment, measures of language, social function and behavior and biomarkers of redox, pterin, monoamine neurotransmitter, NO and immune metabolism were obtained. Two participants discontinued the study, one from mild adverse effects and another due to noncompliance. Overall, improvements in subscales of the Preschool Language Scale (PLS), Vineland Adaptive Behavior Scale (VABS), Aberrant Behavior Checklist (ABC) and autism symptoms questionnaire (ASQ) were seen. Significant changes in biomarkers of pterin, redox and NO were found. Improvement on several subscales of the PLS, VABS, ABC and ASQ were moderated by baseline and changes in biomarkers of NO and pterin metabolism, particularly baseline NO metabolism. These data suggest that behavioral improvement associated with daily 20 mg kg(-1) sapropterin treatment may involve NO metabolism, particularly the status of pretreatment NO metabolism.

The development of hyperpolarized tracers has been limited by short nuclear polarization lifetimes. The dominant relaxation mechanism for many hyperpolarized agents in solution arises from intramolecular nuclear dipole-dipole coupling modulated by molecular motion. It has been previously demonstrated that nuclear spin relaxation due to this mechanism can be removed by storing the nuclear polarization in long-lived, singlet-like states. In the case of N(2)O, storing the polarization of the nitrogen nuclei has been shown to substantially increase the polarization lifetime. The feasibility of utilizing N(2)O as a tracer is investigated by measuring the singlet-state lifetime of the N(2)O when dissolved in a variety of solvents including whole blood. Comparison of the singlet lifetime to longitudinal relaxation and between protonated and deuterated solvents is consistent with the dominance of spin-rotation relaxation, except in the case of blood., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Rapid elimination of nitrous oxide from the lungs at the end of inhalational anesthesia dilutes alveolar oxygen, producing "diffusion hypoxia." A similar dilutional effect on accompanying volatile anesthetic agent has not been evaluated and may impact the speed of emergence., Methods: Twenty patients undergoing surgery were randomly assigned to receive an anesthetic maintenance gas mixture of sevoflurane adjusted to bispectral index, in air-oxygen (control group) versus a 2:1 mixture of nitrous oxide-oxygen (nitrous oxide group). After surgery, baseline arterial and tidal gas samples were taken. Patients were ventilated with oxygen, and arterial and tidal gas sampling was repeated at 2 and 5 min. Arterial sampling was repeated 30 min after surgery. Sevoflurane partial pressure was measured in blood by the double headspace equilibration technique and in tidal gas using a calibrated infrared gas analyzer. Time to eye opening and time extubation were recorded. The primary endpoint was the reduction in sevoflurane partial pressures in blood at 2 and 5 min., Results: Relative to baseline, arterial sevoflurane partial pressure was 39% higher at 5 min in the control group (P < 0.04) versus the nitrous oxide group. At 30 min the difference was not statistically significant. Time to eye opening (8.7 vs. 10.1 min) and time to extubation (11.0 vs.13.2 min) were shorter in the nitrous oxide group versus the control group (P < 0.04)., Conclusions: Elimination of nitrous oxide at the end of anesthesia produces a clinically significant acceleration in the reduction of concentrations of the accompanying volatile agents, contributing to the speed of emergence observed after inhalational nitrous oxide anesthetic.

Aim: To elucidate the role of nitrous oxide (NO) in development of severe primary arterial hypertension (AH) including malignant hypertension and concomitant ischemic heart disease (IHD)., Material and Method: Patients with diagnosis of primary 1-3 degree AH (n=62, 21 men, 41 women aged 39-87 years, mean age 63.7+/-2.7 years) and 28 subjects with normal arterial pressure (AP) (n=28, 13 men, 15 women aged 30-85 years, mean age 57.5+/-7.8 years). Blood serum levels of NO stable metabolites (nitrates and nitrites) were measured by reaction of their reduction in the presence of vanadium chloride and by reaction of diazotization of sulfanilamide by generated nitrite (modification by R.M.Miranda et al., 2001)., Results: NO level (level of its stable metabolites) was substantially elevated in patients with various severity of AH compared with subjects with normal AP. Severe and malignant course of AH was not associated with substantial lowering of NO level in blood serum. Relation between NO level and age found in subjects with normal AP, was not observed in patients with labile and stable course of AH. In patients with AH, normal serum NO level and signs of chronic involvement of cardiovascular system the disease was several times more often associated with atrial fibrillation and class II-III angina than in patients with high NO levels. Patients with AH combined with IHD more often had signs of heart failure and history of myocardial infarction.

Vascular endothelium is not simply a barrier between blood and extra vascular bed but is a source of large number of mediators regulating various functions of the body among which nitrous oxide appears to be one of most important. Endothelial dysfunction (ED) develops in a number of processes: diabetes mellitus, smoking, arterial hypertension, hypercholesterolemia. ED promotes increase of rate development of cardiovascular diseases. One of most well known markers of ED is microalbuminuria (MAU). Drug and nondrug means are used for the treatment of ED. Calcium antagonists and angiotensin converting enzyme inhibitors both separately and as components of combination therapy are able to maximally diminish MAU.

We assessed effect of antihypertensive drugs from various classes on humoral parameters of endothelial function - levels of asymmetrical dimethyl-arginine (ADMA) and metabolites of nitrous oxide (MNO) - in 106 patients with I-II degree arterial hypertension before and after 2 weeks of treatment. Two weeks treatment with various antihypertensive drugs did not lead to significant changes of ADMA levels. However antihypertensive drugs from various classes produced different effects on levels of MNO. Combination antihypertensive preparation indapamide and perindopril caused significant elevation of MNO level in patients with I-II degree arterial hypertension what appears to be indirect reflection of augmentation of nitrous oxide formation and improvement of endothelial function.

For nitrous oxide, the first anesthetic for which uptake was measured in humans, Severinghaus noted empirically that a plot of the log of uptake against the log of elapsed time produced a straight line with slope -0.5, suggesting that uptake is proportional to the inverse square root of time. This result is something of a black box model, based on empirical curve fitting without regard to physiology. Some authors (e.g., Lowe) repeatedly returned to this inverse square root of time model as a benchmark while others (e.g., Hendrickx) questioned its validity and demanded the relationship be expressed with a physiologic model whose structure matches the known physiology being modeled. Nevertheless, the fact that authors have repeatedly come back to this inverse square root of time model as a benchmark suggests that it might have some underlying validity which has not previously been recognized. We re-explored this mathematically in an attempt to reveal hitherto undiscovered insights or limitations. In this study, we examined the square root of time model (viewed as a power function) and compared it with multi-compartment models. Further, we explored the stability of this relationship to systematic variation in the power value and also to the superimposition of noise-like perturbations, seeking conditions under which it might not work. Based upon this theoretical analysis, we also speculate on the existence of a physiological compartment with a time constant between that of the vessel-rich group (VRG) and muscle, and what the identity of such a compartment might be.

Background: A number of studies have demonstrated a faster rate of increase in end-expired partial pressure as a fraction of inspired (Pa/Pi) for volatile agents in the presence of high concentrations of nitrous oxide, consistent with the second gas effect. However, no study has demonstrated a similar effect on arterial blood concentrations., Methods: The authors compared arterial and end-tidal partial pressures of sevoflurane (Pa/Pisevo and Pa/Pisevo) in 14 patients for 30 min after introduction of either 70% nitrous oxide or nitrous oxide-free gas mixtures to determine the magnitude of the second gas effect. Blood partial pressures were measured using a double headspace equilibration technique., Results: Both Pa/Pisevo and Pa/Pisevo were significantly higher in the nitrous oxide group than in the control group (P < 0.001 on two-way analysis of variance). This difference was significantly greater (P < 0.05) for Pa/Pisevo (23.6% higher in the nitrous oxide group at 2 min, declining to 12.5% at 30 min) than for Pa/Pisevo (9.8% higher in the nitrous oxide group at 2 min) and was accompanied by a significantly lower Bispectral Index score at 5 min (40.7 vs. 25.4; P = 0.004)., Conclusion: Nitrous oxide uptake exerts a significant second gas effect on arterial sevoflurane partial pressures. This effect is two to three times more powerful than the effect on end-expired partial pressures. The authors explain how this is due to the influence of ventilation-perfusion scatter on the distribution of blood flow and gas uptake in the lung.

Background: Measurement of the partial pressure of volatile anesthetics in blood is usually done using a "headspace equilibration" method with gas chromatography. However, it is not often performed in clinical studies because of the technical, equipment, and logistic requirements. To improve the accessibility of this measurement, we tested the use of a common infrared clinical gas analyzer, the Datex-Ohmeda Capnomac, for this purpose., Methods: After characterization of the linearity of the device in measuring the volatile anesthetic concentration in the presence of nitrous oxide, carbon dioxide, and water vapor, blood was tonometered with known concentrations of sevoflurane (actual value between 0.5% and 5.0%) in oxygen and oxygen/nitrous oxide mixtures, as well as mixtures of isoflurane and desflurane in oxygen., Results: Mean bias (standard deviation) overall for sevoflurane in oxygen relative to the tonometered reference partial pressure was -4.5 (4.8%) of the actual concentration. This was not altered significantly by measurement in 40% oxygen/60% nitrous oxide. For isoflurane and desflurane it was -3.9 (3.3%) and -4.6 (3.8%), respectively, of the actual concentration., Conclusions: The accuracy and precision of measurement of volatile anesthetic gas partial pressures in blood by a double headspace equilibration technique, using a clinical infrared gas analyzer, were comparable to that achieved by previous studies using gas chromatography.

Objectives: Although the genotoxicity related to waste anaesthetic gases is controversial, a consistent number of observations have provided evidence for an increased level of DNA strand breaks. The goal of the research was to investigate this hypothesis and estimate the genoprotective role of antioxidant supplementation in technical anaesthesiology staff working in operating theatres., Methods: Heparinized venous blood samples were collected from 17 exposed technical anaesthesiology staff (mean age 34.3 +/- 3.5 years) and non-exposed control group (mean age 32.2 +/- 3.4 years) and examined in the alkaline comet assay for DNA strand breakage. Vitamin E (300 mg/day) plus vitamin C (500 mg/day) were supplemented to the technical anaesthesiology staff for 12 weeks and blood samples were retaken and evaluated by comet assay., Results: The DNA breakage observed in the lymphocytes of the technical anaesthesiology staff was 21.5 +/- 5.0, as calculated by total comet score (TCS). This score was significantly higher (P<0.001) than in the controls (8.6 +/- 4.7) before antioxidant treatment. Supplementation of vitamins E plus C significantly (P<0.01) reduced the mean TCS as 14.2 +/- 6.1., Conclusion: The results of our study indicate that occupational exposure to anaesthetic gases induces oxidative DNA damage. Supplementation of the diet for 12 weeks with vitamin C and vitamin E resulted in a significant decrease in the DNA damage.

Purpose: A study was undertaken to compare the influence of midazolam, isoflurane, and aminophylline (which may antagonize anesthetic action) on bispectral index (BIS) and regional cerebral oxygen saturation (rSO(2)) during propofol/N(2)O anesthesia, and to test the hypothesis that the drug-induced changes in BIS values are accompanied by a change in rSO(2)., Methods: General anesthesia was administered to 36 patients with a continuous infusion of propofol to maintain a BIS value of 40 +/- 5. After baseline recordings, patients were randomly assigned to receive either midazolam, isoflurane, or aminophylline. Bispectral index values, rSO(2) using near-infrared spectroscopy, and hemodynamic parameters were recorded for 60 min., Results: Midazolam (0.05 mg x kg(-1)) significantly decreased the BIS from 47.8 +/- 5.4 to 35.0 +/- 4.5 at five minutes after injection (P < 0.001 vs control) during propofol anesthesia, whereas the rSO(2) was unchanged. Similarly, isoflurane (1.1% end-tidal) decreased the BIS from 42.5 +/- 7.5 to 27.8 +/- 6.9 (P < 0.001) without affecting rSO(2). In contrast, aminophylline (3 mg.kg(-1)) was associated with an increase in BIS from 41.6 +/- 2.1 to 48.3 +/- 9.2 at five minutes after injection (P < 0.05) without affecting rSO(2)., Conclusions: Midazolam or isoflurane-induced decreases in the BIS during propofol anesthesia were not accompanied by a decrease in rSO(2). Aminophylline significantly increased the BIS score during propofol anesthesia, suggesting that aminophylline can antagonize, at least in part, the sedative actions of propofol.

Paediatric anaesthetists are at higher risk of exposure to waste anaesthetic gases, which often exceed set safety limits. Recommended personal diffusive sampling techniques for monitoring exposure to waste anaesthetic gases may not give a true profile of exposure and hence biological sampling may also be necessary. We evaluated the exposure of paediatric anaesthetists to nitrous oxide and sevoflurane as assessed by personal environmental and biological samples. The influence of venue and technique, and the strength of the relationship among the various sampling techniques were analysed. The study found that exposure to nitrous oxide during paediatric anaesthetic inductions is still a major problem, although exposure to sevoflurane was usually within the accepted limits. The type of breathing system used and the presence of scavenging seem to influence this exposure, though surprisingly, the induction technique or the methods of airway control do not. No significant relationship was found between the various biological indicators measured.

Background and Objective: There are little data on nitrous oxide (N2O) concentrations in neonatal blood at delivery. We investigated the effects of the time elapsing between the induction of anaesthesia and delivery (the I-D interval) on umbilical blood N2O concentrations., Methods: Maternal and neonatal blood N2O concentrations were measured in 27 patients undergoing Caesarean section under N2O 67% anaesthesia. The duration of N2O administration (range 2-50 min) was arbitrarily divided into three groups (each n = 9): short (2-9 min), medium (9.1-14 min) and long duration (14.1-50 min)., Results: Compared with a rapid increase in the maternal arterial N2O concentration (48.9 +/- 4.7%), the umbilical venous N2O concentration (17.9 +/- 8.3%) rose slowly in the short duration group, whereas the N2O concentrations became more similar (61.6 +/- 4.3 and 43.2 +/- 10.0%, respectively) in the long duration group. The ratio of umbilical vein to maternal artery N2O concentrations correlated with the duration of N2O anaesthesia (r = 0.739), resulting in ratios of 0.37 +/- 0.18, 0.61 +/- 012 and 0.70 +/- 0.13 for the short, medium and long duration groups, respectively. The Apgar score at 1 min correlated inversely with the duration of anaesthesia and with the umbilical vein N2O concentration (r = -0.457 and -0.423, respectively)., Conclusions: The data suggest that placental N2O transfer during Caesarean section is time-dependent and slower compared with maternal N2O uptake. They also suggest that the Apgar score is less affected by N2O administration when the I-D interval is shorter.

The change in middle ear pressure while breathing gas mixtures containing N(2)O was studied in four monkeys. At each of three experimental sessions, monkeys were anesthetized, acclimated for 60 min, breathed with room air for 60 min, and then breathed with 5, 10, or 20% N(2)O for 60 min. Middle ear pressure, rectal temperature, and vital signs were recorded throughout. The time constant for blood-middle ear N(2)O exchange was calculated from these data. Middle ear pressure decreased during acclimation, was stable during air breathing, and increased during N(2)O breathing. The rate of pressure change was similar for both ears of each animal and was directly related to N(2)O percent. The calculated time constant ranged from 0.003 to 0.008 min(-1) across animals but was not different for a given ear across sessions. These results show that breathing gas mixtures containing N(2)O causes predictable and quantifiable increases in middle ear pressure.

Background: Molecular Adsorbents Recirculating System (MARS) is a new promising artificial liver support therapy, the aim of this study was to assess the effectiveness of MARS to remove nitrous oxide (NO) and cytokines in severe liver failure patients with multiple organ dysfunction syndrome (MODS)., Methods: Sixty single MARS treatments were performed with length of 6-24 h on 24 severe liver failure patients (18 males/6 females) with MODS., Results: The MARS therapy was associated with a significant removal of NO and certain cytokines such as TNF-alpha, IL-6, IL-8, and INF-gamma, together with marked reduction of other non-water-soluble albumin bound toxins and water-soluble toxins, these were associated with a improvement of the patients' clinical conditions including hepatic encephalopathy, deranged hemodynamic situation and as well as renal and respiratory function, thus resulted into marked decrease of Sequential Organ Failure Assessment (SOFA) score and improved outcome: nine patients were able to be discharged from the hospital or bridged to successful liver transplantation, the overall survival of 24 patients was 37.5%., Conclusion: We can confirm the positive therapeutic impact and safety to use MARS on liver failure patients with MODS associated with elevated levels of NO and cytokines.

This study utilized Takayasu arteritis (TA) model to do the experiment in order to observe the remodeling of arterial geometry. Plasma estrogen, progesterone and products of nitrous oxide (NO2- and NO3-) were examined. Qualitative analyses of maximum (MAX), minimum (MIN) and mean (MEAN) velocity of blood flow, resistant index (PI), pulsatile index (PI), and shear stress (SS) of abdominal aorta were performed. The results showed that plasma estrogen, progesterone and products of nitrous oxide were respectively 1137.80 +/- 189.30 pg.ml-1, 14.10 +/- 1.61 micrograms.ml-1 and 195.78 +/- 53.01 mumol.L-1 in experiment group, whereas in control group, they were 34.74 +/- 10.20 pg.ml-1, 2.60 +/- 1.83 micrograms.ml-1 and 12.16 +/- 3.28 mumol.L-1 respectively, P < 0.01. In comparison of hemodynamic parameters of abdominal aorta, the MAX and MIN of experiment group were profoundly higher than those of control group. SS increased markedly in experiment group. The observation of arterial remodeling in vitro found wall thickening. The thickness of abdominal aortic wall and inside diameter of vessel cavity ratio (h/Di) was 0.6145 +/- 0.1654 in experiment group and 0.2151 +/- 0.0266 in control group, P < 0.01. The arterial collagen content in experimental group was significantly higher than that in control group. Hyperestrinemia gives rise to a series of hemodynamic alterations, influences vessel remodeling along with TA, and finally results in arterial stenosis, occlusion or aneurysms due to the constitutional composition of vascular wall reforming.

We studied the role of inducible nitric oxide synthase (iNOS) in septic lung injury using a novel and selective iNOS inhibitor (a fused piperidine derivative; ONO-1714) following a cecal ligation and puncture (CLP) procedure. All rats that received CLP died within 48 h after the intervention. The subcutaneous injection of ONO-1714 at 0.03 mg/kg every 12 h resulted in a significantly longer survival time than the saline control only when administration was started 12 h after the CLP procedure. The other administration schedules, which started immediately or 6 h after the intervention, did not show any improvement in the survival rates in comparison with the saline control. The administration of ONO-1714 at higher (0.1 mg/ kg) or lower (0.01 mg/kg) doses when given anytime after the intervention did not improve the survival rates. The NO(x) (NO(2)(-) + NO(3)(-)) levels in the plasma significantly increased 12 h after intervention in comparison with NO(x) at 0 h and thereafter further increased in parallel with the time elapsed. The CLP rats that were initially treated with ONO-1714 (0.03 mg/kg subcutaneously every 12 h) 12 h after intervention showed significantly reduced NO(x) levels in the plasma in comparison with the saline control. The NO synthase activity in lung homogenates increased from 6 to 24 h after the CLP and thereafter decreased to 42 h. The administration of ONO-1714 inhibited iNOS activity (under calcium-free conditions) in preference to total iNOS activity (under calcium-dependent conditions) in lung homogenates, which thus suggested that this compound selectively inhibited iNOS in lung tissue. The iNOS protein expression in the lung and liver homogenates showed a similar time course with alterations of NOS activity, namely a maximum level at 24 h after the intervention followed by decreasing levels to 42 h. On the other hand, other isozymes of NOS, eNOS, and nNOS in lung homogenates, were constantly expressed over the time course after the CLP. Since the iNOS mRNA expression in lung homogenates continued to elevate until 42 h, the decrease in iNOS activity and protein expression later than 24 h after the CLP was thus considered to be due to some posttranscriptional mechanism during the late phase of sepsis. In conclusion, intervention with a potent and selective iNOS inhibitor seemed to improve survival in CLP rats when used at the appropriate doses and time points. However, the self-limited mechanism of iNOS regulation in the lungs may also indicate that iNOS plays only a limited role in sepsis and septic shock.

Background: The combination of propofol and alfentanil with nitrous oxide provides balanced anesthesia with rapid recovery and minimal emetic side effects. The object of this study was to compare recovery parameters at varying proportions of propofol and alfentanil, and to determine the dosing rate and plasma concentration of propofol necessary to supplement nitrous oxide in the presence of varying concentrations of alfentanil, Methods: Forty-eight patients were anesthetized with nitrous oxide, targeted manual infusions of alfentanil (target plasma concentrations of 0, 50, 100, and 150 ng/ml), and propofol at rates that were varied up or down by 25% depending on the response (movement/no movement) of the preceding patient (at the same alfentanil target concentrations) to ulnar-nerve stimulation. The minimum concentrations of propofol and alfentanil required to prevent movement in 50% of patients (EC50) was determined by logistic regression. Speed of emergence and recovery of cognitive function, time to discharge, and incidence of side effects were compared for four different combinations of propofol and alfentanil with nitrous oxide., Results: The EC50 for propofol alone with nitrous oxide was 6.1 microg/ml. AlfentaniL at concentrations of 41+/-17 (SD), 113+/-54, and 130+/-61 ng/mL reduced the EC50 of propofol to 3.3, 2.3, and 2.2 microg/ml, respectively, and decreased emergence time (eye opening) to 8.1, 4.9, and 3.4 min, compared with 24.3 min for propofol alone. Side effects did not differ between groups., Conclusions: The authors conclude that there is a synergistic effect between propofol and alfentanil, and that combining alfentanil with propofol is associated with faster early recovery.

Purpose: To investigate ventilation and gas elimination during the emergence from inhalational anesthesia with controlled normoventilation with either sevoflurane/N2O or sevoflurane alone., Methods: Twenty-four ASA I-II patients scheduled for abdominal hysterectomy were randomly allocated to receive either 1.3 MAC sevoflurane/N2O (n = 12) or equi-MAC sevoflurane (n = 12) in 30% oxygen (O2). Expired minute ventilation volumes (V(E)), end-tidal (ET) concentrations of O2, carbon dioxide (CO2), sevoflurane and N2O as well as pulse oximetry saturation (SpO2) and CO2 elimination rates (VCO2) were measured. The ET concentrations of sevoflurane and N2O were converted to total MAC values and gas elimination was expressed in terms of MAC reduction. Time to resumption of spontaneous breathing and extubation were recorded and arterial blood gas analysis was performed at the end of controlled normoventilation and at the beginning of spontaneous breathing., Results: Resumption of spontaneous breathing and extubation were 8 and 13 min less, respectively, in the sevoflurane/N2O than in the sevoflurane group. Spontaneous breathing was resumed in both groups when pH had decreased by 0.07-0.08 and PaCO2 increased by 1.3-1.5 kPa. Depression of V(E) and VCO2 were less, and MAC reduction more rapid in the sevoflurane/N2O than in the sevoflurane group., Conclusions: Respiratory recovery was faster after sevoflurane/N2O than sevoflurane anesthesia. Changes in pH and PaCO2 rather than absolute values were important for resumption of spontaneous breathing after controlled normoventilation. In both groups, the tracheas were extubated at about 0.2 MAC.

Objective: The purpose of this study was to examine the effect of cardiopulmonary bypass flow rate on cerebral blood flow and cerebral metabolic rate for oxygen during hypothermic (27 degrees C) cardiopulmonary bypass., Design, Setting, and Participants: The investigation was a prospective, randomized study in a tertiary care hospital setting. The 30 participants were volunteer adult cardiac surgical patients at a single institution., Interventions: The N2O saturation method of Kety and Schmidt was used to determine global cerebral blood flow and metabolic rate during four periods: prebypass, cardiopulmonary bypass (CPB) (27 degrees C) flow rates of 2.3 and 1.2 L/min/m2, and 30 minutes post-CPB. Anesthesia consisted of fentanyl and midazolam; pH management was alpha-stat, and mean arterial pressure was maintained at 50 to 70 mmHg throughout CPB., Measurements and Main Results: In the context of an unchanged mean arterial pressure, the pump flow did not affect cerebral blood flow or metabolic rate during hypothermic CPB. Systemic venous oxygen saturation was also maintained during reduced flow at 27 degrees C. Hemodilution during hypothermic CPB maintained cerebral blood flow at prebypass levels. In the postbypass period, persistent hemodilution resulted in an elevated cerebral blood flow., Conclusions: Brain oxygenation is well maintained at lower than conventional pump flow levels during CPB. There may be practical advantages to reduced flows during hypothermia, and flow reductions do not appear to adversely affect cerebral blood flow or metabolism.

One hour after a bone marrow biopsy and inhalation of Entonox gas (50% nitrous oxide (N2O) and 50% oxygen), a patient had a markedly reduced transfer factor of the lung for carbon monoxide (TL,CO). Three hours after Entonox, the patient had a normal TL,CO. Since carbon monoxide (CO) and N2O have similar spectral wavelengths, it was proposed that residual N2O in the lungs was interfering with the infra-red analysers used to detect CO concentrations. Experiments were performed to verify the "interference" effect and its duration. Five healthy volunteers performed serial triplicate TL,CO measurements over 3 h on two randomized days (Control vs N2O). The first triplicate TL,CO on each day served as a baseline measurement. Following the baseline measurement on the N2O day, each subject inhaled Entonox for 10 min. To serve as a control for the infrared effect, the identical protocol was repeated using a gas chromatography method for TL,CO determination. The infra-red method showed a marked reduction (> 50%) in TL,CO 30 min after N2O inhalation. This reduction did not return to baseline levels for at least 2 h. In comparison, the gas chromatography method showed no significant reduction in TL,CO. In a group of healthy nonsmoking subjects, N2O markedly affected the measurement of the transfer factor of the lungs for carbon monoxide using infra-red analysers. The time course over which the measurement was reduced was at least 2 h for a 10 min inhalation period. The effect was entirely due to a measurement error associated with infra-red technology.

Six mainstream and twelve sidestream infrared carbon dioxide (CO2) analysers were tested for accuracy of the CO2 display value, alarm activation and the effects of nitrous oxide (N2O), oxygen (O2) and water vapour according to the ISO Draft International Standard (DIS)#9918. Mainstream analysers (M-type): Novametrix Capnogard 1265; Hewlett Packard HP M1166A (CO2-module HP M1016A); Datascope Passport; Marquette Tramscope 12; Nellcor Ultra Cap N-6000; Hellige Vicom-sm SMU 611/612 ETC. Sidestream analysers: Brüel & Kjaer Type 1304; Datex Capnomac II; Marquette MGA-AS; Datascope Multinex; Ohmeda 4700 OxiCap (all type S1: respiratory cycles not demanded); Biochem BCI 9000; Bruker BCI 9100; Dräger Capnodig and PM 8020; Criticare Poet II; Hellige Vicom-sm SMU 611/612 A-GAS (all type S2: respiratory cycles demanded). The investigations were performed with premixed test gases (2.5, 5, 10 vol%, error < or = 1% rel.). Humidification (37 degrees C) of gases were generated by a Dräger Aquapor. Respiratory cycles were simulated by manually activated valves. All monitors complied with the tolerated accuracy bias in CO2 reading (< or = 12% or 4 mmHg of actual test gas value) for wet and dry test gases at all concentrations, except that the Marquette MGA-AS exceeded this accuracy limit with wet gases at 5 and 10 vol% CO2. Water condensed in the metal airway adapter of the HP M1166A at 37 degrees C gas temperature but not at 30 degrees C. The Servomex 2500 (nonclinical reference monitor), Passport (M-type), Multinex (S1-type) and Poet II (S2-type) showed the least bias for dry and wet gases. Nitrous oxide and O2 had practically no effect on the Capnodig and the errors in the others were max. 3.4 mmHg, still within the tolerated bias in the DIS (same as above). The difference between the display reading at alarm activation and the set point was in all monitors (except in the Capnodig: bias 1.75 mmHg at 5 vol% CO2) below the tolerated limit of the DIS (difference < or = 0.2 vol%). The authors conclude that the tested monitors are safe for clinical used (except those failing the DIS limits). The accuracy of the CO2-reading (average of mean absolute bias) is better in the M-type than in the S1- or S2-type analysers although no statistical (nor clinical) significant differences could be detected. Most manufacturers work with stricter limits than those proposed by the DIS.

Nitrous oxide (N2O) was assayed in 676 urine samples and 101 blood samples provided after exposure by operating theatre personnel from nine hospitals. The blood and urine assays were repeated in 25 subjects 18 h after the end of exposure. For 80 subjects, environmental N2O was also measured during intraoperative exposure. Mean urinary N2O in the 676 subjects at the end of exposure was 40 micrograms/l (range 1-3805 micrograms/l); in 10 of the 676 subjects, urinary N2O was in the range 279-3805 micrograms/l (mean 1202 micrograms/l). The 98th percentile was 120 micrograms/l. Mean blood N2O at the end of exposure, measured in 101 subjects, was 21 micrograms/l (median 16 micrograms/l, range 1-75 micrograms/l). Blood and urine N2O (1.5 micrograms/l and 4.9 micrograms/l, respectively) in 25 subjects, 18 h after exposure, was significantly higher than in occupationally non-exposed subjects (blood 0.91 microgram/l, urine 1 microgram/l). Environmental exposure was significantly related to blood and urinary N2O (r = 0.59 and r = 0.64, respectively). Blood and urinary N2O were significantly related to each other (r = 0.71), and were equivalent to about 25% of the environmental exposure level. The mean urinary N2O of 1202 micrograms/l in 10/676 subjects was not related to environmental exposure in the operating theatre. The highest urinary N2O levels measured in these 10/676 subjects could be explained by an asymptomatic urinary infection.

The concentration of 12 environmental chemical pollutants was measured in the blood of the general population. With reference to the 12 different pollutants, the blood samples tested varied from 88 for acetone to 431 for benzene. Nine of these agents (benzene, toluene, styrene, cumene, xilene, n-hexane, nitrous oxide (N20), acetone and carbon disulphide) were present in all or almost all (100-94%) blood samples. The three chlorides (chloroform, trichloroethylene and tetrachloroethylene) were present only in 60-85% of samples. After acetone and carbon disulphide, with blood concentrations in microgram/l (mean 840 micrograms/l and 2.4 micrograms/l respectively), the highest mean blood levels were those of toluene (1097 ng/l), chloroform (955 ng/l), N2O (915 ng/l), and n-hexane (642 ng/l). Trichloroethylene and free carbon disulphide had similar values (458 and 438 ng/l, respectively). Finally, benzene, styrene and tetrachloroethylene had the lowest values (262, 217 and 149 ng/l, respectively). There was generally a significant difference between rural and urban workers in terms of blood benzene (200 ng/l vs. 264 ng/l), trichloroethylene (180 ng/l vs 763 ng/l) and tetrachloroethylene (62 ng/l vs. 263 ng/l). In a group of subjects potentially exposed to industrial solvents, classed as chemical workers, blood benzene, toluene, chloroform and n-hexane were significantly higher than in rural and urban workers. Smokers showed a significantly higher blood concentration than non-smokers for benzene (381 ng/l vs. 205 ng/l), toluene (1431 ng/l vs. 976 ng/l) and n-hexane (803 ng/l vs. 505 ng/l).

Background: Our previous observation that nitric oxide (NO) is synthesized during antigen-specific immune reactions in vitro led us to investigate whether NO is produced during the in vivo immune response to a vascularized organ allograft., Methods: Orthotopic small-bowel transplantation in the rat was performed by standard microsurgical techniques in the LBNF1 to Lewis (rejection alone), Lewis to LBNF1 (graft-versus-host disease [GVHD] alone), and a syngeneic strain combination with and without immunosuppressive therapy with FK 506. The recipient serum NO2-/NO3- levels (stable end products of NO metabolism) were measured and erythrocytes were evaluated for the presence of nitrosylferrohemoglobin (specific for NO bound to hemoglobin)., Results: Animals that acutely rejected small-bowel allografts or suffered from acute GVHD showed significantly elevated serum NO2-/NO3- levels on days 6 and 9, and nitrosylferrohemoglobin electron paramagnetic resonance signals of different intensity were detected on days 3, 6, and 9. FK 506-treated allograft recipients and recipients of syngeneic grafts showed normal serum NO2-/NO3- levels and lacked nitrosylferrohemoglobin signals at all time points., Conclusions: This study indicates that NO is produced early during the course of small-bowel allograft rejection and GVHD and might therefore serve as a simple marker to detect such immune reactions.

This study compared the effects of sera from patients given various anesthetics on in vitro mouse preimplantation embryo development. Patients electing bilateral laparoscopic tubal sterilization were subjected to general anesthesia with nitrous oxide (N2O) that included either isofluorane (ISO/N2O) as an inhalant or fentanyl or morphine (FEN/MOR/N2O). The addition of sera collected 1 hr after anesthetic induction significantly reduced the numbers of two-cell mouse embryos that developed to blastocyst in the ISO/N2O group as compared to that of preanesthesia sera. In contrast, no detrimental effects were revealed from sera of patients given FEN/MOR/N2O. Comparison of sera from patients given ISO/N2O and FEN/MOR/N2O for laparoscopic oocyte retrieval and from patients given spinal anesthesia and/or i.v. sedation for ultrasonic retrieval also revealed a decrease in mouse embryo development in the ISO/N2O group, but no differences were seen in the other anesthetic regimens. ISO/N2O anesthesia was also associated with a significantly decreased fertilization rate of mature oocytes retrieved. However, no significant effect of ISO/N2O anesthesia on IVF pregnancy rates could be demonstrated. These studies indicate that embryo toxic effects can be detected in sera from patients given ISO/N2O and that this anesthetic may be detrimental to the success of in vitro fertilization and embryo transfer.

An in vitro constant-flow, alternatively constant-pressure, perfusion method for studying microvascular myogenic responsiveness in otherwise intact rat hindquarters was used to explore how three types of influences affect the pressure-flow induced enhancements of myogenic tone: (1) Changes of potassium concentration over the range 2-50 mmol; (2) Whether myogenic responsiveness, which is fairly weak during these conditions of high shear rates, is enhanced by blockade of endothelial prostacyclin and nitrous oxide formation; (3) Whether some of the drawbacks of the constant-flow technique, like rapid edema formation, is offset by a constant-pressure variant. The result can be summed up as follows. (1) Myogenic responsiveness is also during in vitro conditions markedly influenced by even modest potassium concentration changes around the physiological resting level, e.g. showing a fourfold difference between potassium concentrations of 2.5-4.5 mmol. It was entirely suppressed above 7-8 mmol potassium concentration but also when potassium concentration values above 20 mmol increasingly depolarize and constrict the resistance vessels. (2) While blockade of prostacyclin synthesis was without effect, suppression of endothelial nitrous oxide production could increase myogenic responsiveness up to fourfold, suggesting that shear-stress dependent release of this agent serves to suppress myogenic activity. These effects were, however, quite variable suggesting that also other endothelial inhibitory influences are involved. (3) The constant-pressure variant reduces some of the methodological drawbacks, particularly the oedema formation which can be further reduced by increasing perfusate colloid osmotic pressure. However, interferences by the mentioned, partly unknown endothelial mechanisms still tend to suppress myogenic responsiveness to a varying extent, which hampers quantitative analyses particularly of other inhibitory influences.

1. The reliability of the Kety-Schmidt nitrous oxide (N2O) blood-tissue equilibration method was examined in 50 studies of myocardial blood flow in seven conscious, unrestrained sheep using a newly developed carefully validated gas chromatographic assay for N2O. 2. In 10 studies the arterial and coronary sinus N2O blood concentration-time curves converged as expected at the end of the 10 min sampling period. In 14 studies they crossed over, and in 26 studies, the curves failed to converge. 3. A survey of the literature revealed that such results have been encountered previously but have not been accorded particular significance. An ultimate matching equilibrium between arterial and venous blood N2O concentration-time curves is, however, fundamental to the validity of the method. 4. The results indicate that the use of the Kety-Schmidt method with N2O as the indicator gas is invalid as applied to the measurement of myocardial blood flow in this preparation.

The low solubility of desflurane in blood and tissues suggests that the partial pressures of this agent in blood and tissues should approach the inspired partial pressure more rapidly than would the blood and tissue partial pressures of other potent inhaled anesthetics. We tested this prediction, comparing the pharmacokinetics of desflurane with those of isoflurane, halothane, and nitrous oxide in eight volunteers. We measured the rate at which the alveolar (endtidal) (FA) concentration of nitrous oxide increased towards an inspired (FI) concentration of 65-70%, and then measured the concurrent increase in FA and mixed expired concentrations (FM) of desflurane, isoflurane, and halothane at respective FI values of 2.0%, 0.4%, 0.2%. Minute ventilation (VE) was measured concurrently with the measurements of anesthetic concentrations. The potent vapors were administered for 30 min; administration of nitrous oxide continued throughout the period of anesthesia. For the potent agents, we also measured VE, FA, and FM for 5-7 days of elimination. We used FA/FI and FA/FA0 (FA0 = the last FA during the administration of each anesthetic) to define the rate of increase of anesthetic in the lungs and the rate of elimination of anesthetic, respectively. FA/FI values at 30 min of administration were: (mean +/- SD) nitrous oxide 0.99 +/- 0.01, desflurane 0.90 +/- 0.01, isoflurane 0.73 +/- 0.03, and halothane 0.58 +/- 0.04. FA/FA0 values after 5 min of elimination were: desflurane 0.14 +/- 0.02, isoflurane 0.22 +/- 0.02, and halothane 0.25 +/- 0.02. Recovery (volume of anesthetic recovered during elimination per volume taken up) of desflurane (105 +/- 25%) equalled recovery of isoflurane (102 +/- 13%) and exceeded recovery of halothane (64 +/- 9%). Time constants for a five-compartment mammillary model for halothane and isoflurane differed for the lungs, fat group, and hepatic metabolism, and exceeded those for desflurane for all compartments. In summary, we found that FA/FI of desflurane increases more rapidly and that FA/FA0 decreases more rapidly in humans than do these variables with other available potent anesthetics. We also found that desflurane resists biodegradation in humans and so may have little or no toxic potential.

A technique was developed for the in vivo determination of PO2 and PN2O with a catheter electrode using double-pulse polarography. The method was evaluated in dog studies comparing readings from the electrode with those from a mass spectrometer employing an in vivo probe. The oxygen readings obtained from the catheter electrode were also compared with values obtained by conventional blood-gas analysis. Good agreement was observed between the electrode and the mass spectrometer for both PO2 and PN2O. Similar agreement was found between the electrode readings and blood-gas analysis for PO2. In the presence of halothane, the electrode over-read for both PO2 and PN2O; a remedy is suggested. The in vivo electrode provides an effective, less expensive, alternative to the mass spectrometer for the on-line measurement of PO2 and PN2O in vivo.

Thirty-four cases of death related to the deliberate inhalation of various solvents or gases were studied regarding the toxicology and pathology of this phenomenon. A method was developed for detection of these agents in blood and other autopsy specimens, utilizing flame ionization gas chromatography. The detection in the blood of components of the products inhaled usually confirmed the recent use of the substances. Death was usually sudden, occurring during or shortly after use of the inhalants, and was consistent with the development of cardiac arrhythmias. Of the cases available for histological evaluation, liver damage was apparent in some cases.

Blood-gas partition coefficients of N2O, enflurane, halothane, methoxyflurane, and isoflurane were measured on blood samples from 12 healthy male volunteers before and after eating. The solubility values determined while volunteers fasted substantiate previously reported blood-gas partition coefficients for enflurane, isoflurane, and halothane. Solubility values for methoxyflurane and N2O were slightly greater and smaller, respectively, than accepted values. The uptake and excretion of N2O, enflurane, halothane, and methoxyflurane also were measured in 6 of these subjects in the fasted and postprandial states. Subjects breathed a constant, inspired mixture containing trace concentrations of all 4 gases. Eating increased blood solubility by 17 to 24 percent for all agents except N2O. Accordingly, the rates of rise of the end-tidal enflurane, halothane, and methoxyflurane concentrations were 7 to 8 percent below control, and the rates of anesthetic uptake increased 20 to 23 percent. Simulation studies showed that the increased ventilation induced by eating opposed and, therfore, minimized the impact of increased blood solubility and cardiac output on the rate of end-tidal anesthetic rise. Changes in blood solubility did not correlate with levels of plasma triglycerides and cholesterol.

If a small bubble gas is equilibrated with a volume of blood the partial pressures of the components of the bubble after equilibration approximate to the original tensions in the blood. A method is described in which the bubble is analysed by a respiratory mass spectrometer connected to a mini-computer. The normal respiratory monitoring function of the mass spectrometer need be interrupted for only 20 s for each sample and the complete equilibration and analysis procedure takes only 3 min. Theoretical studies, experimental tests and records of experimental usage show that, in a subject anaesthetized with halothane in nitrous and oxygen, tension can be measured with an overall SD of 5% for carbon dioxide and halothane and, certain reservations, an SD of about 3% for nitrous oxide.

The development of a new polarographic sensor for measuring simultaneously both N2O and O2, in either gas or blood, is described. The cathode is made of silver, and it is shown that silver deposition on normal platinum or gold cathode electrodes can result in an enhancement of a PO2 signal, when measured in the presence of nitrous oxide. Silver can be deposited on the cathode by means of Ag+ ions diffusing through the electrolyte from an Ag/AgCl reference electrode. The use of an Ag cathode enables both O2 and N2O signals to be measured.

A method for determining blood flow, oxygen uptake and carbon dioxide release in individual organs is presented. For blood flow measurement an inert gas (N2O) technique was used. Blood contents of O2, CO2 and N2O were measured by a gas chromatographic method with use of a special vacuum chamber for extracting the gases from blood. There was a strong correlation between the contents of O2 determined by the gas chromatographic and a spectophotometric method (correlation coefficient 0.953). Good agreement was found between CO2 in gas samples analysed by the Scholander technique and by the gas chromatographic method. A correlation coefficient of 0.998 was obtained between the N2O content calculated theoretically and that determined by the gas chromatographic technique. The new technique presented makes it possible to calculate blood flow in ml/100 g tissue/min, O2 uptake and CO2 production in an individual organ, whereby the predominant type of metabolism in the organ can be ascertained.