Nitrogen gas produces less behavioural and neurophysiological excitation than carbon dioxide in mice undergoing euthanasia.

Carbon dioxide (CO2) is one of the most commonly used gas euthanasia agents in mice, despite reports of aversion and nociception. Inert gases such as nitrogen (N2) may be a viable alternative to carbon dioxide. Here we compared behavioural and electrophysiological reactions to CO2 or N2 at either slow fill or rapid fill in C57Bl/6 mice undergoing gas euthanasia. We found that mice euthanised with CO2 increased locomotor activity compared to baseline, whereas mice exposed to N2 decreased locomotion. Furthermore, mice exposed to CO2 showed significantly more vertical jumps and freezing episodes than mice exposed to N2. We further found that CO2 exposure resulted in increased theta:delta of the EEG, a measure of excitation, whereas the N2 decreased theta:delta. Differences in responses were not oxygen-concentration dependent. Taken together, these results demonstrate that CO2 increases both behavioural and electrophysiological excitation as well as producing a fear response, whereas N2 reduces behavioural activity and central neurological depression and may be less aversive although still produces a fear response. Further studies are required to evaluate N2 as a suitable euthanasia agent for mice.

Comparative Noninvasive Measurement of Cardiac Output Based on the Inert Gas Rebreathing Method (Innocor®) and MRI in Patients with Univentricular Hearts.

There are many complex cardiac malformations that are characterized by a functionally univentricular physiology. Staged surgical repair according to the Fontan principle separates the systemic and pulmonary circulations by connecting the systemic venous return to the pulmonary arteries. However, long-term follow-up studies demonstrate a gradual deterioration of cardiac function, particularly from the second or third decade. Noninvasive evaluation of the cardiac function is, therefore, important in the follow-up of these patients. The cardiac index (CI) is a reliable hemodynamic parameter and represents an important marker of cardiac function. We compared CI values determined by cardiac MRI (CMRI) with values obtained by noninvasive inert gas rebreathing (IGR; Innocor® system). Sixteen patients (age range: 7.2-32.7 years) with functionally univentricular hearts (UVH) following total cavopulmonary connection (TCPC) were compared with 12 healthy subjects (age range: 8.5-18.6 years). The standard treadmill protocol of the German Society of Pediatric Cardiology was used for exercise testing. CI was determined at rest and at two standardized submaximal exercise levels. In all subjects, CI increased under exercise conditions, but the values were significantly lower in patients with UVH. There was no significant difference between patients with UVH and predominantly right- or left-ventricular morphology. In comparison with CMRI measurements, the CI values obtained by the IGR method tended to be lower, with a mean difference of 1.02 l/min/m2. Noninvasive measurement of CI with the IGR method is feasible at rest and during exercise, and appears to be suited for routine determination of CI in patients with UVH following TCPC.

Comparison of cardiac output estimates by bioreactance and inert gas rebreathing methods during cardiopulmonary exercise testing.

PURPOSE: This study assessed the agreement between cardiac output estimated by inert gas rebreathing and bioreactance methods at rest and during exercise. METHODS: Haemodynamic measurements were assessed in 20 healthy individuals (11 females, nine males; aged 32 ± 10 years) using inert gas rebreathing and bioreactance methods. Gas exchange and haemodynamic data were measured simultaneously under rest and different stages (i.e. 30, 60, 90, 120, 150 and 180 W) of progressive graded cardiopulmonary exercise stress testing using a bicycle ergometer. RESULTS: At rest, bioreactance produced significantly higher cardiac output values than inert gas rebreathing (7·8 ± 1·4 versus 6·5 ± 1·7 l min-1 , P = 0·01). At low-to-moderate exercise intensities (i.e. 30-90 W), bioreactance produced significantly higher cardiac outputs compared with rebreathing method (P<0·05). At workloads of 120 W and above, there was no significant difference in cardiac outputs between the two methods (P = 0·10). There was a strong relationship between the two methods (r = 0·82, P = 0·01). Bland-Altman analysis including rest and exercise data showed that inert gas rebreathing reported 1·95 l min-1 lower cardiac output than bioreactance, with lower and upper limits of agreement of -3·1-7·07 l min-1 . Analysis of peak exercise data showed a mean difference of 0·4 l min-1 (lower and upper limits of agreement of -4·9-5·7 l min-1 ) between both devices. CONCLUSION: Bioreactance and inert gas rebreathing methods show acceptable levels of agreement for estimating cardiac output at higher levels of metabolic demand. However, they cannot be used interchangeably due to strong disparity in results at rest and low-to-moderate exercise intensity.

Measurement of the distribution of ventilation-perfusion ratios in the human lung with proton MRI: comparison with the multiple inert-gas elimination technique.

We have developed a novel functional proton magnetic resonance imaging (MRI) technique to measure regional ventilation-perfusion (V̇A/Q̇) ratio in the lung. We conducted a comparison study of this technique in healthy subjects (n = 7, age = 42 ± 16 yr, Forced expiratory volume in 1 s = 94% predicted), by comparing data measured using MRI to that obtained from the multiple inert gas elimination technique (MIGET). Regional ventilation measured in a sagittal lung slice using Specific Ventilation Imaging was combined with proton density measured using a fast gradient-echo sequence to calculate regional alveolar ventilation, registered with perfusion images acquired using arterial spin labeling, and divided on a voxel-by-voxel basis to obtain regional V̇A/Q̇ ratio. LogSDV̇ and LogSDQ̇, measures of heterogeneity derived from the standard deviation (log scale) of the ventilation and perfusion vs. V̇A/Q̇ ratio histograms respectively, were calculated. On a separate day, subjects underwent study with MIGET and LogSDV̇ and LogSDQ̇ were calculated from MIGET data using the 50-compartment model. MIGET LogSDV̇ and LogSDQ̇ were normal in all subjects. LogSDQ̇ was highly correlated between MRI and MIGET (R = 0.89, P = 0.007); the intercept was not significantly different from zero (-0.062, P = 0.65) and the slope did not significantly differ from identity (1.29, P = 0.34). MIGET and MRI measures of LogSDV̇ were well correlated (R = 0.83, P = 0.02); the intercept differed from zero (0.20, P = 0.04) and the slope deviated from the line of identity (0.52, P = 0.01). We conclude that in normal subjects, there is a reasonable agreement between MIGET measures of heterogeneity and those from proton MRI measured in a single slice of lung.NEW & NOTEWORTHY We report a comparison of a new proton MRI technique to measure regional V̇A/Q̇ ratio against the multiple inert gas elimination technique (MIGET). The study reports good relationships between measures of heterogeneity derived from MIGET and those derived from MRI. Although currently limited to a single slice acquisition, these data suggest that single sagittal slice measures of V̇A/Q̇ ratio provide an adequate means to assess heterogeneity in the normal lung.

Validation of Noninvasive Measurement of Cardiac Output Using Inert Gas Rebreathing in a Cohort of Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Cardiac output (CO) is a key indicator of cardiac function in patients with heart failure. No completely accurate method is available for measuring CO in all patients. The objective of this study was to validate CO measurement using the inert gas rebreathing (IGR) method against other noninvasive and invasive methods of CO quantification in a cohort of patients with heart failure and reduced ejection fraction. METHODS AND RESULTS: The study included 97 patients with heart failure and reduced ejection fraction (age 42±15.5 years; 64 patients (65.9%) had idiopathic dilated cardiomyopathy and 21 patients (21.6%) had ischemic heart disease). Median left ventricle ejection fraction was 24% (10%-36%). Patients with atrial fibrillation were excluded. CO was measured using 4 methods (IGR, cardiac magnetic resonance imaging, cardiac catheterization, and echocardiography) and indexed to body surface area (cardiac index [CI]). All studies were performed within 48 hours. Median CI measured by IGR was 1.75, by cardiac magnetic resonance imaging was 1.82, by cardiac catheterization was 1.65, and by echo was 1.7 L·min-1·m-2. There were significant modest linear correlations between IGR-derived CI and cardiac magnetic resonance imaging-derived CI (r=0.7; P<0.001), as well as cardiac catheterization-derived CI (r=0.6; P<0.001). Using Bland-Altman analysis, the agreement between the IGR method and the other methods was as good as the agreement between any 2 other methods with each other. CONCLUSIONS: The IGR method is a simple, accurate, and reproducible noninvasive method for quantification of CO in patients with advanced heart failure. The prognostic value of this simple measurement needs to be studied prospectively.

Noninvasive Cardiac Output Estimation by Inert Gas Rebreathing in Mechanically Ventilated Pediatric Patients.

OBJECTIVE: To assess the feasibility and accuracy of inert gas rebreathing (IGR) pulmonary blood flow (Qp) estimation in mechanically ventilated pediatric patients, potentially providing real-time noninvasive estimates of cardiac output. STUDY DESIGN: In mechanically ventilated patients in the pediatric catheterization laboratory, we compared IGR Qp with Qp estimates based upon the Fick equation using measured oxygen consumption (VO2) (FickTrue); for context, we compared FickTrue with a standard clinical short-cut, replacing measured with assumed VO2 in the Fick equation (FickLaFarge, FickLundell, FickSeckeler). IGR Qp and breath-by-breath VO2 were measured using the Innocor device. Sampled pulmonary arterial and venous saturations and hemoglobin concentration were used for Fick calculations. Qp estimates were compared using Bland-Altman agreement and Spearman correlation. RESULTS: The final analysis included 18 patients aged 4-23 years with weight >15 kg. Compared with the reference FickTrue, IGR Qp estimates correlated best and had the least systematic bias and narrowest 95% limits of agreement (results presented as mean bias ±95% limits of agreement): IGR -0.2 ± 1.1 L/min, r = 0.90; FickLaFarge +0.7 ± 2.2 L/min, r = 0.80; FickLundell +1.6 ± 2.9 L/min, r = 0.83; FickSeckeler +0.8 ± 2.5 L/min, r = 0.83. CONCLUSIONS: IGR estimation of Qp is feasible in mechanically ventilated patients weighing >15 kg, and agreement with FickTrue Qp estimates is better for IGR than for other Fick Qp estimates commonly used in pediatric catheterization. IGR is an attractive option for bedside monitoring of Qp in mechanically ventilated children.

[DESCRIPTION AND PRESENTATION OF THE RESULTS OF ELECTROENCEPHALOGRAM PROCESSING USING AN INFORMATION MODEL].

The paper proposes to apply the informational modeling of correlation matrix developed by I.L. Myznikov in early 1990s in neurophysiological investigations, such as electroencephalogram recording and analysis, coherence description of signals from electrodes on the head surface. The authors demonstrate information models built using the data from studies of inert gas inhalation by healthy human subjects. In the opinion of the authors, information models provide an opportunity to describe physiological processes with a high level of generalization. The procedure of presenting the EEG results holds great promise for the broad application.

A randomized trial of the effects of the noble gases helium and argon on neuroprotection in a rodent cardiac arrest model.

BACKGROUND: The noble gas xenon is considered as a neuroprotective agent, but availability of the gas is limited. Studies on neuroprotection with the abundant noble gases helium and argon demonstrated mixed results, and data regarding neuroprotection after cardiac arrest are scant. We tested the hypothesis that administration of 50% helium or 50% argon for 24 h after resuscitation from cardiac arrest improves clinical and histological outcome in our 8 min rat cardiac arrest model. METHODS: Forty animals had cardiac arrest induced with intravenous potassium/esmolol and were randomized to post-resuscitation ventilation with either helium/oxygen, argon/oxygen or air/oxygen for 24 h. Eight additional animals without cardiac arrest served as reference, these animals were not randomized and not included into the statistical analysis. Primary outcome was assessment of neuronal damage in histology of the region I of hippocampus proper (CA1) from those animals surviving until day 5. Secondary outcome was evaluation of neurobehavior by daily testing of a Neurodeficit Score (NDS), the Tape Removal Test (TRT), a simple vertical pole test (VPT) and the Open Field Test (OFT). Because of the non-parametric distribution of the data, the histological assessments were compared with the Kruskal-Wallis test. Treatment effect in repeated measured assessments was estimated with a linear regression with clustered robust standard errors (SE), where normality is less important. RESULTS: Twenty-nine out of 40 rats survived until day 5 with significant initial deficits in neurobehavioral, but rapid improvement within all groups randomized to cardiac arrest. There were no statistical significant differences between groups neither in the histological nor in neurobehavioral assessment. CONCLUSIONS: The replacement of air with either helium or argon in a 50:50 air/oxygen mixture for 24 h did not improve histological or clinical outcome in rats subjected to 8 min of cardiac arrest.

Noninvasive cardiac output estimation by inert gas rebreathing in pediatric and congenital heart disease.

BACKGROUND: Inert gas rebreathing (IGR) techniques provide rapid, reliable estimates of cardiac output in adults with structurally normal hearts. Data on IGR reliability in pediatric and congenital heart disease populations are lacking. Our objective was to validate pulmonary blood flow (Qp) measurement by IGR compared with clinical reference tests, cardiovascular magnetic resonance (CMR), and indirect Fick. METHODS: Pulmonary blood flow was measured by IGR and CMR or indirect Fick in 80 patients grouped by presence and type of shunt lesion. Inert gas rebreathing precision was assessed using Bland-Altman analysis, repeatability coefficient, intraclass correlation, and coefficient of error. Agreement with the reference tests was assessed with Bland-Altman plots. For comparison, agreement between the 2 reference tests, CMR and indirect Fick, was assessed in 34 contemporary patients. RESULTS: Subjects were aged 7-78 years and had a wide range of cardiac diagnoses. Inert gas rebreathing Qp showed good repeatability (95% limits of agreement for 2 trials = ±22%, repeatability coefficient = 1.2 L/min, intraclass correlation = 0.92, and coefficient of error = 5%). In the absence of left-to-right shunting (n = 67), IGR Qp estimates agreed with CMR and indirect Fick Qp estimates, and the reference tests agreed with each other, with mean bias ≤10% (≤0.5 L/min) and 95% limits of agreement ±33%-38%. Conversely, IGR was unreliable in patients with left-to-right shunt (n = 14), with large bias (-58%, -4.0 L/min) and wide limits of agreement (±76%). CONCLUSIONS: Inert gas rebreathing reliably estimates Qp in children and adults with congenital heart disease in the absence of left-to-right shunting, with agreement comparable to that seen between CMR and indirect Fick estimates.

Inhalation gases or gaseous mediators as neuroprotectants for cerebral ischaemia.

Ischaemic stroke is one of the leading causes of morbidity and mortality worldwide. While recombinant tissue plasminogen activator can be administered to produce thrombolysis and restore blood flow to the ischaemic brain, therapeutic benefit is only achieved in a fraction of the subset of patients eligible for fibrinolytic intervention. Neuroprotective therapies attempting to restrict the extent of brain injury following cerebral ischaemia have not been successfully translated into the clinic despite overwhelming pre-clinical evidence of neuroprotection. Therefore, an adequate treatment for the majority of acute ischaemic stroke patients remains elusive. In the stroke literature, the use of therapeutic gases has received relatively little attention. Gases such as hyperbaric and normobaric oxygen, xenon, hydrogen, helium and argon all possess biological effects that have shown to be neuroprotective in pre-clinical models of ischaemic stroke. There are significant advantages to using gases including their relative abundance, low cost and feasibility for administration, all of which make them ideal candidates for a translational therapy for stroke. In addition, modulating cellular gaseous mediators including nitric oxide, carbon monoxide, and hydrogen sulphide may be an attractive option for ischaemic stroke therapy. Inhalation of these gaseous mediators can also produce neuroprotection, but this strategy remains to be confirmed as a viable therapy for ischaemic stroke. This review highlights the neuroprotective potential of therapeutic gas therapy and modulation of gaseous mediators for ischaemic stroke. The therapeutic advantages of gaseous therapy offer new promising directions in breaking the translational barrier for ischaemic stroke.

Evaluation of aortic valve stenosis using a hybrid approach of Doppler echocardiography and inert gas rebreathing.

BACKGROUND: Doppler echocardiography is the method of choice for diagnosis and evaluation of aortic stenosis. However, there are well-known limitations to this method in difficult-to-image patients. Flow acceleration in the left ventricular outflow tract (LVOT) can lead to overestimation of stroke volume (SV) and poor acoustic windows may impede the exact measurement of the LVOT. The present study aimed to evaluate the use of inert gas rebreathing (IGR)-derived SV in this situation. PATIENTS AND METHODS: We replaced Doppler-derived SV measurements in the continuity equation (method A) by SV determined by IGR (method B) and by thermodilution during right heart catheterization (method C) to calculate the aortic valve area (AVA) in 21 consecutive patients with moderate or severe aortic stenosis. RESULTS: Mean SV and AVA did not differ between methods at 72±21 ml and 0.71±0.2 cm(2) (method A) vs. 66±18 ml and 0.67±0.21 cm(2) (method B) vs. 64±15 ml and 0.67±0.21 cm(2) (method C), respectively (all p-values >0.05). The mean difference and limits of agreement for AVA were 0.04±0.23 cm(2) and -0.40 to 0.47 cm(2) between methods A and B, 0.05±0.14 cm(2) and -0.26 to 0.27 cm(2) between A and C, and -0.05±0.23 cm(2) and -0.45 to 0.35 cm(2) between B and C, respectively (all p-values >0.05). CONCLUSION: The presented approach is a reliable method for the calculation of AVA and can add a diagnostic option for the use in difficult-to-image patients. Whereas the use of thermodilution is limited due to its invasive nature, IGR allows the fast and non-invasive determination of cardiac function at low cost.

Pneumatic retinopexy for the management of impending macular hole: an optical coherence tomography study.

The intravitreal injection of an expansile gas bubble can relieve vitreofoveal traction and be used as an outpatient-based procedure for impending macular hole. We present a case in which this procedure was successfully employed and demonstrated with spectral domain optical coherence tomography (OCT) imaging.

Functional lung imaging using hyperpolarized gas MRI.

The noninvasive assessment of lung function using imaging is increasingly of interest for the study of lung diseases, including chronic obstructive pulmonary disease (COPD) and asthma. Hyperpolarized gas MRI (HP MRI) has demonstrated the ability to detect changes in ventilation, perfusion, and lung microstructure that appear to be associated with both normal lung development and disease progression. The physical characteristics of HP gases and their application to MRI are presented with an emphasis on current applications. Clinical investigations using HP MRI to study asthma, COPD, cystic fibrosis, pediatric chronic lung disease, and lung transplant are reviewed. Recent advances in polarization, pulse sequence development for imaging with Xe-129, and prototype low magnetic field systems dedicated to lung imaging are highlighted as areas of future development for this rapidly evolving technology.

Confirming the existence of five peaks in 129Xe rat head spectra.

A series of experiments were performed to investigate why two peaks (D and E) of the five dissolved phase peaks in hyperpolarized (129)Xe rat head spectra appeared inconsistently in previous work. Specifically, spectra were acquired under conditions of various shim states, anaesthetics, and arterial ligation. The shimming experiments showed that slice-shimming can be used to improve resolution of the dissolved phase peaks, but even so, subtle changes in the shim state that may dramatically alter the shape of peak E remain poorly understood. Also, the inability to shim gas spaces and tissue simultaneously may explain why inconsistent chemical shift values have been reported in the literature. A possible solution for this problem is suggested. The results of pre- and postligation spectra from the same animal indicated that two peaks (A and E) originate from brain. Changing the anaesthetic was found to have no effect on the number of dissolved peaks in xenon spectra.

Heliox y su relación con la fisiología de los flujos respiratorios-aplicación clínica / Heliox and its relation with air way flow physiology: clinical application

Cada día, el hombre se enfrenta a nuevos retos, que lo impulsan a crear y a tratar con nuevas herramientas para mejorar la calidad de vida del paciente en una unidad de cuidado intensivo y en los servicios de urgencias ; puesto que el paciente en estado crítico presenta alteraciones fisiológicas más comúnmente en el sistema respiratorio y cardiovascular, que llevan al deterioro progresivo en su función y a una inadecuada entrega de oxígeno indispensable para el funcionamiento celular. Los últimos estudios traen nuevos tratamientos para enfermedades obstructivas, como la utilización de un gas inerte: el Helio combinado con el oxígeno inhalado, siendo este punto de donde se desprende el interés por saber cómo está siendo aplicado el oxígeno con otros gases, en este caso el Helio. Las enfermedades obstructivas que se presentan en adultos son una condición relativamente frecuente, en donde la obstrucción del aire es irreversible y lentamente progresiva. Al avanzar la enfermedad, hay un aumento de la alteración obstructiva e hiperinsuflación pulmonar con un incremento de la resistencia de la vía aérea.

Soluble gas exchange in the pulmonary airways of sheep.

We studied the airway gas exchange properties of five inert gases with different blood solubilities in the lungs of anesthetized sheep. Animals were ventilated through a bifurcated endobronchial tube to allow independent ventilation and collection of exhaled gases from each lung. An aortic pouch at the origin of the bronchial artery was created to control perfusion and enable infusion of a solution of inert gases into the bronchial circulation. Occlusion of the left pulmonary artery prevented pulmonary perfusion of that lung so that gas exchange occurred predominantly via the bronchial circulation. Excretion from the bronchial circulation (defined as the partial pressure of gas in exhaled gas divided by the partial pressure of gas in bronchial arterial blood) increased with increasing gas solubility (ranging from a mean of 4.2 x 10(-5) for SF6 to 4.8 x 10(-2) for ether) and increasing bronchial blood flow. Excretion was inversely affected by molecular weight (MW), demonstrating a dependence on diffusion. Excretions of the higher MW gases, halothane (MW = 194) and SF6 (MW = 146), were depressed relative to excretion of the lower MW gases ethane, cyclopropane, and ether (MW = 30, 42, 74, respectively). All results were consistent with previous studies of gas exchange in the isolated in situ trachea.

Development of a hyperpolarized 129Xe system on 3T for the rat lungs.

MRI (magnetic resonance imaging) with 129Xe has gained much attention as a diagnostic methodology because of its affinity for lipids and possible polarization. The quantitative estimation of net detectability and stability of hyperpolarized 129Xe in the dissolved phase in vivo is valuable to the development of clinical applications. The goal of this study was to develop a stable hyperpolarized 129Xe experimental 3T system to statistically analyze the dissolved-phase 129Xe signal in the rat lungs. The polarization of 129Xe with buffer gases at the optical pumping cell was measured under adiabatic fast passage against the temperature of an oven and laser absorption at the cell. The gases were insufflated into the lungs of Sprague-Dawley rats (n = 15, 400-550 g) through an endotracheal tube under spontaneous respiration. Frequency-selective spectroscopy was performed for the gas phase and dissolved phase. We analyzed the 129Xe signal in the dissolved phase to measure the chemical shift, T2*, delay and its ratio in a rat lungs on 3T. The polarizer was able to produce polarized gas (1.1+/-0.47%, 120 cm3) hundreds of times with the laser absorption ratio (25%) kept constant at the cell. The optimal buffer gas ratio of 25-50% rendered the maximum signal in the dissolved phase. Two dominant peaks of 211.8+/-0.9 and 201.1+/-0.6 ppm were observed with a delay of 0.4+/-0.9 and 0.9+/-1.0 s from the gas phase spectra. The ratios of their average signal to that of the gas phase were 5.6+/-5.2% and 4.4+/-4.7%, respectively. The T2* of the air space in the lungs was 2.5+/-0.5 ms, which was 3.8 times shorter than that in a syringe. We developed a hyperpolarized 129Xe experimental system using a 3T MRI scanner that yields sufficient volume and polarization and quantitatively analyzed the dissolved-phase 129Xe signal in the rat lungs.

Agreement of an inert gas rebreathing device with thermodilution and the direct oxygen Fick method in measurement of pulmonary blood flow.

OBJECTIVE: Inert gas rebreathing is a well established method for the non-invasive measurement of pulmonary blood flow. We tested the agreement in measurement of pulmonary blood flow (Qt rb) by a new inert soluble gas rebreathing device, the Innocor (Innovision, Copenhagen), with bolus thermodilution (Qt td) and the direct oxygen Fick (Qt Fick) method. METHODS: 9 patients pre- and post-cardiac surgery were recruited resulting in 20 sets of measurements overall. Arterial and mixed venous blood samples were collected simultaneously with a thermodilution measurement and rebreathing manoeuvre to measure both V*O2 and effective pulmonary capillary blood flow. RESULTS: Mean bias (95% confidence limits) was: Qt rb - Qt td 0.01 (+/- 0.42) L/min; Qt rb - Qt Fick + 0.34 (+/-0.59) L/min. The standard deviation of the difference between paired measurements was: Qt td - Qt rb +/- 0.89 L/min; Qt Fick - Qt rb +/- 1.26 L/min. CONCLUSIONS: Acceptable overall agreement between the Innocor and these reference standards was demonstrated.