Serial Arterial Blood Samples Research Articles

Normoxic Management during Cardiopulmonary Bypass Does Not Reduce Cerebral Mitochondrial Dysfunction in Neonatal Swine.

Optimal oxygen management during pediatric cardiopulmonary bypass (CPB) is unknown. We previously demonstrated an increase in cortical mitochondrial reactive oxygen species and decreased mitochondrial function after CPB using hyperoxic oxygen management. This study investigates whether controlled oxygenation (normoxia) during CPB reduces cortical mitochondrial dysfunction and oxidative injury. Ten neonatal swine underwent three hours of continuous CPB at 34 °C (flow > 100 mL/kg/min) via cervical cannulation targeting a partial pressure of arterial oxygen (PaO2) goal < 150 mmHg (normoxia, n = 5) or >300 mmHg (hyperoxia, n = 5). The animals underwent continuous hemodynamic monitoring and serial arterial blood sampling. Cortical microdialysate was serially sampled to quantify the glycerol concentration (represents neuronal injury) and lactate-to-pyruvate ratio (represents bioenergetic dysfunction). The cortical tissue was analyzed via high-resolution respirometry to quantify mitochondrial oxygen consumption and reactive oxygen species generation, and cortical oxidized protein carbonyl concentrations were quantified to assess for oxidative damage. Serum PaO2 was higher in hyperoxia animals throughout CPB (p < 0.001). There were no differences in cortical glycerol concentration between groups (p > 0.2). The cortical lactate-to-pyruvate ratio was modestly elevated in hyperoxia animals (p < 0.03) but the values were not clinically significant (<30). There were no differences in cortical mitochondrial respiration (p = 0.48), protein carbonyls (p = 0.74), or reactive oxygen species generation (p = 0.93) between groups. Controlled oxygenation during CPB does not significantly affect cortical mitochondrial function or oxidative injury in the acute setting. Further evaluation of the short and long-term effects of oxygen level titration during pediatric CPB on cortical tissue and other at-risk brain regions are needed, especially in the presence of cyanosis.

Single time point quantitation of cerebral glucose metabolism by FDG-PET without arterial sampling

BackgroundUntil recently, quantitation of the net influx of 2-[18F]fluorodeoxyglucose (FDG) to brain (Ki) and the cerebrometabolic rate for glucose (CMRglc) required serial arterial blood sampling in conjunction with dynamic positron emission tomography (PET) recordings. Recent technical innovations enable the identification of an image-derived input function (IDIF) from vascular structures, but are frequently still encumbered by the need for interrupted sequences or prolonged recordings that are seldom available outside of a research setting. In this study, we tested simplified methods for quantitation of FDG-Ki by linear graphic analysis relative to the descending aorta IDIF in oncology patients examined using a Biograph Vision 600 PET/CT with continuous bed motion (Aarhus) or using a recently installed Biograph Vision Quadra long-axial field-of-view (FOV) scanner (Bern).ResultsCorrelation analysis of the coefficients of a tri-exponential decomposition of the IDIFs measured during 67 min revealed strong relationships among the total area under the curve (AUC), the terminal normalized arterial integral (theta(52–67 min)), and the terminal image-derived arterial FDG concentration (Ca(52–67 min)). These relationships enabled estimation of the missing AUC from late recordings of the IDIF, from which we then calculated FDG-Ki in brain by two-point linear graphic analysis using a population mean ordinate intercept and the single late frame. Furthermore, certain aspects of the IDIF data from Aarhus showed a marked age-dependence, which was not hitherto reported for the case of FDG pharmacokinetics.ConclusionsThe observed interrelationships between pharmacokinetic parameters in the IDIF measured during the PET recording support quantitation of FDG-Ki in brain using a single averaged frame from the interval 52–67 min post-injection, with minimal error relative to calculation from the complete dynamic sequences.

Feasibility of using abbreviated scan protocols with population-based input functions for accurate kinetic modeling of [18F]-FDG datasets from a long axial FOV PET scanner

BackgroundAccurate kinetic modeling of 18F-fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET) data requires accurate knowledge of the available tracer concentration in the plasma during the scan time, known as the arterial input function (AIF). The gold standard method to derive the AIF requires collection of serial arterial blood samples, but the introduction of long axial field of view (LAFOV) PET systems enables the use of non-invasive image-derived input functions (IDIFs) from large blood pools such as the aorta without any need for bed movement. However, such protocols require a prolonged dynamic PET acquisition, which is impractical in a busy clinical setting. Population-based input functions (PBIFs) have previously shown potential in accurate Patlak analysis of [18F]-FDG datasets and can enable the use of shortened dynamic imaging protocols. Here, we exploit the high sensitivity and temporal resolution of a LAFOV PET system and explore the use of PBIF with abbreviated protocols in [18F]-FDG total body kinetic modeling.MethodsDynamic PET data were acquired in 24 oncological subjects for 65 min following the administration of [18F]-FDG. IDIFs were extracted from the descending thoracic aorta, and a PBIF was generated from 16 datasets. Five different scaled PBIFs (sPBIFs) were generated by scaling the PBIF with the AUC of IDIF curve tails using various portions of image data (35–65, 40–65, 45–65, 50–65, and 55–65 min post-injection). The sPBIFs were compared with the IDIFs using the AUCs and Patlak Ki estimates in tumor lesions and cerebral gray matter. Patlak plot start time (t*) was also varied to evaluate the performance of shorter acquisitions on the accuracy of Patlak Ki estimates. Patlak Ki estimates with IDIF and t* = 35 min were used as reference, and mean bias and precision (standard deviation of bias) were calculated to assess the relative performance of different sPBIFs. A comparison of parametric images generated using IDIF and sPBIFs was also performed.ResultsThere was no statistically significant difference between AUCs of the IDIF and sPBIFs (Wilcoxon test: P > 0.05). Excellent agreement was shown between Patlak Ki estimates obtained using sPBIF and IDIF. Using the sPBIF55–65 with the Patlak model, 20 min of PET data (i.e., 45 to 65 min post-injection) achieved < 15% precision error in Ki estimates in tumor lesions compared to the estimates with the IDIF. Parametric images reconstructed using the IDIF and sPBIFs with and without an abbreviated protocol were visually comparable. Using Patlak Ki generated with an IDIF and 30 min of PET data as reference, Patlak Ki images generated using sPBIF55–65 with 20 min of PET data (t* = 45 min) provided excellent image quality with structural similarity index measure > 0.99 and peak signal-to-noise ratio > 55 dB.ConclusionWe demonstrate the feasibility of performing accurate [18F]-FDG Patlak analysis using sPBIFs with only 20 min of PET data from a LAFOV PET scanner.

PET Imaging of Leg Arteries for Determining the Input Function in PET/MRI Brain Studies Using a Compact, MRI-compatible PET System.

In this study, we used a compact, high-resolution, and MRI-compatible PET camera (VersaPET) to assess the feasibility of measuring the image-derived input function (IDIF) from arteries in the leg with the ultimate goal of enabling fully quantitative PET brain imaging without blood sampling. We used this approach in five 18F-FDG PET/MRI brain studies in which the input function was also acquired using the gold standard of serial arterial blood sampling. After accounting for partial volume, dispersion, and calibration effects, we compared the metabolic rates of glucose (MRglu) quantified from VersaPET IDIFs in 80 brain regions to those using the gold standard and achieved a bias and variability of <5% which is within the range of reported test-retest values for this type of study. We also achieved a strong linear relationship (R2 >0.97) against the gold standard across regions. The results of this preliminary study are promising and support further studies to optimize methods, validate in a larger cohort, and extend to the modeling of other radiotracers.

CaliPER: A software for blood-free parametric Patlak mapping using PET/MRI input function

Routine clinical use of absolute PET quantification techniques is limited by the need for serial arterial blood sampling for input function and more importantly by the lack of automated pharmacokinetic analysis tools that can be readily implemented in clinic with minimal effort. PET/MRI provides the ability for absolute quantification of PET probes without the need for serial arterial blood sampling using image-derived input functions (IDIFs). Here we introduce caliPER, a modular and scalable software for simplified pharmacokinetic modeling of PET probes with irreversible uptake or binding based on PET/MR IDIFs and Patlak Plot analysis. caliPER generates regional values or parametric maps of net influx rate (Ki) using reconstructed dynamic PET images and anatomical MRI aligned to PET for IDIF vessel delineation. We evaluated the performance of caliPER for blood-free region-based and pixel-wise Patlak analyses of [18F] FDG by comparing caliPER IDIF to serial arterial blood input functions and its application in imaging brain glucose hypometabolism in Frontotemporal dementia. IDIFs corrected for partial volume errors including spill-out and spill-in effects were similar to arterial blood input functions with a general bias of around 6–8%, even for arteries <5 mm. The Ki and cerebral metabolic rate of glucose estimated using caliPER IDIF were similar to estimates using arterial blood sampling (<2%) and within limits of whole brain values reported in literature. Overall, caliPER is a promising tool for irreversible PET tracer quantification and can simplify the ability to perform parametric analysis in clinical settings without the need for blood sampling.

CRISIS Ventilator: Pilot Study of a Three-Dimensional-Printed Gas-Powered Resuscitator in a Porcine Model

Abstract The coronavirus disease of 2019 (COVID-19) has altered medical practice around the globe and revealed critical deficiencies in hospital supply chains ranging from adequate personal protective equipment to life-sustaining ventilators for critically ill hospitalized patients. We developed the CRISIS ventilator, a gas-powered resuscitator that functions without electricity, and which can be manufactured using hobby-level three-dimensional (3D) printers and standard off-the-shelf equipment available at the local hardware store. CRISIS ventilators were printed and used to ventilate sedated female Yorkshire pigs over 24-h. Pulmonary and hemodynamic values were recorded throughout the 24-h run, and serial arterial blood samples were obtained to assess ventilation and oxygenation. Lung tissue was obtained from each pig to evaluate for signs of inflammatory stress. All five female Yorkshire pigs survived the 24-h study period without suffering from hypoxemia, hypercarbia, or severe hypotension requiring intervention. One animal required rescue at the beginning of the experiment with a traditional ventilator due to leakage around a defective tracheostomy balloon. The wet/dry ratio was 6.74 ± 0.19 compared to historical controls of 7.1 ± 4.2 (not significantly different). This proof-of-concept study demonstrates that our 3D-printed CRISIS ventilator can ventilate and oxygenate a porcine model over the course of 24-h with stable pulmonary and hemodynamic function with similar levels of ventilation-related inflammation when compared with a previous control porcine model. Our work suggests that virtual stockpiling with just-in-time 3D-printed equipment, like the CRISIS ventilator, can temporize shortages of critical infrastructure needed to sustain life for hospitalized patients.

Location matters: Overlooked ethnic-geographic effect in China and Austria on propofol/cisatracurium sex differences among a population pharmacokinetic/pharmacodynamic (PopPK/PD) covariate analysis in men, women, and one transgender subject.

A quick literature search using "sex/gender" vs. the commonly used hypnotic propofol or neuromuscular-blocking agent cisatracurium will reveal numerous contradictory sex difference publications depending on the ethnic-geographic location of where these studies were conducted. We induced anesthesia with cisatracurium besylate (GlaxoSmithKline) 100μgkg-1 administered exactly 1minute following propofol (AstraZeneca) 2mgkg-1 . In 20male and 20 female ethnic Han-Chinese test set patients (Xi'an China), and in similar ethnic white Austrian validation set patients (Graz Austria), we quantified propofol/cisatracurium pharmacodynamic parameters namely propofol onset time, lag time, plasma concentrations (Cp ) at loss-of-behavioral response (LOBR) using bispectral index (BIS); cisatracurium onset time, lag time, and Cp at T1 % (first twitch of train-of-four) complete twitch suppression using mechanomyography (MMG). Serial arterial blood samples were collected for population pharmacokinetic (PopPK) analysis of all demographic and biological covariates (region, sex, age, weight, and height) versus volumes of distribution and clearances pharmacokinetic parameters. In Chinese women (but not in white women), propofol Cp at LOBR was 33.60% lower than men and cisatracurium Cp at T1 % complete twitch suppression was 21.49% lower than men, a clear pharmacodynamic assertion. Region and weight were significant PopPK covariates. We demonstrated that sex differences are influenced by ethnic-geographic location as only in Chinese women (but not in white women) propofol Cp at LOBR and cisatracurium Cp at T1 % complete twitch suppression were lower than in men. When defining sex differences, ethnic-geographic location should be taken into consideration as a predictive factor for optimizing propofol/cisatracurium initial loading recommended dosages.

Noninvasive quantification of nonhuman primate dynamic 18F-FDG PET imaging

18F-FDG uptake rate constant Ki is the main physiology parameter measured in dynamic PET studies. A model-independent graphical analysis using Patlak plot with plasma input function (PIF) is a standard approach used to estimate Ki . The PIF is the 18F-FDG time activity curve (TAC) in plasma that is obtained by serial arterial blood sampling. The purpose of the study is to evaluate a Patlak plot-based optimization approach with reduced blood samples for noninvasive quantification of dynamic 18F-FDG PET imaging. Eight 60 min rhesus monkey brain dynamic 18F-FDG PET scans with arterial blood samples were collected. The measured PIF (mPIF) was determined by arterial blood samples. TACs of seven cerebral regions of interest were generated from each study. With a given number of blood samples, the population-based PIF (pPIF) was determined by either interpolation or extrapolation method using scale calibrated population mean of normalized PIF. The optimal sampling scheme with given blood sample size was determined by maximizing the correlations between the Ki estimated from pPIF and those obtained by mPIF. A leave-two-out cross-validation method was used for evaluation. The linear correlations between the Ki estimates from pPIF with optimal sampling schemes and those from mPIF were: Ki (pPIF 1 sample at 40 min) = 1.015 Ki (mPIF) − 0.000, R 2 = 0.974; Ki (pPIF 2 samples at 35 and 50 min) = 1.052 Ki (mPIF) − 0.001, R 2 = 0.976; Ki (pPIF 3 samples at 12, 40, and 50 min) = 1.030 Ki (mPIF) − 0.000, R 2 = 0.985; and Ki (pPIF 4 samples at 10, 20, 40, and 50 min) = 1.016 Ki (mPIF)- 0.000, R 2 = 0.993. As the sample size became greater or equal to 4, the Ki estimates from pPIF with the optimal protocol were almost identical to those from mPIF. The Patlak plot-based optimization approach is a reliable method to estimate PIF for noninvasive quantification of non-human primate dynamic 18F-FDG PET imaging and is potentially extendable to further translational human studies.

Literature Review for Office-Based Anesthesia.

Literature Review for Office-Based Anesthesia.

Test–retest characteristic of [18F]MK-6240 quantitative outcomes in cognitively normal adults and subjects with Alzheimer’s disease

[18F]MK-6240 is a selective, high-affinity PET radiotracer for imaging neurofibrillary tangles (NFT) in Alzheimer’s disease (AD). Herein, we report test–retest (T–RT) reproducibility of [18F]MK-6240 in AD and healthy volunteers (HV). Twelve subjects with AD and three cognitively normal HV were enrolled in the study and dynamically scanned for 150 min with [18F]MK-6240 under a T–RT protocol. Two radioactivity doses were investigated: 165 ± 3 MBq (n = 6) and 300 ± 40 MBq (n = 9). Serial arterial blood samples were taken for each scan to obtain metabolite-corrected input functions. Following intravenous administration of [18F]MK-6240, the tracer rapidly partitioned into the brain and its heterogenous distribution pattern was consistent with known NFT pathology in AD. In contrast, uptake in HV was low and uniform across the brain parenchyma. Across all subjects, average T–RT variabilities in NFT-rich regions were ∼21%, ∼14% and ∼6% for various quantitative metrics: total distribution volume (VT), binding potential (BPND), and standardized uptake ratio (SUVR90–120), respectively. No significant differences in SUVR T–RT variability were observed between the high and low injected radioactivity groups (5.6% and 6.1%, respectively). This work suggests [18F]MK-6240 has adequate SUVR T–RT characteristics supporting the use of this outcome in future studies.

Non-invasive kinetic modelling of PET tracers with radiometabolites using a constrained simultaneous estimation method: evaluation with 11C-SB201745

BackgroundKinetic analysis of dynamic PET data requires an accurate knowledge of available PET tracer concentration within blood plasma over time, known as the arterial input function (AIF). The gold standard method used to measure the AIF requires serial arterial blood sampling over the course of the PET scan, which is an invasive procedure and makes this method less practical in clinical settings. Traditional image-derived methods are limited to specific tracers and are not accurate if metabolites are present in the plasma.ResultsIn this work, we utilise an image-derived whole blood curve measurement to reduce the computational complexity of the simultaneous estimation method (SIME), which is capable of estimating the AIF directly from tissue time activity curves (TACs). This method was applied to data obtained from a serotonin receptor study (11C-SB207145) and estimated parameter results are compared to results obtained using the original SIME and gold standard AIFs derived from arterial samples. Reproducibility of the method was assessed using test-retest data. It was shown that the incorporation of image-derived information increased the accuracy of total volume of distribution (V T) estimates, averaged across all regions, by 40% and non-displaceable binding potential (BP ND) estimates by 16% compared to the original SIME. Particular improvements were observed in K1 parameter estimates. BP ND estimates, based on the proposed method and the gold standard arterial sample-derived AIF, were not significantly different (P=0.7).ConclusionsThe results of this work indicate that the proposed method with prior AIF information obtained from a partial volume corrected image-derived whole blood curve, and modelled parent fraction, has the potential to be used as an alternative non-invasive method to perform kinetic analysis of tracers with metabolite products.

Population Pharmacokinetic Modeling of Remifentanil in Infants with Unrepaired Tetralogy of Fallot.

Although there is literature suggesting that pathophysiologic changes in children with congenital heart disease alter the pharmacokinetics of anesthetics and may result in dosage adjustment, limited information exists regarding the pharmacokinetics of remifentanil in infants with unrepaired tetralogy of Fallot (TOF). The objectives of the current analysis were to characterize the population pharmacokinetics of remifentanil in infants, and to evaluate the effects of TOF on remifentanil's pharmacokinetics. Twenty-seven infants (16 with TOF and 11 with normal cardiac anatomy; aged 114-360days) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received remifentanil 1μg/kg/min intravenously for anesthesia induction and early maintenance [until ~ 20min before cardiopulmonary bypass (CPB) for patients with TOF]. Serial arterial blood samples were drawn and analyzed. Population pharmacokinetics of remifentanil was characterized using NONMEM software. The estimates were standardized to a 70-kg adult using a per-kilogram model. A two-compartment disposition model adequately described the pharmacokinetics of remifentanil. Besides body weight, the introduction of any other covariates, including TOF status, did not improve the model significantly (P > 0.05). The population parameter estimates for systemic clearance (Cl1) and inter-compartment clearances (Cl2) were 6.03 × (WT/70kg) and 1.23 × (WT/70kg) L/min, respectively, and central volume of distribution (V1) and peripheral volumes of distribution (V2) were 19.6 × (WT/70kg) and 21.7 × (WT/70kg) L, respectively. Unrepaired TOF does not change the pharmacokinetics of remifentanil, suggesting a similar dosage for infants with TOF compared to normal cardiac anatomy infants. The patient enrollment in this study started at 2012, so we do not have clinic trial number, but we still think this is a valuable research and hope it could be considered for publication.

Evaluating the methods used for measuring cerebral blood flow at rest and during exercise in humans.

The first accounts of measuring cerebral blood flow (CBF) in humans were made by Angelo Mosso in ~1880, who recorded brain pulsations in patients with skull defects. In 1890, Charles Roy and Charles Sherrington determined in animals that brain pulsations-assessed via a similar method used by Mosso-were altered during a variety of stimuli including sensory nerve stimulation, asphyxia, and pharmacological interventions. Between 1880 and 1944, measurements for CBF were typically relied on skull abnormalities in humans. Thereafter, Kety and Schmidt introduced a new methodological approach in 1945 that involved nitrous oxide dilution combined with serial arterial and jugular venous blood sampling. Less than a decade later (1950's), several research groups employed the Kety-Schmidt technique to assess the effects of exercise on global CBF and metabolism; these studies demonstrated an uncoupling of CBF and metabolism during exercise, which was contrary to early hypotheses. However, there were several limitations to this technique related to low temporal resolution and the inability to measure regional CBF. These limitations were overcome in the 1960's when transcranial Doppler ultrasound (TCD) was developed as a method to measure beat-by-beat cerebral blood velocity. Between 1990 and 2010, TCD further progressed our understanding of CBF regulation and allowed forinsight into other mechanistic factors, independent of local metabolism, involved in regulating CBF during exercise. Recently, it was discovered that TCD may not be accurate under several physiological conditions. Other measures of indexing CBF such as Duplex ultrasound and magnetic resonance imaging, although not without some limitations, may be more applicable for future investigations.

Age and gender effects of 11C-ITMM binding to metabotropic glutamate receptor type 1 in healthy human participants

We examined possible age- and gender-related changes in binding of the selective antagonist N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-11C-methoxy-N-methylbenzamide (11C-ITMM) to metabotropic glutamate receptor type 1 in healthy human brains. Dynamic 11C-ITMM positron emission tomography scans (90 min) with serial arterial blood sampling were performed in 15 young and 24 older healthy adult volunteers. The total distribution volume (VT) of several brain regions was estimated with 2-tissue compartment model analysis. The VTs of the cerebellar cortex, parietal cortex, putamen, amygdala, and hippocampus in older adult participants were significantly higher than in young participants. The age-related VT increase was only observed in male participants. Our data suggest that an age-dependent increase in metabotropic glutamate receptor type 1 availability in several brain regions may exist predominantly in males.

Pulmonary gas exchange and acid-base status during immobilisation of black rhinoceroses (Diceros bicornis) in Zimbabwe.

When immobilising wildlife, adverse side effects can include hypoxaemia, acidosis and hypertension. Pulmonary gas exchange and acid–base status were evaluated during immobilisation of 25 free-ranging and one boma-held black rhinoceros (Diceros bicornis) in Zimbabwe. The effect of different body positions on arterial oxygenation was evaluated. A combination of the following drugs was used: an opioid (etorphine or thiafentanil), azaperone and an α2-adrenoceptor agonist (detomidine or xylazine). Respiratory and heart rates, rectal temperature and pulse oximetry–derived haemoglobin oxygen saturation were recorded. Serial arterial blood samples were analysed immediately in the field. Marked hypoxaemia and hypercapnia were recorded in immobilised free-ranging black rhinoceroses. Arterial oxygenation was higher during sternal compared to lateral recumbency. Most rhinoceroses developed acidaemia of respiratory and metabolic origin. Initially high lactate concentrations in free-ranging rhinoceroses decreased during immobilisation. Pulse oximetry was unreliable in the detection of hypoxaemia. Positioning in sternal recumbency and routine use of oxygen supplementation are recommended in the management of immobilised rhinoceroses as measures to improve arterial oxygenation.

5-HT2A receptor SPECT imaging with [123I]R91150 under P-gp inhibition with tariquidar: More is better?

IntroductionPharmacological P-glycoprotein (P-gp) inhibition with tariquidar (TQD) is considered a promising strategy for the augmentation of radiotracer brain uptake. However, a region-dependent effect may compromise the robustness of quantitative studies. For this reason, we studied the effect of a TQD pretreatment on 5-HT2A imaging with [123I]R91150 and compared results with those obtained in Mdr1a knock-out (KO) rats. MethodsEx vivo autoradiography was performed in TQD (15mg/kg) pretreated wild-type (WT-TQD), Mdr1a knock-out (KO) and untreated WT rats for Specific Binding Ratio (SBR) estimation. In vivo dynamic SPECT imaging with serial arterial blood sampling was performed in the former two groups of rats and kinetic analysis was performed with a one tissue-compartment (1TC) model and the Specific Uptake Ratio (SUR). Results were analyzed statistically using repeated measures ANOVA. ResultsSBR values differed between WT-TQD, Mdr1a KO and WT rats in a region-dependent manner (p<0.0001). In vivo brain uptake of radiotracer did not differ between groups. Similarly, kinetic analysis provided distribution volume (VT) values that did not differ significantly between groups. SUR binding potential (BPND) values from both groups highly correlated with corresponding VT (r=0.970, p<0.0001 and r=0.962, p<0.0001, respectively). However, SUR measured over averaged images between 100 and 120min, using cerebellum as reference region, demonstrated values that were, by average, 2.99±0.53 times higher in the WT-TQD group, with the difference between groups being region-dependent (p<0.001). In addition, coefficient of variation of the SUR BPND values across brain regions was significantly higher in the WT-TQD rats (41.25%±9.63% versus 11.13%±5.59%, p<0.0001). ConclusionP-gp inhibition with TQD leads to region-dependent effect in the rat brain, with probably sub-optimal effect in cerebellum. This warrants attention when it is used as a reference region for quantitative studies.

Preliminary evaluation of MRI-derived input function for quantitative measurement of glucose metabolism in an integrated PET-MRI.

PET semi-quantitative methods such as relative uptake value can be robust but offer no biological information and do not account for intra-subject variability in tracer administration or clearance. Simultaneous multimodal measurements that combine PET and MRI not only permit crucial multiparametric measurements, it provides means of applying tracer kinetic modelling without the need for serial arterial blood sampling. In this study we adapted an image-derived input function (IDIF) method to improve characterization of glucose metabolism in an ongoing dementia study. Here we present preliminary results in a small group of frontotemporal dementia patients and controls. IDIF was obtained directly from dynamic PET data guided by regions of interest drawn on carotid vessels on high resolution T1-weighted MR Images. IDIF was corrected for contamination of non-arterial voxels. A validation of the method was performed in a porcine model in a PET-CT scanner comparing IDIF to direct arterial blood samples. Metabolic rate of glucose (CMRglc) was measured voxel-by-voxel in gray matter producing maps that were compared between groups. Net influx rate (Ki) and global mean CMRglc are reported. A good correlation (r = 0.9 p<0.0001) was found between corrected IDIF and input function measured from direct arterial blood sampling in the validation study. In 3 FTD and 3 controls, a trend towards hypometabolism was found in frontal, temporal and parietal lobes similar to significant differences previously reported by other groups. The global mean CMRglc and Ki observed in control subjects are in line with previous reports. In general, kinetic modelling of PET-FDG using an MR-IDIF can improve characterization of glucose metabolism in dementia. This method is feasible in multimodal studies that aim to combine PET molecular imaging with MRI as dynamic PET can be acquired along with multiple MRI measurements.

What is the potential role of transcutaneous carbon dioxide in guiding acute noninvasive ventilation?

Transcutaneous carbon dioxide (PtcCO2 ) monitoring is rarely used in the acute hospital setting, where serial samples of arterial blood are instead taken to measure carbon dioxide tension (PaCO2 ). In this pilot observational study, we assessed the potential of PtcCO2 monitoring to calculate pH and guide management of acute noninvasive ventilation (NIV). Ten subjects with acute hypercapnic respiratory failure were recruited. All had arterial lines placed to guide acute NIV. PtcCO2 was monitored for 12 h (TOSCA TCM4) and compared with PaCO2 . Noninvasive transcutaneous pH was determined from PtcCO2 and calculated bicarbonate and then compared with true arterial pH. Agreements between PCO2 and pH methods were assessed using Bland-Altman analysis of limits of agreement and Pearson correlation coefficients. Hypothetical adjustments to acute NIV settings were based on transcutaneous data alone and evaluated in comparison with true management. Pain scores for each method were compared using the Wilcoxon signed-rank test. PCO2 time trends were concordant. Mean PCO2 bias was -2.33 (95% limits of agreement of -9.60 to 5.03) mm Hg, and r = 0.89 (P < .001). Mean pH bias was 0.012 (95% limits of agreement of -0.070 to 0.094), and r = 0.84 (P < .001). Hypothetical clinical decisions based on transcutaneous data alone matched true management on 85% of 34 occasions. Initiation of transcutaneous monitoring was less painful than the arterial equivalent (P = .008). This pilot study demonstrates that PtcCO2 monitoring provides a continuous and reliable trend and also allows pH prediction. This patient-friendly approach is a promising alternative to repeated arterial blood gas sampling in patients requiring NIV for acute hypercapnic respiratory failure.

Evaluation of [11C]oseltamivir uptake into the brain during immune activation by systemic polyinosine-polycytidylic acid injection: a quantitative PET study using juvenile monkey models of viral infection

BackgroundAbnormal behaviors of young patients after taking the anti-influenza agent oseltamivir (Tamiflu®, F. Hoffmann-La Roche, Ltd., Basel, Switzerland) have been suspected as neuropsychiatric adverse events (NPAEs). Immune response to viral infection is suspected to cause elevation of drug concentration in the brain of adolescents. In the present study, the effect of innate immune activation on the brain uptake of [11C]oseltamivir was quantitatively evaluated in juvenile monkeys.MethodsThree 2-year-old monkeys underwent positron emission tomography (PET) scans at baseline and immune-activated conditions. Both scans were conducted under pre-dosing of clinically relevant oseltamivir. The immune activation condition was induced by the intravenous administration of polyinosine-polycytidylic acid (poly I:C). Dynamic [11C]oseltamivir PET scan and serial arterial blood sampling were performed to obtain [11C]oseltamivir kinetics. Brain uptake of [11C]oseltamivr was evaluated by its normalized brain concentration, brain-to-plasma concentration ratio, and plasma-to-brain transfer rate. Plasma pro-inflammatory cytokine levels were also measured.ResultsPlasma interleukin-6 was elevated after intravenous administration of poly I:C in all monkeys. Brain radioactivity was uniform both at baseline and under poly I:C treatment. The mean brain concentrations of [11C]oseltamivir were 0.0033 and 0.0035% ID/cm3 × kg, the mean brain-to-plasma concentration ratios were 0.58 and 0.65, and the plasma-to-brain transfer rates were 0.0047 and 0.0051 mL/min/cm3 for baseline and poly I:C treatment, respectively. Although these parameters were slightly changed by immune activation, the change was not notable.ConclusionsThe brain uptake of [11C]oseltamivir was unchanged by poly I:C treatment in juvenile monkeys. This study demonstrated that the innate immune response similar to the immune activation of influenza would not notably change the brain concentration of oseltamivir in juvenile monkeys.

Challenges of a mechanistic feedback model describing nicotinic acid-induced changes in non-esterified fatty acids in rats

Previously, we developed a feedback model to describe the tolerance and oscillatory rebound of non-esterified fatty acid (NEFA) plasma concentrations in male Sprague Dawley rats after intravenous infusions of nicotinic acid (NiAc). This study challenges that model, using the following regimens of intravenous and oral NiAc dosing in male Sprague Dawley rats (n = 95) to create different patterns of exposure: (A) 30 min infusion at 0, 1, 5 or 20 μmol kg(-1) body weight; (B) 300 min infusion at 0, 5, 10 or 51 μmol kg(-1); (C) 30 min infusion at 5 μmol kg(-1), followed by a stepwise decrease in rate every 10 min for 180 min; (D) 30 min infusion at 5 μmol kg(-1), followed by a stepwise decrease in rate every 10 min for 180 min and another 30 min infusion at 5 μmol kg(-1) from 210 to 240 min; (E) an oral dose of 0, 24.4, 81.2 or 812 μmol kg(-1). Serial arterial blood samples were taken for measurement of plasma NiAc and NEFA concentrations. The gradual decrease in infusion rate in (C) and (D) were also designed to test the hypothesis that a gradual reduction in NiAc plasma concentration may be expected to reduce or prevent rebound. The absorption of NiAc was described by parallel linear and non-linear processes and the disposition of NiAc by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. NEFA (R) turnover, which was driven by the plasma concentration of NiAc via an inhibitory drug-mechanism function acting on NEFA formation, was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M 1) inhibited the formation of R and the last compartment (M N ) stimulated the loss of R. All processes regulating the plasma NEFA concentration were assumed to be captured by the moderator function. Data were analyzed using non-linear mixed effects modeling (NONMEM). The potency IC 50 of NiAc was 68 nmol L(-1), the fractional turnover rate k out 0.27 L mmol(-1) min(-1), and the turnover rate of moderator k tol 0.023 min(-1). The lower physiological limit of NEFA, which was modeled as a NiAc-independent release (k cap ) of NEFA into plasma, was estimated to 0.023 mmol L(-1) min(-1). The parameter estimates derived in this study were consistent with our previous estimates, suggesting that the model may be used for prediction of the NEFA response time-course following different modes and routes administration of NiAc or NiAc analogues. In order to avoid NiAc-induced NEFA rebound, a slow decline in the NiAc exposure pattern is needed at or below IC (50).