Contrast-Enhanced Ultrasonography-Based Hepatic Perfusion for Early Prediction of Prognosis in Acute Liver Failure.

BACKGROUND AND AIMS: Acute liver failure (ALF) is a rare but dramatic clinical syndrome characterized by massive hepatic necrosis leading to multiorgan failure. It is difficult to predict the outcomes in patients with ALF using existing prognostic models. We aimed to analyze hepatic perfusion using contrast-enhanced ultrasound and Doppler ultrasound in patients with ALF and investigate its utility as a prognostic biomarker. APPROACH AND RESULTS: In this prospective observational study, 208 patients with acute liver injury/ALF were enrolled from 2015 to 2019. We evaluated 50 consecutive patients with ALF with Doppler ultrasound and contrast-enhanced ultrasound performed on admission. The cases were divided into the following two groups: survivors (recovered without surgical intervention) and nonsurvivors (died of ALF or underwent liver transplantation). The time to peak and peak intensity of hepatic artery, portal vein, hepatic vein, and liver parenchyma were calculated using the time-intensity curve analysis. The hepatic artery (HA) resistive index was calculated using the fast Fourier transform analysis of Doppler ultrasound. The time interval (TI) between the time to peak of HA and liver parenchyma (LP) was significantly shorter in the nonsurvivors than in the survivors (P < 0.0001). The area under the receiver operating curve values for TI (HA, LP), Japanese scoring system, HE prediction model, Model for End-Stage Liver Disease score, and King's College Hospital criteria for the prediction of poor prognosis were 0.953, 0.914, 0.861, 0.816, and 0.731, respectively. The most appropriate cutoff value of TI (HA, LP) was 6.897 seconds; the sensitivity, specificity, positive and negative predictive values were 94.4%, 90.6%, 85.0%, and 96.7%, respectively. CONCLUSIONS: TI (HA, LP) accurately predicts the outcome in patients with ALF and may be useful in clinical decision making.

A Novel Method for Assessing Cardiac Output With the Use of Oxygen Circulation Time.

BACKGROUND: We investigated whether a simple breath hold would yield dynamic oxygen (O2) saturation change and whether the derived circulation time would be useful in assessing cardiac function. METHODS AND RESULTS: Patients undergoing right heart catheterization for clinical indications (n = 48), including heart failure (HF; n = 24), were prospectively recruited. Each subject was instructed to hold their breath for 20-40 seconds. Lung to finger circulation time (LFCT), defined as the time from the point of rebreathing to nadir O2 desaturation, was correlated with cardiac output. Among 48 subjects recruited, 37 manifested ≥3% O2 desaturation allowing for an LFCT measurement. Mean LFCT was 38.5 ± 17.5 seconds (range 18.9-94.7 s). LFCT in patients with a clinical diagnosis of HF was significantly longer than those without (45.9 ± 19.9 s vs 31.5 ± 11.5 s; P = .01). Overall, the LFCT was inversely correlated with cardiac output (Fick: r = -0.56; P < .001 [n = 37]; thermodilution: r = -0.6; P = .001 [n = 27]). CONCLUSIONS: LFCT is prolonged in low cardiac output. LFCT is a novel method that may be useful to noninvasively assess cardiac function in HF.

Improved Accuracy of Automated Estimation of Cardiac Output Using Circulation Time in Patients with Heart Failure.

BACKGROUND: Lung-to-finger circulation time of oxygenated blood during nocturnal periodic breathing in heart failure patients measured using polysomnography correlates negatively with cardiac function but possesses limited accuracy for cardiac output (CO) estimation. METHODS AND RESULTS: CO was recalculated from lung-to-finger circulation time using a multivariable linear model with information on age and average overnight heart rate in 25 patients who underwent evaluation of heart failure. The multivariable model decreased the percentage error to 22.3% relative to invasive CO measured during cardiac catheterization. CONCLUSIONS: This improved automated noninvasive CO estimation using multiple variables meets a recently proposed performance criterion for clinical acceptability of noninvasive CO estimation, and compares very favorably with other available methods.

Detection of delayed cerebral ischemia (DCI) in subarachnoid haemorrhage applying near-infrared spectroscopy: elimination of the extracerebral signal by transcutaneous and intraparenchymatous measurements in parallel.

BACKGROUND: Detection of delayed cerebral ischemia (DCI) in high-grade subarachnoid haemorrhage (SAH) is an unsolved issue. Conventional near-infrared spectroscopy (NIRS) with optodes applied over the skin is controversial because the NIRS signal is contaminated by extracerebral tissue. The objective is to quantify and subtract the contribution from extracerebral tissue from the signal by using measurements in parallel with a NIRS brain tissue probe and conventional NIRS. METHODS: In a patient with high-grade SAH, two approaches for NIRS were applied. First, a conventional brain tissue probe for intracranial pressure (ICP) monitoring, supplied by optical fibres, was placed into the brain tissue 2 cm deep from the dura. Second, for conventional NIRS, a plaster-based patch carrying optodes (one emitter, two detectors) was attached to the skin. Central venous injections of 0.3 mg/kg body weight (bw) indocyanine green (ICG) were performed. ICG dye dilution curves obtained with the probe and patch were collected simultaneously and analysed for blood flow values. RESULTS: Twelve measurements in parallel with the probe and patch were performed. Mean cerebral blood flow (CBF) for the probe was higher (24.8 ± 9.1 ml/100 g/min) compared with the values obtained with the patch (for detector 1, extra-cerebral blood flow [ECBF] mean 5.1 ± 1.8 ml/100 g/min; p = 0.002; for detector 2, 6.6 ± 2.1 ml/100 g/min; p = 0.002). CBF values obtained with the probe correlated with blood flow values obtained with the patch (for CBF vs. ECBF detector 1, r = 0.72 [p = 0.008]; ECBF detector 2, r = 0.79 [p = 0.002]). CONCLUSIONS: Blood flow values obtained with conventional NIRS correlated significantly with absolute CBF values obtained directly within the brain tissue. Simultaneous measurements with the NeMo Probe and NeMo Patch allow quantification and subtraction of the contribution from extracerebral tissues from the signal obtained with conventional NIRS.

Relationship between angiographic vasospasm, cerebral blood flow, and cerebral infarction after subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) and cerebral infarction are major contributors to poor functional recovery after subarachnoid hemorrhage (SAH). Cerebral vasospasm, the narrowing of proximal intracranial arteries after SAH, has long been assumed to be the primary cause of DCI, and has therefore been the primary therapeutic target in attempts to diminish disability after SAH. However, emerging evidence has questioned the strength and causality of the relationship between vasospasm and DCI. To address this fundamental question, we performed two parallel studies assessing the relationship between the presence of vasospasm in a vascular territory and both regional reductions in cerebral blood flow (CBF) and development of cerebral infarction.In a cohort of SAH patients at high-risk for DCI, we identified regions of hypoperfusion using positron emission tomography (PET) and compared their distribution with territories exhibiting vasospasm on concurrent angiography. We found that regional hypoperfusion was common in the absence of proximal vasospasm and that some patients without any significant vasospasm still could have hypoperfused brain regions. Similarly, our parallel study demonstrated that both patients and brain territories without vasospasm could develop delayed cerebral infarction, and that such vasospasm-independent infarcts account for more than a quarter of the infarct burden from DCI. These findings suggest that other processes, perhaps at a microvascular level, contribute at least part of the burden of DCI and future interventions should also address these other pathophysiologic processes.

Computed tomography-guided screening of surfactant effect on blood circulation time of emulsions: application to the design of an emulsion formulation for paclitaxel.

PURPOSE: In an effort to apply the imaging techniques currently used in disease diagnosis for monitoring the pharmacokinetics and biodisposition of particulate drug carriers, we sought to use computed tomography (CT) scanning methodology to investigate the impact of surfactant on the blood residence time of emulsions. METHODS: We prepared the iodinated oil Lipiodol emulsions with different compositions of surfactants and investigated the impact of surfactant on the blood residence time of emulsions by CT scanning. RESULTS: The blood circulation time of emulsions was prolonged by including Tween 80 or DSPE-PEG (polyethylene glycol 2000) in emulsions. Tween 80 was less effective than DSPE-PEG in terms of prolongation effect, but the blood circulating time of emulsions was prolonged in a Tween 80 content-dependent manner. As a proof-of-concept demonstration of the usefulness of CT-guided screening in the process of formulating drugs that need to be loaded in emulsions, paclitaxel was loaded in emulsions prepared with 87 or 65% Tween 80-containing surfactant mixtures. A pharmacokinetics study showed that paclitaxel loaded in 87% Tween 80 emulsions circulated longer in the bloodstream compared to those in 65% Tween 80 emulsions, as predicted by CT imaging. CONCLUSIONS: CT-visible, Lipiodol emulsions enabled the simple evaluation of surfactant composition effects on the biodisposition of emulsions.

Physiologically based structure of mean residence time.

A mean residence time (MRT) is an important pharmacokinetic parameter. To the author's knowledge, however, a physiologically based structure of MRT (thereafter MRT structure) has not been published so far. Primarily this is because MRT structures cannot be identified by traditional pharmacokinetic methods used for the determination of MRT. Therefore, tools from the theory of linear dynamic systems were used for the structural identification of MRT in this study. The MRT structure identified is physiologically meaningful. Accordingly, it seems that the MRT structure identified may contribute to already established knowledge about MRT.

Investigating the effect of polymeric approaches on circulation time and physical properties of nanobubbles.

PURPOSE: A challenge in the field of nanobubbles, including lipobubbles and polymeric nanobubbles, is identification of formulation approaches to enhance circulation time or "bubble life" in the specific organ to allow for organ visualization. The aim of this study was to investigate the potential of two specific preparation approaches, polymeric surface modification to lipobubbles and a one-step approach for the preparation of ionotropically originated polymeric hydrogel nanobubbles for the production of biocompatible, biodegradable, and sufficiently echogenic ('flexible') bubbles, preferably within the nanometer range, that possess an enhanced in vivo lifetime compared to an unmodified lipobubble to allow visualization of the lymph node vasculature. METHODS: In the first approach, formed liposomes (basic and polymerically enhanced) were sequentially layered with appropriate cationic and anionic polyelectrolytes followed by transformation into polymer-coated nanobubbles. In addition, a one-step approach was employed for the fabrication of ionotropically originated polymeric hydrogel bubbles. RESULTS: Bubble lifetime was marginally enhanced by self-deposition of polyelectrolytes onto the normal lipobubble, however, not significantly (P = 0.0634). In general, formulations possessing a higher ratio of anionic:cationic coats and highly anionic overall surface charge (-20.62 mV to -17.54 mV) possessed an enhanced lifetime. The improvement in bubble lifetime was significant when a purely polymeric polyionic hydrogel bubble shell was instituted compared to a normal unmodified lipobubble (P = 0.004). There was enhanced persistence of these systems compared to lipobubbles, attributed to the highly flexible, interconnected hydrogel shell which minimized gas leakage. The prolonged contrast signal may also be attributed to a degree of polymeric deposition/endothelial attachment. CONCLUSIONS: This study identified the relevance of polymeric modifications to nanobubbles for an improved circulating lifetime, which would be essential for application of these systems in passive drug or gene targeting via the enhanced permeability and retention effect.

Lung-to-finger circulation time can be measured stably with high reproducibility by simple breath holding method in cardiac patients.

Lung to finger circulation time (LFCT) has been used to estimate cardiac function. We developed a new LFCT measurement device using a laser sensor at fingertip. We measured LFCT by measuring time from re-breathing after 20 s of breath hold to the nadir of the difference of transmitted red light and infrared light, which corresponds to percutaneous oxygen saturation. Fifty patients with heart failure were enrolled. The intrasubject stability of the measurement was assessed by the intraclass correlation coefficient (ICC). The ICC calculated from 44 cases was 0.85 (95% confidence interval: 0.77-0.91), which means to have "Excellent reliability." By measuring twice, at least one clear LFCT value was obtained in 89.1% of patients and the overall measurability was 95.7%. We conducted all LFCT measurements safely. High ICCs were obtained even after dividing patients according to age, cardiac index (CI); 0.85 and 0.84 (≥ 75 or < 75 years group, respectively), 0.81 and 0.84 (N = 26, ≥ or < 2.2 L/min/M2). These results show that our new method to measure LFCT is highly stable and feasible for any type of heart failure patients.

Rapid and local autoregulation of cerebrovascular blood flow: a deep-brain imaging study in the mouse.

The brain obtains energy by keeping the cerebral blood flow constant against unexpected changes in systemic blood pressure. Although this homeostatic mechanism is widely known as cerebrovascular autoregulation, it is not understood how widely and how robustly it works in the brain. Using a needle-like objective lens designed for deep-tissue imaging, we quantified the degree of autoregulation in the mouse hippocampus with single-capillary resolution. On average, hippocampal blood flow exhibited autoregulation over a comparatively broad range of arterial blood pressure and did not significantly respond to pressure changes induced by the pharmacological activation of autonomic nervous system receptors, whereas peripheral tissues showed linear blood flow changes. At the level of individual capillaries, however, about 40% of hippocampal capillaries did not undergo rapid autoregulation. This heterogeneity suggests the presence of a local baroreflex system to implement cerebral autoregulation.

Cerebral blood flow in immediate and sustained anxiety.

The goal of this study was to compare cerebral blood flow (CBF) changes associated with phasic cued fear versus those associated with sustained contextual anxiety. Positron emission tomography images of CBF were acquired using [O-15]H2O in 17 healthy human subjects as they anticipated unpleasant electric shocks that were administered predictably (signaled by a visual cue) or unpredictably (threatened by the context). Presentation of the cue in either threat condition was associated with increased CBF in the left amygdala. A cue that specifically predicted the shock was associated with CBF increases in the ventral prefrontal cortex (PFC), hypothalamus, anterior cingulate cortex, left insula, and bilateral putamen. The sustained threat context increased CBF in the right hippocampus, mid-cingulate gyrus, subgenual PFC, midbrain periaqueductal gray, thalamus, bilateral ventral striatum, and parieto-occipital cortex. This study showed distinct neuronal networks involved in cued fear and contextual anxiety underlying the importance of this distinction for studies on the pathophysiology of anxiety disorders.

PET O-15 cerebral blood flow and metabolism after acute stroke in spontaneously hypertensive rats.

Hypertension is a major stroke risk factor and is correlated with worse outcome after stroke. Thus, the effects of hypertension on cerebral hemodynamics and metabolism within an hour after stroke must be evaluated in detail. Cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate for oxygen (CMRO2) and cerebral metabolic rate for glucose (CMRglc) were measured 1 h after the occlusion of the right middle cerebral artery (MCA) in male spontaneously hypertensive rats (SHR) and male normotensive Wistar Kyoto rats (WKY). Physiological responses were determined by positron emission tomography (PET) using 15O-H2O and radiolabeled 15O-O2 blood (methodology previously developed in this laboratory) and by autoradiography (ARG) using 18F-FDG. The right hemisphere of SHR showed lower CBF values than the left hemisphere after stroke (right: 0.17+/-0.07 mL/min/g; left: 0.29+/-0.08 mL/min/g), CMRO2 (right: 2.55+/-0.80 mL/min/100 g; left: 4.11+/- 0.84 mL/min/100 g) and CMRglc (right: 52.4+/-16.2 mg/min/100 g; left: 65.6+/-10.2 mg/min/100 g). WKY rats exhibited significant decreases only in CBF and CMRO2. These results suggest greater underlying physiologic disturbances in SHR. Also, the occlusion significantly reduced CBF in both hemispheres of SHR compared with WKY, suggesting a disturbance of the autoregulatory mechanism in SHR. In summary, our results indicate that hypertension intensifies metabolic disturbances after the onset of stroke, at least in the first hour. Therefore, we suggest that hypertension not only increases the incidence of stroke but also exacerbates stroke-mediated damage.

Endothelin-1 and cerebral blood flow in a porcine model.

The purpose of the study was to investigate whether provoked changes of cerebral perfusion pressure and arterial carbon dioxide tension are able to influence the cerebral metabolism of endothelin-1 (ET-1) in a porcine model. Brain tissue oxygen tension, regional cerebral blood flow and mean arterial blood pressure were monitored in 10 healthy pigs during induced hyperventilation (HV), hypertension (HrT) and hypotension (HoT). ET-1 was determined in the arterial and cerebrovenous blood. Microdialysis samples (lactate, glucose and pyruvate) were taken from brain and subcutaneous tissue. A significant decrease (p<0.05) of the arterial ET-1 (1.46+/-0.33 fmol/mL) compared to the baseline (2.18+/-0.36 fmol/mL) was observed after the HoT-period. We detected a positive correlation between cerebrovenous ET-1 and extracellular cerebral glucose (0.68; p<0.05) after the baseline as well as a negative correlation of -0.81 (p<0.005) between the cerebrovenous ET-1 level and the extracellular cerebral lactate after the HoT-period. These data imply that with increasingly pathological changes of the cerebral metabolism endothelin becomes progressively more important in the regulation of cerebral vascular tone.

Difference in Cerebral Circulation Time between Subtypes of Moyamoya Disease and Moyamoya Syndrome.

In this study, we evaluated the differences in hemodynamics between hemorrhagic and non-hemorrhagic moyamoya disease (MMD) and moyamoya syndrome (MMS) by measuring cerebral circulation time (CCT). This case-control study included 136 patients with MMD or MMS diagnosed between April 2015 and July 2016 at Beijing Tian Tan Hospital. Each hemisphere was analyzed separately. The difference in clinical, radiological characteristics and CCT between subtypes of MMD and MMS were analyzed statistically. The results showed that total CCT between hemorrhagic and non-hemorrhagic sides was not statistically different (16.55 s vs. 16.06 s, P = 0.562). The cerebral filling circulation time (CFCT) of hemorrhagic sides was significantly shorter than that of non-hemorrhagic sides (4.52 s vs. 5.41 s, P < 0.001), and the cerebral venous circulation time (CVCT) of hemorrhagic sides was significantly longer than that of non-hemorrhagic sides (12.02 s, vs. 10.64 s, P < 0.001). The ratio of CFCT to CVCT (F-V ratio) was inversely correlated with the possibility of hemorrhagic stroke. Therefore, we conclude that the rapid filling and poor venous drainage of cerebral circulation are likely risk factors of hemorrhagic stroke secondary to MMD or MMS. The F-V ratio can be used to identify individuals at high risk of hemorrhagic stroke.

The intraluminal thread model revisited: rat strain differences in local cerebral blood flow.

There are major differences in the outcome of focal cerebral ischemia between rat strains. This study aimed to investigate whether inter-strain differences exist in the local cerebral blood flow, changes produced by intraluminal middle cerebral artery occlusion (MCAO). Fifty-four male Long-Evans, Sprague-Dawley or Wistar rats were subjected to 60 minutes of transient MCAO, carried out with a silicone-coated 4-0 nylon monofilament. Local cerebral blood flow was monitored on the parietal cortex with laser-Doppler flowmetry. The decrease in local cerebral blood flow during the first 20 minutes of occlusion was significantly greater in Long-Evans (74.6 +/- 8.9%) than in Sprague-Dawley (50.7 +/- 26.8%) and Wistar (49.0 +/- 21.9%) rats. Strain differences in local cerebral blood flow reduction were maintained, or increased, throughout the occlusion period. These results show that the intraluminal model of MCAO produces a more pronounced, persistent and stable local cerebral blood flow reduction, with less interanimal variability, in Long-Evans than in Sprague-Dawley or Wistar rats.

Determination of blood circulation times of superparamagnetic iron oxide nanoparticles by T2* relaxometry using ultrashort echo time (UTE) MRI.

Blood circulation is an important determinant of the biodistribution of superparamagnetic iron oxide nanoparticles. Here we present a magnetic resonance imaging (MRI) technique based on the use of ultrafast echo times (UTE) for the noninvasive determination of blood half-lives at high particle concentrations, when conventional pulse sequences fail to produce a useful MR signal. Four differently coated iron oxide nanoparticles were administered intravenously at a dose of 500 µmol Fe/kg bodyweight and UTE images of C57BL/6 mice were acquired on a 1-T ICON scanner (Bruker). T2* relaxometry was done by acquiring UTE images with echo times of 0.1, 0.8 and 1.6 ms. Blood circulation time was then determined by fitting an exponential curve to the time course of the measured relaxation rates. Circulation time was shortest for particles coated with malic acid (t1/2=23 min) and longest for particles coated with tartaric acid (t1/2=63 min). UTE-based T2* relaxometry allows noninvasive determination of blood circulation time and is especially useful when high particle concentrations are present.

A nanoparticle-encapsulated non-nucleoside reverse-transcriptase inhibitor with enhanced anti-HIV-1 activity and prolonged circulation time in plasma.

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs), major components of highly active antiretroviral therapy (HAART), are effective in suppressing viral replication and preventing the progress of HIV-1 infection to AIDS. However, rapid blood clearance in vivo could significantly impair the efficiency of the anti-HIV-1 activity and result in multiple daily doses which might lead to poor patient compliance. Here we attempted to employ biodegradable organic nanoparticles (NPs) to encapsulate DAAN15h, a derivative of 4-substituted 1, 5-diarylaniline with potent anti-HIV activities. Nanoparticles encapsulating DAAN15h (NP-DAAN15h) displayed a spherical shape with a size of 97.01 ± 3.64 nm and zeta potential of -19.1 ± 3.78 mV, and they exhibited a sustained controlled release behavior in vitro. The cellular uptake of NPs on TZM-b1 cells, MT-2 cells and M7 cells, possibly through lipid raft-mediated and energydependent active transport processes, was significantly enhanced. NP-DAAN15h, which possessed no significant in vitro cytotoxicity, showed improved antiviral activity against laboratory-adapted and primary HIV-1 isolates with different subtypes and tropisms, including RT-resistant variants. NP-DAAN15h exhibited a significantly prolonged blood circulation time, decreased plasma elimination rate, and enhanced AUC(0-t). NP-DAAN15h, a nanoparticle-encapsulated NNRTI, exhibits enhanced cellular uptake, improved anti-HIV-1 efficacy and prolonged in vivo circulation time, suggesting good potential for further development as a new NNRTI formulation for clinical use.

Reproducibility of the blood flow index as noninvasive, bedside estimation of cerebral blood flow.

OBJECTIVE: To investigate the feasibility and reproducibility of the blood flow index (BFI) method for measuring cerebral blood flow. DESIGN AND SETTING: Prospective functional study in pediatric intensive care. PATIENTS AND PARTICIPANTS: 14 consecutive patients with median age of 2 months (range 1 days-11 years) requiring artificial ventilation, invasive arterial blood pressure monitoring, and central venous access. INTERVENTIONS: The first passage of an intravenous indocyanine green (ICG) bolus through the cerebral vasculature was monitored by noninvasive near-infrared spectroscopy. BFI was calculated by dividing maximal ICG absorption change by rise time. Reproducibility was evaluated by six ICG injections at 5-min intervals. RESULTS: Of all ICG injections 6% were canceled, and 4% were eliminated due to injection failures. Median BFI of 17 reproducibility determinations was 71 (range 12-213) and median coefficient of variation (CV) of BFI was 10% (4.9-18.5). The quantity of ICG bolus did not affect the CV (0.1 vs. 0.3 mg ICG/kg). Eight reproducibility tests in patients after cardiac surgery had smaller CV than the others, and the eight in newborns had higher CV than in older children. Patient parameters such as arterial blood pressure, endtidal CO(2), and percutaneous oxygen saturation were stable and showed CV below 2% during reproducibility determination. CONCLUSIONS: The BFI method allows rapid and repeated measurements of CBF with good feasibility and reproducibility. As a relative but not absolute measure of CBF, BFI seems to be suited for clinical evaluation of intraindividual CBF changes during determination of cerebrovascular reactivities or during therapeutic interventions.