Injection Of Radioactive Microspheres Research Articles

Simplification strategies for a patient-specific CFD model of particle transport during liver radioembolization

BackgroundPatient-specific 3D computational fluid dynamics (CFD) simulations have been used previously to identify the impact of injection parameters (e.g. injection location, velocity, etc.) on the particle distribution and the tumor dose during transarterial injection of radioactive microspheres for treatment of hepatocellular carcinoma. However, these simulations are computationally costly, so we aim to evaluate whether these can be reliably simplified. MethodsWe identified and applied five simplification strategies (i.e. truncation, steady flow modelling, moderate and severe grid coarsening, and reducing the number of cardiac cycles) to a patient-specific CFD setup. Subsequently, we evaluated whether these strategies can be used to (1) accurately predict the CFD output (i.e. particle distribution and tumor dose) and (2) quantify the sensitivity of the model output to a specific injection parameter (injection flow rate). ResultsFor both accuracy and sensitivity purposes, moderate grid coarsening is the most reliable simplification strategy, allowing to predict the tumor dose with only a maximal deviation of 1.4 %, and a similar sensitivity (deviation of 0.7 %). The steady strategy performs the worst, with a maximal deviation in the tumor dose of 20 % and a difference in sensitivity of 10 %. ConclusionThe patient-specific 3D CFD simulations of this study can be reliably simplified by coarsening the grid, decreasing the computational time by roughly 45 %, which works especially well for sensitivity studies.

Safety of Radioembolization via the Cystic Artery in Patients with Hepatocellular Carcinoma and Parasitized Arterial Supply

PurposeTo evaluate the safety and effectiveness of radioembolization through the cystic artery supplying hepatocellular carcinoma (HCC) adjacent to the gallbladder. Materials and MethodsThis retrospective, single-center study included 24 patients who underwent radioembolization via the cystic artery between March 2017 and October 2022. The median tumor size was 8.3 cm (range, 3.4–20.4 cm). Twenty-two (92%) patients had Child-Pugh Class A disease, and 2 (8%) patients had Class B cirrhosis. Technical issues, adverse events, and tumor response were analyzed. ResultsInfusion of radioactive microspheres was performed from the main cystic artery (n = 6), the deep cystic artery (n = 9), and small feeders from the cystic artery (n = 9). The cystic artery supplied the primary index tumor in 21 patients. The median radiation activity delivered via the cystic artery was 0.19 GBq (range, 0.02–0.43 GBq). The median total radiation activity administered was 4.1 GBq (range, 0.9–10.8 GBq). There was no case of symptomatic cholecystitis requiring invasive intervention. One patient experienced abdominal pain during injection of radioactive microspheres via the cystic artery. Eleven (46%) patients received pain medication during or within 2 days of the procedure. Twelve (50%) patients had gallbladder wall thickening on a 1-month follow-up computed tomography scan. Based on follow-up imaging, 23 (96%) patients showed an objective response (complete or partial response) of the tumor supplied by the cystic artery. ConclusionRadioembolization via the cystic artery may be safe in patients with HCC partially supplied by the cystic artery.

Intraprocedural MRI-based dosimetry during transarterial radioembolization of liver tumours with holmium-166 microspheres (EMERITUS-1): a phase I trial towards adaptive, image-controlled treatment delivery

PurposeTransarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 (166Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing 166Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry.MethodsSix patients were treated with 166Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, 166Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for 166Ho TARE.ResultsAdministration of 166Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3–4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend.ConclusionThis study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization.RegistrationClinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered).

Development of an MRI-Guided Approach to Selective Internal Radiation Therapy Using Holmium-166 Microspheres.

Simple SummarySelective internal radiation therapy (SIRT) is a treatment for patients with liver cancer that involves the injection of radioactive microspheres into the liver artery. For a successful treatment, it is important that tumours are adequately covered with these microspheres; however, there is currently no method to assess this intraoperatively. As holmium microspheres are paramagnetic, MRI can be used to visualize the holmium deposition directly after administration, and possibly to adapt the treatment if necessary. In order to exploit this advantage and provide a personally optimized approach to SIRT, the administration could ideally be performed within a clinical MRI scanner. It is, however, unclear whether all materials (catheters, administration device) used during the procedure are safe for use in the MRI suite. Additionally, we explore the capability of MRI to visualize the microspheres in near real-time during injection, which would be a requirement for successful MRI-guided treatment. We further illustrate our findings with an initial patient case.Selective internal radiation therapy (SIRT) is a treatment modality for liver tumours during which radioactive microspheres are injected into the hepatic arterial tree. Holmium-166 (166Ho) microspheres used for SIRT can be visualized and quantified with MRI, potentially allowing for MRI guidance during SIRT. The purpose of this study was to investigate the MRI compatibility of two angiography catheters and a microcatheter typically used for SIRT, and to explore the detectability of 166Ho microspheres in a flow phantom using near real-time MRI. MR safety tests were performed at a 3 T MRI system according to American Society for Testing of Materials standard test methods. To assess the near real-time detectability of 166Ho microspheres, a flow phantom was placed in the MRI bore and perfused using a peristaltic pump, simulating the flow in the hepatic artery. Dynamic MR imaging was performed using a 2D FLASH sequence during injection of different concentrations of 166Ho microspheres. In the safety assessment, no significant heating (ΔTmax 0.7 °C) was found in any catheter, and no magnetic interaction was found in two out of three of the used catheters. Near real-time MRI visualization of 166Ho microsphere administration was feasible and depended on holmium concentration and vascular flow speed. Finally, we demonstrate preliminary imaging examples on the in vivo catheter visibility and near real-time imaging during 166Ho microsphere administration in an initial patient case treated with SIRT in a clinical 3 T MRI. These results support additional research to establish the feasibility and safety of this procedure in vivo and enable the further development of a personalized MRI-guided approach to SIRT.

Effects of ischemic preconditioning and arterial collateral flow on ST-segment elevation and QRS complex prolongation in a canine model of acute coronary occlusion

Background During acute myocardial infarction, both ST elevation and QRS distortion on the initial electrocardiogram (ECG) have been correlated with poorer prognosis. Studies in dogs and humans suggest that these ECG markers provide information about myocardial protection from both collateral blood flow and ischemic preconditioning. Methods In a protocol designed to precondition the heart with ischemia, we examined both ST-segment elevation and QRS complex prolongation in lead II of the ECG in 23 mongrel dogs during the first and fourth episode of 5 minutes of left circumflex artery occlusion. Myocardial collateral flow was measured during each of these episodes by injection of radioactive microspheres 2.5 minutes into the episode of ischemia. Results During ischemia, the degree of elevation of the ST segments was reduced markedly in hearts preconditioned with ischemia and/or in hearts with the greatest amounts of collateral arterial flow. During the first episode of ischemia, the ST segments increased to a similar extent in severe and moderate ischemia, but less in hearts in which the ischemia was mild. However, marked QRS prolongation was present only in hearts with severe ischemia, and decreased when the hearts were preconditioned. In addition, large ischemic beds exhibited the most marked QRS prolongation, whereas small but even severely ischemic beds showed little or no change in QRS duration. Conclusion Both ST elevation and QRS prolongation are reduced by the presence of collateral flow and ischemic preconditioning. The QRS complex merits further study as an important marker of the degree of myocardial protection during human acute myocardial ischemia/infarction.

Effect of androgen concentration on seminal vesicle blood flow in rats—establishment of new highly sensitive simultaneous androgen measurement method

Objectives To clarify the effect of androgen concentration on blood flow regulation in seminal vesicles and to identify the androgen most responsible for this effect. Methods The androgen concentrations in the seminal vesicles and the seminal vesicle blood flow were measured at 0, 3, 6, 12, 24, 48, and 72 hours after castration. The androgen concentration was measured with a newly developed highly sensitive simultaneous androgen quantification method that uses liquid chromatography-tandem mass spectrometry. The blood flow was measured with the radioactive microsphere injection method. The change in seminal vesicle blood flow in 6-hour castrated rats after administration of 3 mg/kg testosterone, 3 mg/kg dihydrotestosterone (DHT), 3 mg/kg dehydroepiandrosterone, or 3 mg/kg testosterone plus 20 mg/kg finasteride was evaluated. Results A correlation was observed between the DHT concentration and blood flow in the rat seminal vesicle after castration. The DHT concentration and blood flow decreased after castration to 31.6% and 37.9%, respectively, of the normal level at 6 hours. The decline in DHT concentration and blood flow decreased further thereafter to 2.2% and 18.1%, respectively, of the normal level at 72 hours. Both testosterone and DHT fully restored the organ blood flow in castrated rat seminal vesicles. However, the blood-flow-increasing effect of testosterone was attenuated by more than 50% when administered in combination with finasteride. Dehydroepiandrosterone did not increase seminal vesicle blood flow. Conclusions The results of our study showed a strong correlation between the organ DHT concentration and blood flow in rat seminal vesicles. Of the various androgens, the most active androgen in the regulation of seminal vesicle blood flow was DHT.

Hemodilution elevates cerebral blood flow and oxygen metabolism during cardiopulmonary bypass in piglets

Background Hemodilution continues to be widely used during cardiopulmonary bypass (CPB) for both adults and children. Previous studies with nonbypass models have suggested that an increase in cerebral blood flow (CBF) compensates for the reduced oxygen-carrying capacity; however, this increased CBF is achieved by an increase in cardiac output. We hypothesized that even with the fixed-flow perfusion of CPB, CBF would be increased during hemodilution. Methods Two experiments were conducted and analyzed separately. In each experiment, 10 piglets were randomized to two different groups, one with a total blood prime yielding a high hematocrit (25% or 30%), and the other with a crystalloid prime resulting in a low hematocrit (10% or 15%). Animals were cooled with pH-stat strategy at full flow (100 or 150 mL · kg −1 · min −1) to a nasopharyngeal temperature of 15°C, a period of low flow (50 mL · kg −1 · min −1) preceding deep hypothermic circulatory arrest (45 or 60 minutes), and a period of rewarming at full flow. Cerebral blood flow was measured at the beginning of CPB, at the end of cooling, at the end of low flow, 5 minutes after the start of rewarming, and at the end of rewarming by injection of radioactive microspheres. Results Mean arterial pressure was significantly greater with higher hematocrit at each time point ( p< 0.05). Cerebral blood flow and the cerebral metabolic rate of oxygen decreased during cooling and further during low flow bypass but were significantly greater with lower hematocrit during mild hypothermia and at the end of rewarming ( p< 0.05). Conclusions Hemodilution is associated with decreased perfusion pressure, increased CBF and increased the cerebral metabolic rate of oxygen during hypothermic CPB.

Extending fluorescent microsphere methods for regional organ blood flow to 13 simultaneous colors

Seven fluorescent microsphere colors can be used in a single experiment to estimate regional blood flow without correcting for spillover of emitted fluorescence. To extend the method to 13 colors, we compared the accuracy of three methods for spillover correction. Fixed wavelength intensities were corrected by matrix inversion, and synchronous scan spectra were corrected by least squares fit of an overdetermined system of linear equations and by least squares fit of a sum of Gaussian and Lorentzian functions. Correction methods were validated in pigs and sheep by simultaneous injections of radioactive microspheres and fluorescent microspheres of 7, 10, and 13 different colors. We induced extreme changes in flow to create regions with low fluorescent signals bound on either side by high fluorescent signals. Blood flow was determined by radioactivity and by fluorescence using both fixed excitation and emission wavelength pairs and synchronous scanning and then corrected for spillover. Correlation between fluorescent intensity and radioactivity were excellent for all three correction methods [R2 = 0.98 +/- 0.02 (mean +/- SD)]. Low-flow regions requiring large spillover correction had systematic errors for some color combinations in all methods. We conclude that for 13 fluorescent colors spillover error can be minimized so that all three correction methods provide accurate estimates of regional blood flow.

Distribution of pulmonary blood flow in the perfluorocarbon-filled lung.

Partial liquid ventilation (PLV) improves gas exchange in animal studies of lung injury. Perfluorocarbons (PFCs) are heavy liquids and are therefore preferentially delivered to the most dependent areas of lung. We hypothesised that improved oxygenation during PLV might be the consequence of a redistribution of pulmonary blood flow away from poorly ventilated, dependent alveoli, leading to improved ventilation/perfusion (V/Q) matching. This study investigated whether partially filling the lung with PFC would result in a redistribution of pulmonary blood flow. Prospective experimental study. Hospital research institute laboratory. Six anaesthetised pigs without lung injury. Animals were anaesthetised and ventilated (gas tidal volume 12 ml/kg, PEEP 5, FIO2 1.0, rate 16). Whilst the pigs were maintained in the supine position, regional pulmonary blood flow was measured during conventional gas ventilation and repeated during PLV. Flow to regions of lung was determined by injection of radioactive microspheres (Co(57), Sn(113), Sc(46)). Measurements were performed with ventilation held at end-expiratory pressure and, in two PLV animals only, repeated with ventilation held at peak inspiratory pressure. During conventional gas ventilation, blood flow followed a linear distribution with the highest flow to the most dependent lung. In the lung partially filled with PFC a diversion of blood flow away from the most dependent lung was seen (p = 0.007), resulting in a more uniform distribution of flow down the lung (p = 0.006). Linear regression analysis (r2 = 0.75) also confirmed a difference in distribution pattern. On applying an inspiratory hold to the liquid-containing lung, blood flow was redistributed back towards the dependent lung. Partially filling the lung with PFC results in a redistribution of pulmonary blood flow away from the dependent region of the lung. During PLV a different blood flow distribution may be seen between inspiration and expiration. The clinical significance of these findings has yet to be determined.

Endothelin-1 in the superior colliculus of rats induces depressor responses due to peripheral hemodynamic changes

Microinjection of endothelin-1 (ET-1; 10 pmol) into the superficial layer of the superior colliculus caused systemic and regional hemodynamic changes, as measured by injection of radioactive microspheres at the peak of the hypotensive effect of endothelin-1. Endothelin-1 decreased total peripheral resistance by 39 ± 2% (n = 5); the vascular resistances were decreased in the spleen, the mesentery, the large intestine and the small intestine. Moreover, we found that in consequence of the increased fraction of cardiac output received by the above organs, decreases in vascular resistances were associated with increases in blood flows in them. Interestingly, ET-1 also decreased the vascular resistances and increased the total blood flows in the kidneys. The haemodynamic changes induced by injection of endothelin-1 to the superior colliculus were associated with significant decreases in the mean arterial blood pressure (37 ± 4 mHg, n = 6) and no changes in heart rate. Exogenous ET-1, therefore, within the SC decreases blood pressure due to peripheral hemodynamic changes.

REDUCED EFFECT OF cGMP PHOSPHODIESTERASE ON O2 CONSUMPTION IN RENAL HYPERTENSION-INDUCED CARDIAC HYPERTROPHY IN RABBITS

S518 Introduction: Cyclic GMP (cGMP), has been shown to exert negative metabolic and functional effects on the heart [1]. It has also been demonstrated that changes in cGMP levels lead to inverse changes in myocardial O2 consumption (O2 Cons) [2]. However, the importance and actions of cGMP in cardiac hypertrophy have been little studied. We studied the effect of topically applied zaprinast, a specific inhibitor of cGMP phosphodiesterase (PDE), on myocardial O2 Cons in renal hypertension-induced cardiac hypertrophy. Methods: Renal hypertension (HTN) was induced in rabbits using the surgical procedure of one-kidney-one clip (1K1C). The animals were allowed to recover for 35 days. Four groups of anesthetized open-chest New Zealand rabbits (N=26) were utilized. An intra-atrial cannula was inserted to allow injection of radioactive microspheres for coronary blood flow measurements, and a catheter-tip transducer was introduced into left ventricle (LV). A data acquisition system was employed to record HR, aortic BP, LV BP and dP/dt. Either vehicle or zaprinast (3 mM) were topically applied to LV surface of control or 1K1C rabbits for 15 min. Coronary flow and O2 extraction (microspetrophotometry) were used to determine O2 Cons. Myocardial cGMP levels were determined by radioimmunoassay. Data were presented as Mean +/- S.E.M. ANOVA was used. Results: 1K1C rabbits had a greater heart wt-to-body wt ratios (2.94 +/- 0.08) than controls (2.58 +/- 0.17). Systolic BP was higher in 1K1C (102 +/- 9 mm Hg) than controls (86 +/- 3 mm Hg). Zaprinast significantly and similarly increased cGMP level (pmol/g) in both control subepicardium (EPI) (3.90 +/- 0.47 to 4.66 +/- 0.89) and subendocardium (ENDO) (5.08 +/- 0.69 to 7.06 +/- 1.36) and 1K1C hearts (5.53 +/- 0.61 to 7.48 +/- 1.51 for EPI and 6.48 +/- 0.42 to 8.88 +/- 1.08 for ENDO). Myocardial O2 Cons (ml O2/min/100 g) was significantly lower in the controls treated with zaprinast (EPI: 8.8 +/- 0.1; ENDO: 9.5 +/- 1.9) compared to controls treated with vehicle (EPI: 13.6 +/- 1.3; ENDO: 16.2 +/- 2.9). This effect was diminished in 1K1C rabbits treated with zaprinast (EPI: 10.3 +/- 2.4; ENDO: 11.2 +/- 2.6) compared to the vehicle treated 1K1C group (EPI: 13.3 +/- 1.2; ENDO: 14.5 +/- 2.4). Discussion: There was a similar increase in myocardial cGMP after treatment with zaprinast, but a greater depression of myocardial O2 consumption in the control animals compared to 1K1C after treatment with zaprinast. This suggested that the sensitivity of myocardial O2 consumption to increases in cGMP caused by inhibition of cGMP PDE was blunted by 1K1C cardiac hypertrophy.

Effects of serotonin on cerebral circulation after middle cerebral artery occlusion.

Serotonin (5-HT) produces constriction of peripheral collateral blood vessels. Using an animal model, the authors tested the hypothesis that 5-HT constricts collateral vessels in the cerebrum. A branch of the middle cerebral artery (MCA) was occluded proximally and cannulated distally in anesthetized dogs. Blood flow to the area at risk for infarction was detected by perfusing the cannulated MCA branch with microsphere-free blood during systemic injection of radioactive microspheres (shadow flow technique). Blood flow to collateral-dependent and normal cerebrum was measured during intravenous infusion of 5-HT (10 and 40 mg/kg/minute). Serotonin produced a dose-related reduction of blood flow to collateral-dependent cerebrum, increased collateral vessel resistance in large cerebral arteries and collateral vessels, and decreased cerebral artery perfusion pressure. In contrast, blood flow to normal cerebrum was not altered because a decrease in small vessel resistance effectively compensated for a decrease in MCA perfusion pressure. These findings indicate that 5-HT produces constriction of collateral vessels in the cerebrum. This response is clearly different from normal small cerebral vessels, which dilate during 5-HT infusion.

Effects of Thiopental on Regional Blood Flows in the Rat

The goal of this investigation was to characterize the effects of thiopental on cardia output and regional blood flows in the rat. Blood flows influence thiopental pharmacokinetics. Acquisition of these data may ultimately permit evaluation of the contribution of thiopental-induced alterations in regional blood flows to the disposition and hypnotic effect of this drug. Chronically instrumented unrestrained Wistar rats (n=20) aged 3-4 months received either a dose of thiopental sufficient to induce a brief period of unconsciousness (20 mg.kg(-1)) or a larger dose achieving electroencephalographic burst suppression (45 mg.kg(-1)). Cardiac output and blood flows to 14 tissues were determined at 4 times in each rat for a period of 420 min using injections of radioactive microspheres (expressed as mean +/- SD). Mean arterial pressure, heart rate, and blood gas tensions were determined at all measurement times. Arterial plasma concentrations were sampled at postinfusion times. No important changes in systemic cardiovascular measurements were detected after the smaller dose of thiopental. One minute after the larger dose, cardiac output decreased from baseline (123 +/- 14 to 84 +/- ml.min (-1), P< 0.01), flow to muscle and fat decreased, and muscle and fat resistance increased. At 5 min, compared to baseline, no difference in cardiac output was detected (123 +/- vs. 119 +/- ml.min (-1)), intestinal flows increased and intestinal resistances decreased. Cardiac output was again depressed at 30, 90, and 180 min. Brain blood flow decreased 25 +/- 19 % (P< 0.01) from baseline for the duration of the study. Thiopental acutely decreases cardiac output, and blood flows to muscle and fat tissue. The temporary return of cardiac output to baseline may be related to intestinal vasodilation. These blood flow alterations may influence the pharmacokinetics of thiopental.

Gender does not influence acute myocardial infarction in adult dogs

Mechanisms responsible for the well-documented “protection” against myocardial ischemia and infarction in young women and subsequent loss of protection after menopause remain speculative. One possibility is that gender-related variables (such as endogenous hormone levels or regular loss of stored iron) alter the susceptibility of the heart to ischemia: if so, then premenopausal women when compared with men may manifest endogenous protection against acute myocardial ischemic injury. Using the canine model we therefore sought to determine whether gender influences acute myocardial ischemia and infarction. Retrospective analysis was performed on data compiled from 60 mature adult dogs subjected to 1 hour of coronary artery occlusion and ≥4 hours of reperfusion. We first compared the incidence of lethal ventricular fibrillation in the male and female cohorts and then for survivors compared collateral blood flow during coronary occlusion (by injection of radioactive microspheres), infarct size (assessed by tetrazolium staining and expressed as a percentage of the myocardium at risk), and regional wall motion (by somomicrometry) in the infarct-related area. The incidence of lethal ventricular fibrillation was 23% in the male dogs and 19% in the female dogs ( p = 0.70, difference not significant). For survivors, the area at risk of infarction was comparable in males and females (23 ± 2% and 22% ± 1% of the total left ventricular weight), and the groups were equally ischemic during coronary occlusion, with collateral blood flow to the ischemic subendocardium averaging 0.05 ± 0.02 and 0.07 ± 0.01 ml/min/g tissue. There was no difference in infarct size between the two cohorts: area of necrosis was 17% ± 6% and 18% ± 3% of the myocardium at risk in the males and females, respectively. In addition, the groups were equally dyskinetic during occlusion and equally hypokinetic after reperfusion. We conclude that gender does not influence acute myocardial ischemia and infarction in the canine model.

Regional myocardial function during contiguous ischaemia in an anaesthetized canine model: comparison of six methods of measurement

During acute myocardial ischaemia, the function of the unaffected muscle is the primary determinant of residual cardiac performance. We compared six methods of measuring regional function in the remaining non-ischaemic segment after acute ligation of the left anterior descending (LAD) coronary artery in 16 dogs. Preparation included left ventricular micromanometers, regional sonomicrometer transducers to measure segment length and wall thickness, caval occluders and left atrial catheters for injection of radioactive microspheres to measure regional blood flow. Pulmonary artery, central venous and systemic arterial pressures were measured and regional coronary venous blood was collected for direct myocardial oxygen consumption (VO2) calculations. Under basal high-dose fentanyl-neuromuscular blocker anaesthesia, the LAD was occluded after addition of halothane or isoflurane at 0.5 or 1.5 MAC concentrations. Regional myocardial function of the non-ischaemic segment was assessed by the following computer-derived indices: percent systolic wall thickening (% WT), velocity of shortening (vs), percent systolic shortening (%SS), regional stroke work (RSW), regional preload recruitable stroke work (RPRSW) and regional end-systolic elastance (Ees). No index demonstrated enhanced function in the non-ischaemic segment after LAD ligation and all monitors, except Ees, were sensitive to depression of function represented by a decrease in values after administration of halothane and isoflurane (P < 0.05). Ees values increased with the addition of isoflurane and remained constant with halothane. Circulating concentrations of catecholamines were unchanged after ischaemia, while inhalation agents caused a decrease in the concentrations of adrenaline and dopamine (P < 0.05), but not noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Local Mitochondrial Enzyme Activity Correlates with Myocardial Blood Flow at Basal Workloads

To study whether heterogeneous myocardial blood flow relates to the local oxidative capacity of cardiac muscle, local blood flow at resting cardiac workloads and the activity of the mitochondrial enzyme succinate dehydrogenase (SDH) were determined in small regions of the left ventricle of seven anaesthetized, mechanically ventilated, open-chest pigs (25-35 kg). Following injection of radioactive microspheres (15 μm Ø) into the left atrium, the heart was rapidly excised and cut into five transverse slices, which were simultaneously freeze-clamped between two aluminum blocks precooled at -80°C. The left ventricle was then subdivided into 84 samples of about 0.9 g. Myocardial blood flow was 0.88 ± 0.34 ml/min/g wet weight (ww), and SDH activity 1.46 ± 0.33 μmol/min/g ww (mean ± S.D., n = 7). Local data were normalized to their respective mean values in each pig, and then pooled. Local blood flow ranged from 0.32 to 1.63 of the mean, and blood flow heterogeneity characterized by the coefficient of variation (CV=S.D./mean) was 18.4%. Normalized local SDH activity ranged from 0.16 to 1.94, with a CV of 21.8%, significantly exceeding measurement error (CV=4.5%). Local blood flows and SDH activities did not vary among transmural sublayers of the left ventricle, but variation within each sublayer was considerable. In six of the seven pigs, local blood flow correlated (P < 0.05) with SDH activity, with correlation coefficient (r) ranging from 0.26 to 0.54 (for pooled data: r=0.27, P < 0.0001). When expressed per gram dry weight, heterogeneity of SDH activity increased (P < 0.05), and here also local blood flow correlated with SDH activity in all pigs (for pooled data: r=0.45, P < 0.001). Hence, heterogeneity of mitochondrial capacity within cardiac muscle partly explains the heterogeneity of myocardial blood flow, even though myocardial perfusion at rest was studied in relation with a maximal enzyme rate. The low correlation coefficient clearly indicates that at resting workloads other factors also play a role.

Cerebral pressure-flow relationship during cardiopulmonary bypass in the dog at normothermia and moderate hypothermia.

We studied cerebral autoregulation by analyzing cerebral pressure-flow curves during cardiopulmonary bypass (CPB) with alpha-stat (alpha-stat) acid-base management at 28 (n = 9) and 37 degrees C (n = 9) in two groups of dogs. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were determined multiple times in each animal over an extensive range of cerebral perfusion pressure (CPP). The CPP was altered by changing perfusion flow rate. The dependence of CBF on CPP during normothermic and moderate hypothermic CPB was assessed using a block design analysis of covariance with CPP as the covariate. We anticipated maximal statistical power with this analysis to define if cerebral autoregulation was intact. This method of statistical analysis was compared with the conventional interpretation by linear regression analysis. Animals were administered sodium thiopental until an isoelectric electroencephalogram was obtained to assure stable depth of anesthesia independently of temperature effects. The animals were randomly assigned to either temperature group. The CBF was determined by injection of radioactive microspheres at each of five target CPPs randomly allocated (50, 60, 70, 80, and 90 mm Hg). The brain oxygen content difference was defined as arterial minus superior sagittal sinus (SSS) oxygen content. No difference in CPP, hemoglobin, arterial carbon dioxide tension, or pH was seen between groups at any time period. In both groups, total CBF (tCBF) increased significantly with increasing CPP (p = 0.012 and 0.017 for normothermic and hypothermic CPB, respectively; CPP as covariate). The between-group difference in slopes (CPP x temperature effect) approached statistical significance (p = 0.059).(ABSTRACT TRUNCATED AT 250 WORDS)

Conscious rabbits become tolerant to multiple episodes of ischemic preconditioning.

Although ischemic preconditioning protects myocardium from infarction in isolated hearts and in anesthetized open-chest animals, its effects have not been examined in unanesthetized animals. Furthermore, it is unknown whether animals become tolerant to multiple episodes of ischemic preconditioning. Rabbits were chronically instrumented with a balloon occluder around a major branch of the left coronary artery for reversible coronary occlusion, a left atrial catheter for radioactive microsphere injections, ECG electrodes for monitoring of myocardial ischemia, and, in some cases, a carotid artery catheter for pressure measurements and timed withdrawal of reference arterial blood samples. Eight control rabbits underwent a 30-minute coronary occlusion and then 180 minutes of reperfusion. Five of the eight rabbits developed ventricular tachycardia or fibrillation during ischemia, and infarct size averaged 37.7 +/- 2.6% of the risk area. Eight rabbits experienced a 5-minute coronary occlusion and 10 minutes of reperfusion before the 30-minute occlusion. In these preconditioned animals, potentially fatal arrhythmias during ischemia were significantly reduced (one of eight, P < .05), and infarct size was much smaller (5.6 +/- 1.1%, P < .0001). The difference could not be explained by hemodynamics or collateral blood flow, which were nearly identical in the two groups. But when the 30-minute coronary occlusion was preceded by 40 to 65 five-minute occlusions during a 3- to 4-day period in seven animals, protection was markedly attenuated. Potentially lethal arrhythmias were very common, and infarct size averaged 26.5 +/- 2.9%, substantially larger than in rabbits with only one preconditioning occlusion (P < .0001).(ABSTRACT TRUNCATED AT 250 WORDS)

NG-nitro L-arginine methyl ester: systemic and pulmonary haemodynamics, tissue blood flow and arteriovenous shunting in the pig.

The effects of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the endothelial nitric oxide (NO) biosynthesis, on systemic and pulmonary haemodynamics, and tissue as well as arteriovenous anastomotic blood flows were investigated in the anaesthetized pig, using simultaneous injections of radioactive microspheres of two different sizes (diameter: 15 and 50 microns). L-NAME (1, 3 and 10 mg.kg-1) reduced systemic and pulmonary artery conductance and cardiac output, but heart rate and mean arterial blood pressure remained unchanged. L-arginine reversed the systemic and pulmonary haemodynamic changes induced by L-NAME. As detected with 15 microns microspheres, L-NAME (1 and 3 mg.kg-1) decreased tissue blood flow to and vascular conductance in the eyes, lungs, atria, kidneys, adrenals and liver. Furthermore, the difference between blood flows simultaneously measured with 15 and 50 microns microspheres, which can be equated to blood flow through arteriovenous anastomoses with a diameter between about 28 and 90 microns, was reduced by L-NAME (3 mg.kg-1) in the skin of head and gluteal regions and, as indicated by the microsphere content of the lungs, in the total systemic circulation. These results suggest that in the anaesthetized pig (i) NO is involved in the regulation of both systemic and pulmonary vascular conductance, (ii) the decrease in systemic vascular conductance is in part due to constriction of systemic arteriovenous anastomoses, and (iii) the decrease in pulmonary vascular conductance, leading to reduction of cardiac output, seems to negate the expected rise in arterial blood pressure observed, for example, in rats and rabbits following inhibition of NO-synthesis.

Effect of coronary reocclusion after initial reperfusion on ventricular function and infarct size

Reocclusion of a coronary artery after thrombolytic therapy occurs in approximately 12% to 33% of patients; however, there are few experimental data concerning reocclusion. Accordingly, to compare the effects of reocclusion versus sustained occlusion on the myocardium, a canine model (n = 12) of 2 h of left circumflex artery occlusion, 1 h of reperfusion and 1 h of reocclusion was studied. In a control group (n = 11), 3 h of circumflex artery occlusion was followed by 1 h of reperfusion. As a result, both groups had the same total duration of ischemia (3 h) and reperfusion (1 h). Hemodynamic measurements, radioactive microsphere injections and two-dimensional echocardiography were performed at baseline, occlusion and reperfusion for both groups and at the end of reocclusion for the experimental group. In vivo risk area was determined with Evans blue dye and infarct size with triphenyltetrazolium staining methods.Similar decreases in myocardial blood flow after coronary occlusion and similar reperfusion blood flows occurred in both groups. Despite intervening reperfusion in the reocclusion group, no significant difference was found in the infarct size/risk area ratio between the reocclusion and control groups (54.5 ± 6.9% vs. 48.4 ± 5.1%, respectively, p = NS). Two-dimensional echocardiography demonstrated a similar degree and extent (159 ± 9 ° vs. 153 ± 12 °, p = NS) of left ventricular dysfunction with both the occlusion and reocclusion. In addition, there were no significant differences in global or regional left ventricular function between the two groups. However, reocclusion after reperfusion did produce a further deterioration in ischemic zone wall thickening (9.5 ± 2.0% to 0.7 ± 1.8%, p < 0.001).It is concluded that coronary reocdusion after initial reperfusion contributes to additional ischemic damage, so that the beneficial salvaging effects of reperfusion are negated. Furthermore, coronary reocdusion results in further ischemic dysfunction in the reperfused but hypokinetic myocardium.