Computer simulation of cerebrovascular circulation : assessment of intracranial hemodynamics during induction of anesthesia

The purpose of this project was to develop a computer model of cerebrovascular hemodynamics interacting with a pharmacokinetic drug model to examine the effects of various stimuli during anesthesia on cerebral blood flow and intracranial pressure. The mathematical model of intracranial hemodynamics is a seven compartment constant volume system. A series of resistances relate blood and cerebrospinal fluid fluxes to pressure gradients between compartments. Arterial, venous, and tissue compliance are also included. Autoregulation is modeled by transmural pressure dependent arterial-arteriolar resistance. The effect of a drug (thiopental) on cerebrovascular circulation was simulated by a variable arteriolar-capillary resistance. Thiopental concentration, in turn, was predicted by a three-compartment pharmacokinetic model. The effect site compartment was included to account for a disequilibrium between drug plasma and biophase concentrations. The model was validated by comparing simulation results with available experimental observations. The simulation program is written in VisSiM® dynamic simulation language for an IBM-compatible PC. The model developed was used to calculate cerebral blood flow and intracranial pressure changes which occur during the induction phase of general anesthesia. Responses to laryngoscopy and intubation were predicted for simulated patients with elevated intracranial pressure and nonautoregulated cerebral circulation. Simulation shows that the induction dose of thiopental reduces intracranial pressure up to 15%. The duration of this effect is limited to less than three minutes by rapid redistribution of thiopental and cerebral autoregulation. Subsequent laryngoscopy causes acute intracranial hypertension exceeding the initial intracranial pressure. Further simulation predicts that this untoward effect can be minimized by an additional dose of thiopental administered immediately prior to intubation. The presented simulation allows comparison of various drug administration schedules to control intracranial pressure and preserve cerebral blood flow during induction of anesthesia. The model developed can be extended to analyze more complex intraoperative events by adding new submodels

Impaired endothelial function of the retinal vasculature in hypertensive patients

<p><b>Background and Purpose:</b> Arterial hypertension constitutes a central factor in the pathogenesis of stroke. We examined endothelial function of the retinal vasculature as a model of the cerebral circulation.</p> <p><b>Methods:</b> Thirty-eight young subjects (19 hypertensive and 19 normotensive) were treated with the AT1-receptor blocker candesartan cilexetil and placebo, each over 7 days. Retinal capillary flow and blood flow velocity in the central retinal artery were assessed with scanning laser Doppler flowmetry and pulsed Doppler ultrasound, respectively. NG-monomethyl-L-arginine (L-NMMA) was infused to inhibit nitric oxide (NO) synthesis. Diffuse luminance flicker was applied to stimulate NO release.</p> <p><b>Results:</b> In normotensive subjects, L-NMMA decreased retinal capillary flow by 8.2%±13% (P<0.05) and flickering light increased mean blood flow velocity in the central retinal artery by 19%±29% (P<0.01). In contrast, no significant change to these provocative tests was seen in hypertensive subjects. Treatment with candesartan cilexetil restored a normal pattern of reactivity in retinal capillaries (L-NMMA: decrease in perfusion by 10%±17%, P<0.05) and the central retinal artery (flicker: increase in mean blood flow velocity by 42%±31%, P<0.001) in hypertensive patients.</p> <p><b>Conclusions:</b> Endothelial function of the retinal vasculature is impaired in early essential hypertension but can be improved by AT1-receptor blockade.</p&gt

Evidence for involvement of both IKCa and SKCa channels in hyperpolarizing responses of the rat middle cerebral artery

Endothelium-derived hyperpolarizing factor responses in the rat middle cerebral artery are blocked by inhibiting IKCa channels alone, contrasting with peripheral vessels where block of both IKCa and SKCa is required. As the contribution of IKCa and SKCa to endothelium-dependent hyperpolarization differs in peripheral arteries, depending on the level of arterial constriction, we investigated the possibility that SKCa might contribute to equivalent hyperpolarization in cerebral arteries under certain conditions. METHODS: Rat middle cerebral arteries (approximately 175 microm) were mounted in a wire myograph. The effect of KCa channel blockers on endothelium-dependent responses to the protease-activated receptor 2 agonist, SLIGRL (20 micromol/L), were then assessed as simultaneous changes in tension and membrane potential. These data were correlated with the distribution of arterial KCa channels revealed with immunohistochemistry. RESULTS: SLIGRL hyperpolarized and relaxed cerebral arteries undergoing variable levels of stretch-induced tone. The relaxation was unaffected by specific inhibitors of IKCa (TRAM-34, 1 micromol/L) or SKCa (apamin, 50 nmol/L) alone or in combination. In contrast, the associated smooth-muscle hyperpolarization was inhibited, but only with these blockers in combination. Blocking nitric oxide synthase (NOS) or guanylyl cyclase evoked smooth-muscle depolarization and constriction, with both hyperpolarization and relaxation to SLIGRL being abolished by TRAM-34 alone, whereas apamin had no effect. Immunolabeling showed SKCa and IKCa within the endothelium. CONCLUSIONS: In the absence of NO, IKCa underpins endothelium-dependent hyperpolarization and relaxation in cerebral arteries. However, when NOS is active SKCa contributes to hyperpolarization, whatever the extent of background contraction. These changes may have relevance in vascular disease states where NO release is compromised and when the levels of SKCa expression may be altered

Clinical and radiological recurrence after childhood arterial ischemic stroke

Background: Data on rates and risk factors for clinical and radiological recurrence of childhood arterial ischemic stroke (AIS) might inform secondary prevention strategies. Methods and Results: Consecutive Great Ormond Street Hospital patients with first AIS were identified retrospectively (1978–1990) and prospectively (1990–2000). Patients underwent repeat neuroimaging at the time of clinical recurrence or, if asymptomatic, at least 1 year after AIS. Cox and logistic regression analyses were used to explore the relationships between risk factors and clinical and radiological recurrence, respectively. A total of 212 patients were identified, of whom 97 had another prior diagnosis. Seventy-nine children had a clinical recurrence (29 strokes, 46 transient ischemic attacks [TIAs], 4 deaths with reinfarction 1 day to 11.5 years (median 267 days) later); after 5 years, 59% (95% confidence interval, 51% to 67%) were recurrence free. Moyamoya on angiography and low birth weight were independently associated with clinical recurrence in the whole group. Genetic thrombophilia was associated with clinical recurrence in previously healthy patients, independent of the presence of moyamoya. Sixty of 179 patients who had repeat neuroimaging had radiological reinfarction, which was clinically silent in 20. Previous TIA, bilateral infarction, prior diagnosis (specifically immunodeficiency), and leukocytosis were independently associated with reinfarction. Previous TIA and leukocytosis were also independently associated with clinically silent reinfarction. Conclusions: Clinical and radiological recurrence are common after childhood AIS. The risk of clinical recurrence is increased in children with moyamoya and, in previously healthy patients, in those with genetic thrombophilia. Preexisting pathology, including immunodeficiency, and persistent leukocytosis are risk factors for radiological recurrence, which suggests a potential role for chronic infection

Renal Autotransplant and Celiac Artery Bypass for Aneurysmal Degeneration Related to Neurofibromatosis Type 1

We present a case of an 18-year-old female with neurofibromatosis type 1 who presented with abdominal pain and weight loss secondary to chronic mesenteric ischemia due to celiac axis occlusion and was subsequently found to have multiple visceral artery aneurysms. Of clinical significance, 2 aneurysms of the right renal artery were noted at the hilum, with the larger one having a diameter of 2.4 cm. After initial endovascular treatment with stenting of a concurrent pancreaticoduodenal artery pseudoaneurysm, staged aorto-hepatic bypass and right nephrectomy with renal autotransplantation after back table resection of the aneurysmal segments were successfully completed

Rheoencefalographic study of the cerebrovascular circulation in human lead poisoning

Cerebralna cirkulacija je ispitivana reoencefalografskom (REG) metodom na grupi od 34 radnika u kojih je kliničkim i laboratorijskim ispitivanjem dokazano trovanje olovom. Kontrolna grupa se sastojala od 24 osobe, približno iste starosti, koje u svojoj profesionalnoj aktivnosti nisu bile eksponirane olovu. U osoba trovanih olovom nađeno je signifikantno produženje trajanja anakrotske faze reograma uz morfološke alteracije reografskih talasa, koje ukazuju na smanjenu rastegljivost i povećan tonus cerebralnih arterija, pretežno arteriola. U 7 ispitanika nađene su reografske promene koje govore u prilog difuznih promena na cerebralnim arterijama. Autori smatraju da je glavobolja pri trovanju olovom vaskularne geneze.Cerebral circulation was investigated by the REG method in a group of thirty-four workers in whom lead poisoning had been proved by clinical and laboratory examinations. A control group consisted of twenty-four subjects of approximately the same age, with no previous occupational exposure to lead. The duration of the anacrotic phase was significantly longer in lead poisoned subjects. In addition, morphological alterations of REG waves in these subjects indicated a decreased distensibility and increased tonus of cerebral blood vessels, primarily arterioles. Seven subjects showed REG changes which reflected diffuse alterations of the cerebral artery. The authors consider that headache in subjects poisoned by lead is of vascular origin

Interactions of the Gasotransmitters Contribute to Microvascular Tone (Dys)regulation in the Preterm Neonate

Background & Aims Hydrogen sulphide (H2S), nitric oxide (NO), and carbon monoxide (CO) are involved in transitional microvascular tone dysregulation in the preterm infant; however there is conflicting evidence on the interaction of these gasotransmitters, and their overall contribution to the microcirculation in newborns is not known. The aim of this study was to measure the levels of all 3 gasotransmitters, characterise their interrelationships and elucidate their combined effects on microvascular blood flow. Methods 90 preterm neonates were studied at 24h postnatal age. Microvascular studies were performed by laser Doppler. Arterial COHb levels (a measure of CO) were determined through co-oximetry. NO was measured as nitrate and nitrite in urine. H2S was measured as thiosulphate by liquid chromatography. Relationships between levels of the gasotransmitters and microvascular blood flow were assessed through partial correlation controlling for the influence of gestational age. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow and derive a theoretical model of their interactions. Results No relationship was observed between NO and CO (p = 0.18, r = 0.18). A positive relationship between NO and H2S (p = 0.008, r = 0.28) and an inverse relationship between CO and H2S (p = 0.01, r = -0.33) exists. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow. The model with the best fit is presented. Conclusions The relationships between NO and H2S, and CO and H2S may be of importance in the preterm newborn, particularly as NO levels in males are associated with higher H2S levels and higher microvascular blood flow and CO in females appears to convey protection against vascular dysregulation. Here we present a theoretical model of these interactions and their overall effects on microvascular flow in the preterm newborn, upon which future mechanistic studies may be based.The authors would like to acknowledge the parents of the neonates enrolled in the 2CANS study for their participation, the staff of the Kaleidoscope Neonatal Intensive Care Unit at the John Hunter Children’s Hospital, and Kimberly-Clark Australia for providing the diapers used in this stud

Regulation of blood-brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide.

BACKGROUND: Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied. RESULTS: Here, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner. CONCLUSION: Our findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function. Video abstract

Effect of head-upright tilt on the dynamic of cerebral autoregulation.

The effect of head-upright tilting on the rate of cerebral autoregulation was studied in 12 healthy volunteers (nine men and three women; age range 20-36 years). The dynamics of cerebral autoregulation was determined from the rate of change in cerebral resistance (RoR) during a drop in arterial blood pressure induced by rapid deflation of a 3-min ischaemic thigh cuff and from the ratio of changes in cerebral blood flow and arterial blood pressure (CAI) during the recovery period after the drop in arterial blood pressure. The test was performed supine and with 40 degrees head-up tilt (40 degrees HUT). Middle cerebral artery mean blood flow velocity was measured by transcranial Doppler simultaneously with peripheral arterial blood pressure using Finapres. The thigh cuff deflation induced a larger drop in arterial pressure during 40 degrees HUT [median -28% (25 percentile -36, 75 percentile -19)] than in the supine position [-16% (-23, -15)] (P < 0.01) and in cerebral resistance [supine: -12% (-15, -6); 40 degrees HUT: -15% (-20, -12); P < 0.05]. There was no significant change in RoR [15% s-1 (12, 15)] and CAI [1.9 (1.5, 3.1)] measured supine and during 40 degrees HUT [RoR: 13% s-1 (12, 15); CAI: 1.3 (0.99, 1.9)]. During the drop in arterial pressure, the relationship between arterial blood pressure and systolic peak-to-peak interval exhibited an hysteresis loop, indicating a cardiopulmonary and/or baroreflex activation that was not observed with cerebral resistance. The rate of autoregulation is an intrinsic property of the cerebral vascular bed and is not affected by the vasodilator state in the range of arterial blood pressure changes induced by the tight cuff method