Elevated Cerebral Blood Flow Velocity Research Articles

Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-β0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

Associations Between Transcranial Doppler Flow Velocities, Laboratory Parameters, and Clinical Features in Turkish Children With Sickle Cell Disease.

Stroke is one of the major complications of sickle cell disease (SCD). Stroke features either occlusion of, or stenosis at, the origin of one of the large intracerebral arteries, the internal carotid artery (ICA), and/or the middle cerebral artery (MCA). We sought correlations between cerebral blood flow velocities and the laboratory and clinical findings of patients with SCD. Fifty-three pediatric SCD patients (39 with HbSS, 14 with HbSβ0) were analyzed. The mean patient age was 12.9±3.9 years. The control group contained 24 healthy individuals. The time-averaged maximum mean velocity (TAMMV) and resistive index (RI) of the MCA, the TAMMVs of the ICA and vertebral artery (VA), and the diameter of the VA were estimated through transcranial Doppler ultrasonography using a 2.5 MHz transducer, in accordance with the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol. We evaluated the relationships between the TAMMVs, laboratory parameters, and clinical findings. The mean±SD MCA TAMMV was 161.2±35.4 cm/s in patients with HbSS and 185.8±62.9 cm/s in patients with HbSβ0. The mean MCA TAMMV, RI, ICA TAMMV, VA TAMMV, and VA diameter were 168.5±43.9 cm/s, 0.63±0.06, 116.8±25.5 cm/s, 69.2±18.5 cm/s, and 3.5±0.61 mm for all SCD patients, respectively. In the control group, the mean MCA TAMMV, RI, ICA TAMMV, VA TAMMV, and VA diameter were 103.8±28.8 cm/s, 0.53±0.04, 96.4±27.8 cm/s, 40.3±12.1 cm/s, and 3.4±0.6 mm, respectively. Although the differences were not significant, TAMMVs were higher in HbSβ0 patients taking hydroxyurea; those with hemoglobin levels <8 g/dL, ferritin levels >1000 ng/dL, mean platelet volume >12 fL, or red cell distribution width >18%; or required chelation, or were below the third percentiles of weight and height. The TAMMV was significantly higher only in SCD patients who complained of headache. High ferritin and low hemoglobin levels, a high mean platelet volume, a high red cell distribution width, low weight (below the third percentile), and a short height (below the third percentile) may be associated with elevated cerebral blood flow velocities and an increased stroke risk in children with SCD. Children with such features should be closely followed-up through transcranial Doppler ultrasonography examination.

Neutrophil-to-lymphocyte ratio is associated with increased cerebral blood flow velocity in acute bacterial meningitis

In community-acquired bacterial meningitis (CABM) intracranial vascular alterations are devastating complications which are triggered by neuroinflammation and result in worse clinical outcome. The Neutrophil-to-Lymphocyte ratio (NLR) represents a reliable parameter of the inflammatory response. In this study we analyzed the association between NLR and elevated cerebral blood flow velocity (CBFv) in CABM-patients. This study included all (CABM)-patients admitted to a German tertiary center between 2006 and 2016. Patients’ demographics, in-hospital measures, neuroradiological data and clinical outcome were retrieved from institutional databases. CBFv was assessed by transcranial doppler (TCD). Patients’, radiological and laboratory characteristics were compared between patients with/without elevated CBFv. Multivariate-analysis investigated parameters independently associated with elevated CBFv. Receiver operating characteristic(ROC-)curve analysis was undertaken to identify the best cut-off for NLR to discriminate between increased CBFv. 108 patients with CABM were identified. 27.8% (30/108) showed elevated CBFv. Patients with elevated CBFv and normal CBFv, respectively had a worse clinical status on admission (Glasgow Coma Scale: 12 [9–14] vs. 14 [11–15]; p = 0.005) and required more often intensive care (30/30 [100.0%] vs. 63/78 [80.8%]; p = 0.01).The causative pathogen was S. pneumoniae in 70%. Patients with elevated CBFv developed more often cerebrovascular complications with delayed cerebral ischemia (DCI) within hospital stay (p = 0.031). A significantly higher admission-NLR was observed in patients with elevated CBFv (median [IQR]: elevated CBFv:24.0 [20.4–30.2] vs. normal CBFv:13.5 [8.4–19.5]; p < 0.001). Multivariate analysis, revealed NLR to be significantly associated with increased CBFv (Odds ratio [95%CI] 1.042 [1.003–1.084]; p = 0.036). ROC-analysis identified a NLR of 20.9 as best cut-off value to discriminate between elevated CBFv (AUC = 0.713, p < 0.0001, Youden's Index = 0.441;elevated CBFv: NLR ≥ 20.9 19/30[63.5%] vs. normal CBFv: NLR > 20.9 15/78[19.2%]; p < 0.001). Intracranial vascular complications are common among CABM-patients and are a risk factor for unfavorable outcome at discharge. Elevated NLR is independently associated with high CBFv and may be useful in predicting patients’ prognosis.

Haemoglobin oxygen saturation, leucocyte count and lactate dehydrogenase are predictors of elevated cerebral blood flow velocity in Nigerian children with sickle cell anaemia

Background: Transcranial Doppler ultrasound (TCD) scan, which measures blood flow velocity through the time-averaged mean of maximum velocities (TAMMVs) in the internal carotid arteries and middle cerebral arteries, is a useful screening tool for predicting stroke risk in children with sickle cell anaemia (SCA).Aim: To investigate which clinical and laboratory indices predict abnormal TCD velocity in children with SCA.Methods: Fifty-four SCA patients with normal TCD (TAMMV < 170 cm/s), classified as negative TCD (NTCD), and 93 patients with conditional and abnormal TCD velocities (TAMMV ≥ 170 cm/s) classified as positive TCD were recruited. The haemoglobin oxygen saturation, haematological variables, nitric oxide metabolites and lactate dehydrogenase activity of the patients were analysed.Results: The mean (SD) age was 7.16 (3.84) years (range 2–16). The median SpO2 of the patients in the positive TCD group was significantly lower than that of the negative TCD group (p = 0.002). Multivariate logistic regression analysis indicated that the MCV [odds ratio (OR) 1.12, 95% confidence interval (CI) 1.04–1.22, p = 0.01)], MCH (OR 1.34, 95% CI 1.02–1.77, p = 0.04), leucocyte count (OR 1.26, 95% CI 1.07–1.49, p = 0.01) and lactate dehydrogenase (LDH) level (OR 1.00, 95% CI 1.00–1.01, p = 0.01) were independent predictors of high cerebral blood flow velocities.Conclusions: These clinical and laboratory indices are characteristic of chronic hypoxia and severe anaemia and are predictors of abnormal cerebral blood flow velocity. They can be used to predict stroke risk in children with SCA when access to TCD screening is limited.

Abstract TP115: Cerebral Hemodynamic Changes in Military Personnel With Long-term Effects of Concussions

Service members (SMs) suffer from repeated exposure to concussions or mild TBI, which can disrupt cerebral blood flow. This effect is seen in the acute phase of TBI, but the development of vascular wall abnormalities, which can lead to luminal narrowing and abnormally elevated cerebral blood flow velocities (CBFV), has not been studied in the post concussive phase. The purpose of this study was to evaluate the transcranial Doppler (TCD) determined incidence of abnormal cerebral hemodynamics in patients with long-term effects of mTBI. Material and Methods: TCD recordings of mean CBFV in cm/sec and Pulsatility Indices (PI) were recorded from 431 SMs (9 females; ages 24-54, mean age 39.2 ± 6.4 years) who were admitted to the National Intrepid Center of Excellence 4-week Interdisciplinary Outpatient Program. TCD data were analyzed to determine whether SMs exhibited abnormal CBFV s in the middle cerebral artery, internal carotid artery (ICA), and basilar artery. All subjects consented to protocol #362504 prior to any data collection or analysis. Two standard deviation from the mean CBFV in any direction labeled as an abnormal and PI was assumed normal with values between 0.7 and 0.9 Patients with one or more vessels with abnormal CBFV’s and PI’s were labeled as abnormal. Results: Average time since last TBI was 5.1 ± 3.4 years. We observed abnormal CBFV values in 33% of SMs. 149 (35%) and 48 (11%) demonstrated abnormally high CBFV and PIs in one or more vessels, respectively. Abnormal CBFV was observed most frequently in the ICA (48%). Majority of studied patients had patchy pattern of abnormal data presented in one or few vessels. The presence of abnormal cerebral hemodynamics was inversely related to the time since the last mTBI exposure: the likelihood of abnormal CBFV values deceased with increasing time since last head injury was sustained but was still present. Conclusions: Our data reveal that a large proportion of SMs have elevated CBFVs following mTBI exposure in many years after last mTBI. We believe that head injuries due to combat and training blast and blunt force trauma exposure cause early atherosclerotic or fibrotic changes in the large vessel walls of the Circle of Willis, which results in vascular lumen narrowing and increased CBFV’s.

Abstract TP401: Chemotherapy-associated Cerebral Vasospasm in Children With Leukemia: A Prospective Study Using Transcranial Doppler Ultrasound

Introduction: Intrathecal (IT) cytarabine, an antineoplastic agent with poorly understood neurotoxicity, is commonly administered to children with newly diagnosed leukemia on the first day of induction chemotherapy for central nervous system prophylaxis. Five recent case reports demonstrated severe diffuse cerebral vasospasm leading to neurologic sequelae 4-11 days after administration of IT cytarabine. While these patients developed overt consequences, subclinical vasospasm may lead to more subtle forms of neurotoxicity in a larger group of patients. Recognition of subclinical vasospasm could prevent both overt and subtle consequences. Objective and Hypothesis: We evaluated cerebral blood flow velocities (CBFVs), a marker of vasospasm, as measured by transcranial Doppler (TCD) ultrasound, before and after the administration of IT cytarabine. We hypothesized that IT cytarabine increases CBFVs in pediatric leukemia patients in the first two weeks after treatment. Methods: In this prospective before and after study, TCDs were performed on each subject prior to induction chemotherapy and subsequently around days +1, +4, and +8 of induction, before other IT medication administration and within the window of expected vasospasm based on prior cases. Results: In this interim analysis, we found elevated CBFVs compared to age-matched normal values in all arterial distributions measured (though more prominently in anterior circulation), even prior to the administration of IT chemotherapy. Substantial increases in CBFVs were observed after the administration of IT cytarabine in some subjects, though this trend was not observed in all cases. Conclusions: The observed elevations in CBFVs are likely in part due to decreased blood viscosities that resulted from hematologic changes secondary to leukemia. The observed changes in CBFVs after IT cytarabine administration are probably partially due to treatment effects, but the variability between patients suggests that patient and/or disease-specific characteristics may predispose certain children to cerebral vasospasm and its neurologic sequelae. This ongoing study aims to identify clinical features that allow risk stratification in order to develop clinical pathways for preventing neurotoxicity.

Rivipansel: A Small Pan-Selectin Antagonist Improves Cerebral Perfusion and Inhibits Leukocyte Adhesion and in Murine Sickle Cell Disease Model

▪The pathophysiology of sickle cell disease (SCD) is complex and heterogenous. Tissue hypoxia leads to endothelial activation, and formation of multicellular aggregates of red cells, leucocytes and platelets in the microvasculature. This results in a vaso-occlusion further reducing tissue perfusion. Patients with SCD experience intense pain crisis. Some SCD patients also exhibit elevated cerebral blood flow velocities in transcranial Doppler (TCD) and impaired autoregulation. Higher TCD velocities are associated with imminent risk of ischemic stroke and are an indication for transfusion for SCD patients. Similar to human SCD patients, SCD mice also exhibit an increase in cerebral perfusion (Branch et al, Blood, 2015) and irregularly dilated cerebral microvasculature compared to wild-type (WT) mice (Manci et al, Blood, 2006). Selectins play a critical role in mediating initial tethering and adhesion of hematopoietic cells with endothelial cells, and are attractive targets to treat vaso-occlusion. Rivipansel is a potent small molecule pan-selectin inhibitor with a 100 fold greater inhibitory acitivity for E-selectin over P-selectin. Previous studies have demonstrated the effect of Rivipansel (GMI-1070) in chimeric SCD mice using intravital microscopy (IVM) where bone marrow from Berkeley SCD mice was transplanted in wild type (WT) mice (Chang et al, Blood, 2010). Here, we further investigate the effect of Rivipansel on leukocyte rolling in vitro and in vivo in Townes SCD mice with corresponding changes in inflammatory markers. We also extended these studies to explore the effect of Rivipansel in a cerebral perfusion model in Townes SCD mice.The effect of Rivipansel on cell adhesion in vitro was examined using the microfluidic BioFlux shear flow system. HL-60 cells were continuously flown under physiological conditions over confluent monolayers of Chinese Hamster Ovary cells expressing E-selectin (CHO-E) or P-selectin (CHO-P) treated with Rivipansel, Immunoglobulin G (IgG) control antibody or vehicle. Rivipansel dose-dependently reduced the adhesion of HL-60 to CHO-E monolayers compared to vehicle treated cells, or CHO-P monolayers.In the Townes SCD mice, Rivipansel was evaluated using IVM of the cremaster. Surgical manipulation and the chronic inflammatory conditions in Townes mice, induce an acute vaso-occlusive condition in the post-capillary venules. Rivipansel or vehicle control were dosed at 5, 10 or 20 mgs/kg intravenously prior to surgical preparation and a second dose was administered 70 minutes later. Labeled neutrophil and platelet specific antibodies were injected to quantify neutrophil-platelet aggregates and neutrophils adhered to the vasculature. Neutrophil rolling velocity increased 2.5 fold and there was a dose dependent increase in rolling neutrophils. Rivipansel, dosed at 20 mg/kg resulted in a 69% decrease in neutrophil adhesion to the endothelium and an 85% decrease in neutrophil platelet aggregates (NPA) attached to the vasculature compared to vehicle treated mice. No effect on was observed in mice dosed a 5 mg/kg. Plasma soluble P and E-selectin levels were significantly reduced in mice dosed at 10 and 20 mg/kg compared to vehicle treated mice.Additionally, cultured primary brain endothelial cells stimulated with TNF-α demonstrated a 700 fold increase in E-selectin levels as measured by RNAseq. Based on this observation, we studied the effect of Rivipansel on cerebral perfusion studies in a TNFα induced occlusion model in SCD and WT mice where changes in cerebral microcirculation were measured in real time using laser Doppler tissue perfusion. TNFα treated SCD mice demonstrated a marked reduction in tissue perfusion in contrast to WT mice. This was rapidly reversed by intravenous injection of Rivipansel (20 mg/kg). Brains harvested from TNF treated SCD mice showed increased platelet microthrombi compared to WT mice, and treatment with Rivipansel reduced the platelet aggregates seen in the cerebral microvasculature in SCD mice.In summary, we demonstrated dose dependent decrease in leukocyte adhesion in vitro and in vivo in the Townes mice. In addition administration of Rivipansel is beneficial in improving cerebral perfusion as well improving peripheral microvascular flow in the SCD mice.All experiments were within guidelines and were reviewed and approved by Pfizer institutional animal care and use committee. DisclosuresJasuja:Pfizer: Employment. Suidan:Pfizer: Employment. Hett:Pfizer: Employment. Desai:Pfizer: Employment. Le:Pfizer: Employment. Bell:Pfizer: Employment. Murphy:Pfizer: Employment. Pittman:Pfizer: Employment.

Transcranial doppler ultrasonography in children with sickle cell anemia: Clinical and laboratory correlates for elevated blood flow velocities

Transcranial Doppler (TCD) sonography of major cerebral arteries is now recommended for routine screening for stroke risk in children with sickle cell disease (SCD). We performed TCD studies on children with sickle cell anemia (SCA) seen at the pediatric hematology clinic over a period of 2 years. TCD scans were repeated yearly in children with normal flow velocities and every 3 months in children with elevated velocities. Findings were correlated with clinical variables, hematologic indices, and arterial oxygen saturation. Predictors of elevated velocities were identified by multiple linear regressions. We enrolled 237 children and performed a total of 526 TCD examinations. Highest time-averaged maximum flow velocities were ≥170 cm/s in 72 (30.3%) cases and ≥200 cm/s in 20 (8.4%). Young age, low hematocrit, low hemoglobin, and arterial oxygen desaturation <95% showed significant correlations with presence of increased cerebral flow velocities. Low hematocrit, low hemoglobin concentration, young age, and low arterial oxygen desaturation predicted elevated cerebral blood flow velocities and, invariably, increased stroke risk, in children with SCA. Children who exhibit these features should be given high priority for TCD examination in the setting of limited resources.

Does cerebral oxygen delivery limit incremental exercise performance?

Previous studies have suggested that a reduction in cerebral oxygen delivery may limit motor drive, particularly in hypoxic conditions, where oxygen transport is impaired. We hypothesized that raising end-tidal Pco(2) (Pet(CO(2))) during incremental exercise would increase cerebral blood flow (CBF) and oxygen delivery, thereby improving peak power output (W(peak)). Amateur cyclists performed two ramped exercise tests (25 W/min) in a counterbalanced order to compare the normal, poikilocapnic response against a clamped condition, in which Pet(CO(2)) was held at 50 Torr throughout exercise. Tests were performed in normoxia (barometric pressure = 630 mmHg, 1,650 m) and hypoxia (barometric pressure = 425 mmHg, 4,875 m) in a hypobaric chamber. An additional trial in hypoxia investigated effects of clamping at a lower Pet(CO(2)) (40 Torr) from ∼75 to 100% W(peak) to reduce potential influences of respiratory acidosis and muscle fatigue imposed by clamping Pet(CO(2)) at 50 Torr. Metabolic gases, ventilation, middle cerebral artery CBF velocity (transcranial Doppler), forehead pulse oximetry, and cerebral (prefrontal) and muscle (vastus lateralis) hemoglobin oxygenation (near infrared spectroscopy) were monitored across trials. Clamping Pet(CO(2)) at 50 Torr in both normoxia (n = 9) and hypoxia (n = 11) elevated CBF velocity (∼40%) and improved cerebral hemoglobin oxygenation (∼15%), but decreased W(peak) (6%) and peak oxygen consumption (11%). Clamping at 40 Torr near maximal effort in hypoxia (n = 6) also improved cerebral oxygenation (∼15%), but again limited W(peak) (5%). These findings demonstrate that increasing mass cerebral oxygen delivery via CO(2)-mediated vasodilation does not improve incremental exercise performance, at least when accompanied by respiratory acidosis.

Transcranial Doppler ultrasonography in siblings with sickle cell disease.

The risk of stroke in sickle cell disease (SCD) may be influenced by either genetic or environmental factors. Elevated blood flow velocity in the large cerebral arteries, detected by transcranial Doppler (TCD) ultrasonography, predicts an increased stroke risk in children with SCD. We undertook this study to investigate the possibility of a familial predisposition to elevated cerebral blood flow velocity, a surrogate marker for stroke risk. We analysed the results of TCD studies performed on 63 children from 29 families that had more than one child with SCD. We assessed the association of elevated cerebral blood flow velocity with sibling TCD results as well as age and haemoglobin level, which are factors known to affect cerebral blood flow velocity. Positive or negative TCD results were highly correlated between family members (r = 0.61). The presence of a sibling with a positive TCD result was significantly associated with an elevated cerebral blood flow velocity in other siblings with SCD (odds ratio = 50.7, 95% confidence interval 10.1-253.7, P < 0.001). Furthermore, children who had a sibling with a positive TCD result had a significantly higher TCD velocity than children with SCD but without a sibling who were matched for age, sex, genotype and haemoglobin level. Our results are consistent with a familial predisposition to cerebral vasculopathy in SCD.

Transcranial Doppler ultrasonography in siblings with sickle cell disease

Summary. The risk of stroke in sickle cell disease (SCD) may be influenced by either genetic or environmental factors. Elevated blood flow velocity in the large cerebral arteries, detected by transcranial Doppler (TCD) ultrasonography, predicts an increased stroke risk in children with SCD. We undertook this study to investigate the possibility of a familial predisposition to elevated cerebral blood flow velocity, a surrogate marker for stroke risk. We analysed the results of TCD studies performed on 63 children from 29 families that had more than one child with SCD. We assessed the association of elevated cerebral blood flow velocity with sibling TCD results as well as age and haemoglobin level, which are factors known to affect cerebral blood flow velocity. Positive or negative TCD results were highly correlated between family members (r = 0·61). The presence of a sibling with a positive TCD result was significantly associated with an elevated cerebral blood flow velocity in other siblings with SCD (odds ratio = 41·9, 95% confidence interval 8·2–214·7, P &lt; 0·001). Furthermore, children who had a sibling with a positive TCD result had a significantly higher TCD velocity than children with SCD but without a sibling who were matched for age, sex, genotype and haemoglobin level. Our results are consistent with a familial predisposition to cerebral vasculopathy in SCD.

Elevated Cerebral Blood Flow Velocities in Fabry Disease With Reversal After Enzyme Replacement

Fabry disease is an X-linked inherited disorder resulting from a deficiency of alpha-galactosidase A. Cerebrovascular disease in Fabry disease includes small-vessel disease and larger-vessel ectasia in a predominantly posterior distribution. We assessed transcranial Doppler (TCD) blood flow velocities in naive and enzyme-treated Fabry patients. TCD was used to noninvasively examine patients with Fabry disease for abnormal cerebral blood flow velocities. TCD measurements were also made during CO2 retention by breathholding to examine cerebrovascular vessel reactivity. Twenty-six patients were enrolled in a 6-month, double-blind, placebo-controlled trial of enzyme replacement therapy consisting of biweekly intravenous alpha-galactosidase A infusions, with a subsequent 18-month follow-up in an open-label trial. Statistical analysis consisted of applying a mixed-effects ANOVA model for correlated outcomes. Peak velocity, mean velocity, pulsatility index, and resistance index were found to be significantly higher in patients compared with control subjects. When the individual vessels were considered, elevated flow velocities were found in the middle cerebral M1 branch and the posterior cerebral artery. Enzyme replacement therapy significantly decreased peak, mean, and end-diastolic velocities and flow acceleration at the 18-month follow-up time point. Patients with Fabry disease have elevated cerebral blood flow velocities. These velocities significantly improved with enzyme replacement therapy.

Effects of inhibition of nitric oxide synthesis and of hypercapnia on blood pressure and brain blood flow in the turtle.

In the mammalian brain, nitric oxide (NO) is responsible for a vasodilatory tonus as well as the elevation of cerebral blood flow (CBF) induced by hypercapnia. There have been few comparative studies of cerebral vasoregulation in lower vertebrates. Using epi-illumination microscopy in vivo to observe CBF velocity on the brain surface (cerebral cortex), we show that turtles (Trachemys scripta) exposed to hypercapnia (inspired PCO2 = 4.9 kPa) displayed a 62% increase in CBF velocity, while systemic blood pressure remains constant. Exposing turtles to a PCO2 of 14.9 kPa caused an additional increase in CBF velocity, to 104% above control values, as well as a 30% increase in systemic blood pressure. The elevated CBF velocity during hypercapnia could not be blocked by a systemic injection of the NO synthase (NOS) inhibitor NG-nitro-L-arginine (L-NA). However, L-NA injection caused a temporary stop in CBF as well as a persistent increase in systemic blood pressure, suggesting that there is a NO tonus that is attenuated by the NOS inhibitor and that CBF is strongly dependent on this tonus, although compensatory mechanisms exist. Thus, although the cerebrovascular reaction to hypercapnia appeared to be NO-independent, the results suggest that there is a NO-dependent vasodilatory tonus affecting both cerebral and systemic blood circulation in this species.