Abstract 2381: Aneurysmal Subarachnoid Hemorrhage: Metabolic and Blood Flow Patterns

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
parham moftakhar ◽  
Thomas C Glenn ◽  
John Boscardin ◽  
Neil A Martin
Keyword(s):  
Blood Flow ◽  
Phase Ii ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Phase Iii ◽  
Entire Study ◽  
Cerebral Metabolic Rate ◽  
Study Population ◽  
Blood Flow Patterns ◽  
The Brain ◽  
Oxygen Difference

Objective: The purpose of this study is to classify and describe the clinically distinct metabolic and hemodynamic phases post-ASAH. Methods: 224 patients who suffered an ASAH (mean age 55±14; 74% female, 26% male) were examined. Patients underwent daily transcranial Doppler (TCD) and cerebral blood flow (CBF) studies (using 133 Xe clearance). Due to the paucity of data on post-hemorrhage day (PHD) 0, the internal carotid artery end-diastolic (ICA ED ) velocity, a surrogate for CBF, was used for the first 24 hours. The brain arteriovenous oxygen difference (AVDO 2 ) was recorded for each patient and the cerebral metabolic rate of oxygen (CMRO 2 ) was calculated. Clinical outcome was evaluated based on the Glasgow Outcome Scale (GOS) 6 months after rupture. Results: Following ASAH, 3 distinct hemodynamic phases arose for the entire study population. Phase I (hypoperfusion phase), occurs on the day of rupture (PHD 0) and is defined by a low ICA ED velocity (mean 17.8±1.1 cm/s), normal middle cerebral artery (MCA) velocity (mean V MCA 58.0±23.4 cm/s), and normal Lindegaard Ratio ([LR], mean 1.66±0.50). Phase II (relative hyperemia), (PHD 1–3), is characterized by an increasing ICA ED (mean 35.4±1.0 cm/s, p<0.0001), a relative hyperemia (mean CBF 15 40.1±1.5 ml/100g/minute, CMRO 2 1.17±0.41 ml/100g/min), a rising V MCA (mean 71.5±5.8 cm/sec, p<0.0001), and a rising but normal LR (mean 2.21±0.19, p<0.0001). During phase III (vasospasm phase, PHD 4–21), both the ICA ED and CBF decrease (mean ICA ED 19.9±0.9 cm/s, p<0.0001; mean CBF 15 36.8±0.7 ml/100g/minute, p=0.04), V MCA continues to rise (mean 107.6±2.9cm/sec, p<0.0001), and the LR is further increased (mean 3.25±0.08, p<0.0001). The CMRO 2 remains low (mean 1.17±0.40 ml/100g/min, p=1). Based on the GOS up to 90% of patients who experienced either a relative or absolute hyperemia had good outcomes. Conclusions: After an ASAH, 3 discrete metabolic and hemodynamic phases arise each with the potential for its own unique phase-specific management and therapy. Relative hyperemia, or “luxury perfusion,” during Phase II in the setting of non-elevated ICPs may provide some type of benefit for patients.

Neuroimaging in Drug Discovery and Development: Paradigms for Accelerating New Drug Availability

2001 ◽  
Vol 14 (5) ◽  
pp. 407-415
Author(s):  
John T. Metz ◽  
Malcolm D. Cooper ◽  
Terry F. Brown ◽  
Leann H. Kinnunen ◽  
Declan J. Cooper
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glucose Metabolism ◽  
Phase Ii ◽  
New Drugs ◽  
Central Effects ◽  
Drug Discovery And Development ◽  
Psychological Tasks ◽  
The Brain ◽  
Phase Iv

The process of discovering and developing new drugs is complicated. Neuroimaging methods can facilitate this process. An analysis of the conceptual bases and practical limitations of different neuroimaging modalities reveals that each technique can best address different kinds of questions. Radioligand studies are well suited to preclinical and Phase II questions when a compound is known or suspected to affect well-understood mechanisms; they are also useful in Phase IV to characterize effective agents. Cerebral blood flow studies can be extremely useful in evaluating the effects of a drug on psychological tasks (mostly in Phase IV). Glucose metabolism studies can answer the simplest questions about whether a compound affects the brain, where, and how much. Such studies are most useful in confirming central effects (preclinical and early clinical phases), in determining effective dose ranges (Phase II), and in comparing different drugs (Phase IV).

Effects of prior heavy-intensity exercise during single-leg knee extension on v̇o2 kinetics and limb blood flow

2005 ◽  
Vol 99 (4) ◽  
pp. 1462-1470 ◽  
Author(s):  
Nicole D. Paterson ◽  
John M. Kowalchuk ◽  
Donald H. Paterson
Keyword(s):  
Blood Flow ◽  
Phase Ii ◽  
Time Course ◽  
Muscle Blood Flow ◽  
Knee Extension ◽  
Phase Iii ◽  
Limb Blood Flow ◽  
Heavy Exercise ◽  
Pulsed Wave Doppler ◽  
Young Subjects

The effects of prior heavy-intensity exercise on O2 uptake (V̇o2) kinetics of a second heavy exercise may be due to vasodilation (associated with metabolic acidosis) and improved muscle blood flow. This study examined the effect of prior heavy-intensity exercise on femoral artery blood flow (Qleg) and its relationship with V̇o2 kinetics. Five young subjects completed five to eight repeats of two 6-min bouts of heavy-intensity one-legged, knee-extension exercise separated by 6 min of loadless exercise. V̇o2 was measured breath by breath. Pulsed-wave Doppler ultrasound was used to measure Qleg. V̇o2 and blood flow velocity data were fit using a monoexponential model to identify phase II and phase III time periods and estimate the response amplitudes and time constants (τ). Phase II V̇o2 kinetics was speeded on the second heavy-intensity exercise [mean τ (SD), 29 ( 10 ) s to 24 ( 10 ) s, P < 0.05] with no change in the phase II (or phase III) amplitude. Qleg was elevated before the second exercise [1.55 (0.34) l/min to 1.90 (0.25) l/min, P < 0.05], but the amplitude and time course [τ, 25 ( 13 ) s to 35 ( 13 ) s] were not changed, such that throughout the transient the Qleg (and ΔQleg/ΔV̇o2) did not differ from the prior heavy exercise. Thus V̇o2 kinetics were accelerated on the second exercise, but the faster kinetics were not associated with changes in Qleg. Thus limb blood flow appears not to limit V̇o2 kinetics during single-leg heavy-intensity exercise nor to be the mechanism of the altered V̇o2 response after heavy-intensity prior exercise.

Ketogenic Diet, Aging, and Neurodegeneration

2016 ◽  
Author(s):  
Kui Xu ◽  
Joseph C. LaManna ◽  
Michelle A. Puchowicz
Keyword(s):  
Oxidative Stress ◽  
Energy Source ◽  
Blood Flow ◽  
Ketogenic Diet ◽  
Ketone Bodies ◽  
Neurovascular Unit ◽  
Cerebral Metabolic Rate ◽  
Downstream Effects ◽  
Atp Supply ◽  
The Brain

The brain is normally completely dependent on glucose, but is capable of using ketones as an alternate energy source, as occurs with prolonged starvation or chronic feeding of a ketogenic diet. Research has shown that ketosis is neuroprotective against ischemic insults in rodents. This review focuses on investigating the mechanistic links to neuroprotection by ketosis in the aged. Recovery from stroke and other pathophysiological conditions in the aged is challenging. Cerebral metabolic rate for glucose, cerebral blood flow, and the defenses against oxidative stress are known to decline with age, suggesting dysfunction of the neurovascular unit. One mechanism of neuroprotection by ketosis involves succinate-induced stabilization of hypoxic inducible factor-1alpha (HIF1α‎) and its downstream effects on intermediary metabolism. The chapter hypothesizes that ketone bodies play a role in the restoration of energy balance (stabilization of ATP supply) and act as signaling molecules through the up-regulation of salvation pathways targeted by HIF1α‎.

Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer

2015 ◽  
Vol 33 (33) ◽  
pp. 3858-3865 ◽  
Author(s):  
Yung-Jue Bang ◽  
Seock-Ah Im ◽  
Keun-Wook Lee ◽  
Jae Yong Cho ◽  
Eun-Kee Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Double Blind Study ◽  
Double Blind ◽  
Gastric Cancer Cell Lines ◽  
Study Population ◽  
Atm Protein

Purpose Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. Patients and Methods In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m2 per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). Results One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. Conclusion Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. Swiss Group for Clinical Cancer Research.

1994 ◽  
Vol 12 (10) ◽  
pp. 2071-2077 ◽  
Author(s):  
M Borner ◽  
M Bacchi ◽  
A Goldhirsch ◽  
R Greiner ◽  
F Harder ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multicenter Study ◽  
Locoregional Recurrence ◽  
Systemic Treatment ◽  
Local Treatment ◽  
Phase Iii ◽  
Survival Duration ◽  
Entire Study ◽  
Study Population ◽  
Disease Free

PURPOSE We performed a randomized phase III multicenter study to compare systemic treatment versus no treatment after complete excision and radiotherapy for isolated first locoregional recurrence in patients with breast cancer. PATIENTS AND METHODS One hundred sixty-seven good-risk patients with an estrogen receptor (ER+) positive recurrence or, in case of unknown receptor status, a disease-free interval (DFI) of greater than 12 months and < or = three recurrent tumor nodules each < or = 3 cm in diameter were entered onto the study. They were randomized to observation subsequent to local treatment or to receive tamoxifen (TAM) until disease progression. Seventy-nine percent of the patients were postmenopausal. RESULTS The median observation period for the entire study population was 6.3 years. The median disease-free survival (DFS) duration was 26 months for observation and 82 months for TAM patients (P = .007). This was mainly due to the reduction of further local recurrences, whereas the occurrence of early distant metastases was delayed. A multivariate analysis identified DFI and treatment with TAM as significant prognostic factors for DFS. The 5-year overall survival (OS) rates were 76% and 74%, respectively (P = .77). DFI was also a prognostic factor for OS. CONCLUSION Systemic therapy with TAM after isolated locoregional recurrence of breast cancer significantly increased 5-year DFS rates from 36% to 59% compared with observation alone and prolonged median DFS by more than 4.5 years in patients with ER+ tumors or in the case of unknown ER status with a DFI of greater than 12 months and minimal tumor burden. Treatment with TAM currently has no significant impact on OS, but the median survival duration of the study population has not yet been reached.

Weekly nab-paclitaxel in combination with carboplatin as first-line therapy in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7590-7590
Author(s):  
Mark A. Socinski ◽  
Corey J. Langer ◽  
Isamu Okamoto ◽  
Jeremy K. Hon ◽  
Vera Hirsh ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Entire Study ◽  
First Line Therapy ◽  
Line Therapy ◽  
Patient Reported ◽  
Study Population

7590 Background: The median age of advanced NSCLC pts in the US is 71 years; yetelderly pts (≥70 years) are generally undertreated, with only ≈30% receiving systemic therapy. Hence, better, more tolerable therapeutic options are needed for this cohort. In a phase III trial nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C, significantly improved ORR, the primary endpoint (25% vs 33%, P = 0.005), with a 1-month improvement in OS (P = NS) and improved safety. This analysis evaluated efficacy and safety in pts ≥70 and <70 years old. Methods: Pts with untreated stage IIIB/IV NSCLC and with an ECOG score of 0/1 were randomized 1:1 (stratified by age [≥70 vs <70 years], region, stage, gender, and histology) to C AUC 6 day 1 and either nab-P 100 mg/m2 on days 1, 8, 15 or sb-P 200 mg/m2 day 1 q 21 days. ORR and progression-free survival (PFS) were determined by blinded centralized review. Results: Of the phase III study population, 15% were elderly (156/1052; 74 pts in the nab-P/C and 82 in the sb-P/C arms). Most elderly pts were male (72%), Caucasian (71%), and had stage IV disease (64%). In pts both ≥70 and <70 years old, ORR was higher in the nab-P/C vs sb-P/C arm (≥70: 34% vs 24%, P = 0.196; <70: 32% vs 25%, P = 0.013). In pts ≥70 years old, PFS trended in favor of nab-P/C (median 8.0 vs 6.8 months, HR: 0.687, P = 0.134); OS was significantly improved (median 19.9 vs 10.4 months, HR: 0.583, P = 0.009). In contrast, PFS (6.0 vs 5.8 median months, HR: 0.903, P = 0.256) and OS (11.4 vs 11.3 median months, HR: 0.999, P = 0.988) were similar for both treatment arms in pts <70 years old. Adverse events were similar in pts ≥70 years old vs the entire study population, with less grade 3/4 neutropenia (P < 0.05) and neuropathy (P < 0.05) and increased thrombocytopenia (P = NS) and anemia (P < 0.05) in the nab-P/C vs sb-P/C arms. In pts ≥70 years old, patient-reported FACT-taxane subscales revealed significantly less neuropathy, pain, and hearing loss in the nab-P/C vs sb-P/C arms (P < 0.001). Conclusions: In elderly pts with advanced NSCLC, nab-P/C as first-line therapy was well tolerated and led to improved ORR and PFS, with significantly longer OS vs sb-PC.

scholarly journals Overview of Monitoring of Cerebral Blood Flow and Metabolism after Severe Head Injury

1994 ◽  
Vol 21 (S1) ◽  
pp. S6-S11 ◽  
Author(s):  
J. Paul Muizelaar ◽  
Marc L. Schröder
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Severe Head Injury ◽  
Cerebral Metabolism ◽  
Jugular Bulb ◽  
Cerebral Metabolic Rate ◽  
Venous Oxygen Saturation ◽  
Arteriovenous Difference ◽  
The Brain ◽  
Pressure Autoregulation

AbstractThe relationships between cerebral blood flow (CBF), cerebral metabolism (cerebral metabolic rate of oxygen, CMRO2) and cerebral oxygen extraction (arteriovenous difference of oxygen, AVDO2) are discussed, using the formula CMRO2 = CBF × AVDO2. Metabolic autoregulation, pressure autoregulation and viscosity autoregulation can all be explained by the strong tendency of the brain to keep AVDO2 constant. Monitoring of CBF, CMRO2 or AVDO2 very early after injury is impractical, but the available data indicate that cerebral ischemia plays a considerable role at this stage. It can best be avoided by not "treating" arterial hypertension and not using too much hyperventilation, while generous use of mannitol is probably beneficial. Once in the ICU, treatment can most practically be guided by monitoring of jugular bulb venous oxygen saturation. If saturation drops below 50%, the reason for this must be found (high intracranial pressure, blood pressure not high enough, too vigorous hyperventilation, arterial hypoxia, anemia) and must be treated accordingly.

Increase of cerebral blood flow produced by low dosages of cyanide

1963 ◽  
Vol 204 (2) ◽  
pp. 309-313 ◽  
Author(s):  
Mauricio Russek ◽  
Adolfo Fernandez F. ◽  
Cordelia Vega
Keyword(s):  
Blood Flow ◽  
Hind Limb ◽  
Jugular Vein ◽  
Great Increase ◽  
Femoral Vein ◽  
Sagittal Sinus ◽  
Flow Through ◽  
Significant Change ◽  
The Brain ◽  
Oxygen Difference

In cats and rabbits lightly anesthetized with pentobarbital or immobilized with Flaxedil and in encéphale isolé cats, the intravenous injection of NaCN in doses of 0.05 to 0.5 mg/kg produced a great increase in blood flow from the head (jugular vein) without any significant change in the blood flow from a hind limb (femoral vein). This would indicate that the increase in blood flow from the head was probably due to the brain and not to the nonnervous structures. This assumption was further supported by the large increase in the blood flow through the sagittal sinus. The greatest increase in jugular flow, threefold, was produced by 0.2–0.3 mg/kg of cyanide. This dose did not produce any significant change in the arterial, jugular, and femoral vein oxygen concentration, and hence in the A-V oxygen difference of head and limb. The results would indicate that the consumption of the brain is augmented by these dosages of cyanide.

Neuroprotection in hypothermia linked to redistribution of oxygen in brain

2003 ◽  
Vol 285 (1) ◽  
pp. H17-H25 ◽  
Author(s):  
Masaharu Sakoh ◽  
Albert Gjedde
Keyword(s):  
Blood Flow ◽  
Oxygen Consumption ◽  
Energy Metabolism ◽  
Brain Tissue ◽  
Traumatic Injury ◽  
Oxygen Extraction Fraction ◽  
Physiological Variables ◽  
Cerebral Metabolic Rate ◽  
Extraction Fraction ◽  
The Brain

Hypothermia improves the outcome of acute ischemic stroke, traumatic injury, and inflammation of brain tissue. We tested the hypothesis that hypothermia reduces the energy metabolism of brain tissue to a level that is commensurate with the prevailing blood flow and hence allows adequate distribution of oxygen to the entire tissue. To determine the effect of 32°C hypothermia on brain tissue, we measured the sequential changes of physiological variables by means of PET in pigs. Cerebral blood flow and oxygen consumption (cerebral metabolic rate of oxygen) declined to 50% of the baseline in 3 and 5 h, respectively, thus elevating the oxygen extraction fraction to 140% of the baseline at 3 h. The results are consistent with the claim that cooling of the brain to 32°C couples both energy metabolism and blood flow to a lower rate of work of the entire tissue.

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