scholarly journals No evidence for direct effects of recombinant human erythropoietin on cerebral blood flow and metabolism in healthy humans

2018 ◽  
Vol 124 (4) ◽  
pp. 1107-1116 ◽  
Author(s):  
Mark Bitsch Vestergaard ◽  
Otto Mølby Henriksen ◽  
Ulrich Lindberg ◽  
Niels Jacob Aachmann-Andersen ◽  
Kristian Lisbjerg ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Direct Effect ◽  
Low Dose ◽  
Metabolic Response ◽  
Cerebral Metabolism ◽  
Lactate Concentration ◽  
High Dose ◽  
Healthy Humans ◽  
Positron Emission

Erythropoietin (EPO) is expressed in human brain tissue, but its exact role is unknown. EPO may improve the efficiency of oxidative metabolism and has neuroprotective properties against hypoxic injuries in animal models. We aimed to investigate the effect of recombinant human EPO (rHuEPO) administration on healthy cerebral metabolism in humans during normoxia and during metabolic stress by inhalation of 10% O2hypoxic air. Twenty-four healthy men participated in a two-arm double-blind placebo-controlled trial. rHuEPO was administered as a low dose (5,000 IU) over 4 wk ( n = 12) or as a high dose (500 IU·kg body wt−1·day−1) for three consecutive days ( n = 12). Global cerebral blood flow (CBF) and metabolic rate of glucose (CMRglc) were measured with positron emission tomography. CBF, metabolic rate of oxygen ([Formula: see text]), and cerebral lactate concentration were measured by magnetic resonance imaging and spectroscopy. Low-dose treatment increased hemoglobin and was associated with a near-significant decrease in CBF during baseline normoxia. High-dose treatment caused no change in CBF. Neither treatment had an effect on normoxia CMRglc, [Formula: see text], or lactate concentration or an effect on the cerebral metabolic response to inhalation of hypoxic air. In conclusion, the study found no evidence for a direct effect of rHuEPO on cerebral metabolism.NEW & NOTEWORTHY We demonstrate with magnetic resonance imaging and positron emission tomography that administration of erythropoietin does not have a substantial direct effect on healthy human resting cerebral blood flow or effect on cerebral glucose and oxygen metabolism. Also, administration of erythropoietin did not have a direct effect on the metabolic response to acute hypoxic stress in healthy humans, and a suggested neuroprotective effect from erythropoietin is therefore likely not a direct effect of erythropoietin on cerebral metabolism.

Hemodynamic effects of recombinant human erythropoietin on the central nervous system after subarachnoid hemorrhage: reduction of microcirculatory impairment and functional deficits in a rabbit model

2008 ◽  
Vol 109 (6) ◽  
pp. 1155-1164 ◽  
Author(s):  
Amanda M. Murphy ◽  
Anargyros Xenocostas ◽  
Pria Pakkiri ◽  
Ting-Yim Lee
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Recombinant Human Erythropoietin ◽  
Low Dose ◽  
Saline Group ◽  
High Dose ◽  
Hemodynamic Effects ◽  
Neurological Outcomes ◽  
Human Erythropoietin

Object The authors investigated the hemodynamic effects of recombinant human erythropoietin (rhEPO) after subarachnoid hemorrhage (SAH) in rabbits. Methods The authors used male New Zealand White rabbits in this study divided into the following groups: SAH plus saline (16 rabbits), SAH plus low-dose rhEPO (16 rabbits; 1500 IU/kg on Day 0 and 500 IU/kg on Days 2 and 4), SAH plus high-dose rhEPO (10 rabbits; 1500 IU/kg on Days 0, 2, 4, and 6), and sham (6 rabbits). Computed tomography perfusion studies and CT angiography were performed for 1 hour after SAH on Day 0, and once each on Days 2, 4, 7, 9, and 16 after SAH. Assessments of neurological function and tissue histology were also performed. Results The mortality rate was significantly lower after rhEPO treatment (12%) than after saline treatment (44%) (p < 0.05). Neurological outcomes in the low-dose and high-dose rhEPO groups were better than in the saline group after SAH (p < 0.05), and the cerebral blood flow in the high-dose rhEPO group was greater than that in the saline group (p < 0.05). The mean transit time was significantly lower on Days 2 and 4 in the low-dose and high-dose rhEPO groups than in the saline group, but increased significantly on Day 7 in both groups (p < 0.05). The hematocrit increased significantly from baseline values in the high-dose and low-dose rhEPO groups on Days 4 and 7, respectively (p < 0.05). Conclusions Treatment with rhEPO after experimental SAH is associated with improved cerebral blood flow and microcirculatory flow as reflected by lower mean transit times. Improved tissue perfusion correlated with reduced mortality and improved neurological outcomes. Further investigation of the impact of increasing hematocrit on hemodynamic changes is needed.

Cerebral blood flow responsivity to CO2 in anesthetized chronically diabetic dogs

1993 ◽  
Vol 264 (4) ◽  
pp. H1069-H1075 ◽  
Author(s):  
F. E. Sieber ◽  
P. R. Brown ◽  
Y. Wu ◽  
R. C. Koehler ◽  
R. J. Traystman
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Blood Glucose ◽  
Low Dose ◽  
Insulin Treatment ◽  
High Dose ◽  
Acute Hyperglycemia ◽  
Glucose Levels ◽  
Cerebrovascular Resistance ◽  
Diabetic Dogs

The effect of diabetes mellitus on the cerebrovascular response to CO2 is unclear. We examined the effects of diabetes on cerebral blood flow (CBF) and cerebral oxygen uptake (CMRO2) during CO2 alterations. Four groups of dogs were studied: nondiabetic, normoglycemic controls; non-diabetic acute hyperglycemia; diabetic (pancreatectomy) with high-dose insulin treatment to maintain blood glucose between 4.0 and 6.0 mM; and diabetic with low-dose insulin treatment to maintain blood glucose at 13.2 +/- 0.4 mM. Six weeks after either sham surgery or pancreatectomy, dogs were anesthetized with fentanyl (50 micrograms/kg) plus pentobarbital (10 mg/kg), and microsphere determinations of CBF were made during normo-, hypo-, and hypercapnia. On the day of the study, arterial glucose levels in the control, acute hyperglycemia, and high- and low-dose insulin diabetic groups were 4.0 +/- 0.3, 14.9 +/- 2.5, 3.3 +/- 0.8, and 13.3 +/- 0.7 mM, respectively, at control. The corresponding baseline CMRO2 levels were 2.8 +/- 0.2, 3.0 +/- 0.2, 4.1 +/- 0.4, and 4.0 +/- 0.3 ml O2.100 g-1 x min,1, and the values in both diabetic groups were higher than control. Normocapnic CBF in the acute hyperglycemia, high-dose insulin, and low-dose insulin groups was elevated from control (54 +/- 3, 50 +/- 3, 51 +/- 3 vs. 36 +/- 1 ml x 100 g-1 x min-1) and cerebrovascular resistance was lower (2.24 +/- 0.15, 2.51 +/- 0.14, 2.38 +/- 0.21 vs. 3.35 +/- 0.18 mmHg.ml-1 x 100 g.min). CBF responses to both hypercapnia and hypocapnia were similar among groups. Thus both acute hyperglycemia and diabetes decrease cerebrovascular resistance and increase CBF.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Acute Intravenous Low- and High-Dose Cocaine Reduces Quantitative Global and Regional Cerebral Blood Flow in Recently Abstinent Subjects with Cocaine use Disorder

2005 ◽  
Vol 25 (7) ◽  
pp. 928-936 ◽  
Author(s):  
Bankole A Johnson ◽  
Michael A Dawes ◽  
John D Roache ◽  
Lynda T Wells ◽  
Nassima Ait-Daoud ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Ischemic Stroke ◽  
Time Course ◽  
Low Dose ◽  
Statistical Significance ◽  
Cerebral Hypoperfusion ◽  
High Dose ◽  
Double Blind ◽  
Cocaine Use

Cocaine-induced hypoperfusion, a risk factor for ischemic stroke, has not been fully characterized during experimental drug-taking among individuals with cocaine use disorder. We sought to examine cocaine's dose-dependent, time-related effects on cerebral blood flow. In a double-blind, randomized human laboratory study with a counterbalanced order of drug administration, 31 male and female subjects with cocaine use disorder were divided into two groups receiving either (a) low-dose cocaine (0.325 mg/kg intravenously) or placebo ( N = 15) or (b) high-dose cocaine (0.650 mg/kg intravenously) or placebo ( N = 16). The different dose conditions were administered on test days separated by a rest period of ≥48 h. Cerebral blood flow was assessed quantitatively using H2O15 positron emission tomography. Experimentally administered low- and high-dose cocaine conditions versus their corresponding placebo conditions were associated with global and regional hypoperfusion. The trend for high- versus low-dose cocaine to be associated with greater hypoperfusion achieved statistical significance only for the dopamine-rich sublobar and midbrain regions. Cocaine's hypoperfusion effects were maximal at 8 mins after infusion (i.e., at about the expected peak of intravenous cocaine levels) and had mostly dissipated by 32 mins after infusion. Although hypoperfusion occurred throughout the brain, the left hemispheric dopamine-rich sublobar region was the most severely affected. Cocaine-induced cerebral hypoperfusion is associated with the time course of its pharmacological effects, and dopamine-rich areas, particularly in the left hemisphere, may be most vulnerable. Increasingly larger doses of cocaine may be associated with greater risk for ischemic stroke.

Effects of aging on cerebral vascular responses to serotonin in rats

1993 ◽  
Vol 264 (6) ◽  
pp. H2136-H2140 ◽  
Author(s):  
M. A. Hajdu ◽  
R. T. McElmurry ◽  
D. D. Heistad ◽  
G. L. Baumbach
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Low Dose ◽  
Cerebral Arteries ◽  
High Dose ◽  
Aged Rats ◽  
Adult Rats ◽  
Effects Of Aging

The purpose of this study was to examine effects of aging on responses of large cerebral arteries to serotonin. We measured cerebral microvascular pressure (with a micropipette and servo-null method), diameter of pial arterioles, and cerebral blood flow (microspheres) in adult (12- to 14-mo-old, n = 15) and aged (24- to 27-mo-old, n = 14) Wistar rats. Responses to intra-atrial infusion of serotonin (5 and 50 micrograms.kg-1.min-1) were examined. Infusion of the low dose of serotonin decreased mean arterial pressure and pial arteriolar pressure in adult and aged rats to similar levels. Cerebral blood flow was not reduced in adult or aged rats during infusion of the low dose of serotonin. The high dose of serotonin did not affect mean arterial pressure but reduced pial arteriolar pressure [from 46 +/- 4 to 23 +/- 2 (SE) in adult rats and from 52 +/- 3 to 18 +/- 4 mmHg in aged rats]. The high dose of serotonin increased large-artery resistance from 0.9 +/- 0.1 to 1.6 +/- 0.2 in adult rats and from 0.9 +/- 0.1 to 2.7 +/- 0.6 mmHg.ml-1.min.100 g in aged rats. Cerebral blood flow was reduced significantly in aged rats (from 59 +/- 3 to 41 +/- 6 ml.min-1.100 g-1), but not in adult rats, during infusion of the high dose of serotonin. We conclude that aging augments constrictor responses of large cerebral arteries to intravascular serotonin, which results in a reduction of cerebral blood flow in aged but not adult rats.

Effects of indomethacin on brain blood flow, cerebral metabolism, and sagittal sinus prostanoids after hypoxia

1995 ◽  
Vol 269 (4) ◽  
pp. H1450-H1459 ◽  
Author(s):  
M. G. Coyle ◽  
W. Oh ◽  
K. H. Petersson ◽  
B. S. Stonestreet
Keyword(s):  
Blood Flow ◽  
Low Dose ◽  
Cerebral Metabolism ◽  
Brain Regions ◽  
Cerebral Hypoperfusion ◽  
High Dose ◽  
Brain Blood Flow ◽  
Newborn Piglets ◽  
Sagittal Sinus ◽  
Dose Dependent

We tested the hypotheses that during recovery from hypoxia, newborn piglets exhibit a posthypoxic cerebral hyperemia, indomethacin-pretreated piglets exhibit a posthypoxic cerebral hypoperfusion, and that the changes caused by indomethacin are dose dependent and related to the loss of prostanoids. We studied piglets exposed to 40 min of hypoxia after pretreatment with high (5 mg/kg, n = 9) or low (0.3 mg/kg, n = 8) doses of indomethacin or placebo (n = 9) and allowed to recover for 120 min. In the placebo and low-dose pretreatment groups, total and regional brain blood flow increased during hypoxia but returned to baseline 10 min after hypoxia. High-dose indomethacin pretreatment was associated with a posthypoxic hypoperfusion to certain brain regions at 10 min of recovery to values similar to those after indomethacin treatment before the onset of hypoxia. During and after hypoxia, the cerebral metabolic rate of oxygen was preserved in both the placebo and low-dose groups and decreased significantly during hypoxia in the high-dose group. Sagittal sinus prostacyclin was reduced significantly in both indomethacin-treated groups throughout the study. We conclude that a posthypoxic hyperemia is not observed in newborn piglets. This finding was not altered by pretreatment with a therapeutic dose of indomethacin, whereas a pharmacological dose was associated with selective hypoperfusion to certain brain regions both before hypoxia and during recovery from hypoxia.

The effects of etomidate on cerebral metabolism and blood flow in a canine model for hypoperfusion

1991 ◽  
Vol 74 (2) ◽  
pp. 263-269 ◽  
Author(s):  
R. Tyler Frizzell ◽  
Yves J. Meyer ◽  
D. John Borchers ◽  
Bradley E. Weprin ◽  
Elizabeth C. Allen ◽  
...  
Keyword(s):  
Blood Flow ◽  
Dose Group ◽  
Low Dose ◽  
Cerebral Metabolism ◽  
Oxygen Extraction Fraction ◽  
Oxygen Extraction ◽  
High Dose Group ◽  
High Dose ◽  
Cerebral Oxygen ◽  
The Mean

✓ The effects of etomidate, a nonbarbiturate cerebral metabolic depressant, on cerebral metabolism and blood flow were studied in 29 dogs during cerebral hypoperfusion. Three groups of animals were studied during a 45-minute normotensive and a 30-minute hypotensive period: 10 control animals without etomidate, 11 animals receiving a 0.1-mg/kg etomidate bolus followed by an infusion of 0.05 mg/kg/min etomidate (low-dose group), and eight animals receiving doses of etomidate sufficient to suppress electroencephalographic bursts (high-dose group). The mean arterial pressure fell to similar levels (p < 0.05) during hypotension in all three groups (40 ± 5, 38 ± 3, and 27 ± 6 mm Hg, respectively). The mean cerebral oxygen extraction fraction rose (p < 0.05) from 0.23 ± 0.02 to 0.55 ± 0.08 in the five control animals tested and from 0.33 ± 0.02 to 0.53 ± 0.02 in the seven animals tested in the low-dose group, but did not increase (p > 0.05) in the four animals tested in the high-dose group (0.24 ± 0.03 to 0.23 ± 0.05). Mean cerebral blood flow levels decreased in all groups during hypotension (p < 0.05): 42 ± 3 to 21 ±4 ml/100 gm/min (52% ± 12% decrease) in the five animals tested in the control group, 60 ± 8 to 24 ± 6 ml/100 gm/min (56% ± 13% decrease) in the four animals tested in the low-dose group, and 55 ± 8 to 22 ± 3 ml/100 gm/min (60% ± 4% decrease) in the four animals tested in the high-dose group. In summary, the cerebral oxygen extraction fraction increased in the control animals and low-dose recipients during hypotension, suggesting the presence of threatened cerebral tissue. In contrast, the cerebral oxygen extraction did not change during hypotension when high-dose etomidate was administered. It is concluded that high-dose etomidate may preserve the cerebral metabolic state during hypotension in the present model.

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