Healthy Male Subjects Clinical Trial
Official title:
Effect of Sodium Nitroprusside on Cerebral Blood Flow
The brain has a high energy demand and requires continuous blood flow. The blood flow to the
brain appears to be unaffected by small changes in blood pressure, but brain blood flow may
be reduced by a large reduction in blood pressure. Large reductions in blood pressure are
common during anesthesia or bleeding. It is unclear, however, how a given reduction in blood
pressure affects blood flow to the brain.
In this study, medicine called sodium nitroprusside is used to dilate blood vessels and
reduce blood pressure in twenty healthy young men. The study will evaluate whether blood flow
to the brain is affected when sodium nitroprusside is used to induce a moderate and a large
reduction in blood pressure. Blood flow to the brain is evaluated using ultrasound on the
neck.
During breathing, oxygen is inhaled and carbon dioxide is exhaled. Carbon dioxide increases
brain blood flow whereby changes in respiration can affect the blood flow to the brain.
Sodium nitroprusside causes mild hyperventilation, whereby more carbon dioxide is exhaled,
which will contribute to a reduction in brain blood flow. Thus, the study will also evaluate
how brain blood flow is affected by hyperventilation and by breathing a mix of air and carbon
dioxide.
Background Cerebral autoregulation is generally considered to maintain cerebral blood flow
(CBF) if mean arterial pressure (MAP) is between 60 and 150 mmHg. Yet, it is controversial
whether there is a plateau for CBF. Thus, blood velocity of the middle cerebral artery (MCA
Vmean), as an index of CBF, is affected by pharmacological changes in MAP between
approximately 40-125 mmHg. In contrast, internal carotid artery blood flow is unaffected by a
moderate decrease in blood pressure.
The brain is supplied by the internal carotid and vertebral arteries that have different
regulation with higher CO2 reactivity and larger orthostatic reduction for the internal
carotid than the vertebral artery. The different regulation of the two arteries may reflect
higher sympathetic innervation of arteries that originate from the internal carotid artery
than those of the vertebral artery. The internal carotid artery may contribute to cerebral
autoregulation as the vessel dilates during a moderate decrease in MAP while internal carotid
artery blood flow is maintained. The arterial CO2 tension (PaCO2) is an important regulator
of CBF and also maintenance of central blood volume and cardiac output is important for
regulation of CBF. In the present study, internal carotid and vertebral artery blood flow is
evaluated using duplex ultrasound in 20 healthy men when MAP is reduced by sodium
nitroprusside, a potent short-lasting vasodilator.
Objective The purpose of the study is to evaluate whether CBF is affected by 20% and 40%
reductions in MAP by sodium nitroprusside. The CO2 reactivity of the internal carotid and
vertebral arteries is evaluated in order to control for hyperventilation during sodium
nitroprusside induced hypotension. Further, the study will evaluate whether changes in
internal carotid and vertebral artery blood flow by a 40% reduction in MAP are different and
whether the arteries have different CO2 reactivity. Lastly, the study will evaluate whether
the slope of the linear regression of CBF and MAP is higher for the evaluations when MAP is
reduced by 40% and 20% than that of the evaluations at baseline and when MAP is reduced by
20%.
Hypotheses
- Sodium nitroprusside-induced reduction in MAP by 40% reduces CBF
- Sodium nitroprusside-induced reduction in MAP by 20% reduces CBF
- Sodium nitroprusside-induced reduction in MAP by 40% causes a larger relative reduction
in internal carotid artery blood flow than that of the vertebral artery
- The CO2 reactivity of the internal carotid artery is higher than that of the vertebral
artery
- The slope of linear regression of MAP and CBF at the evaluations when MAP is reduced by
20% and 40% by sodium nitroprusside is higher than that of the evaluations at baseline
and when MAP is reduced by 20%
Methods The study will include 20 healthy men. The experiment lasts for approximately three
hours and the subject must be fasting for at least 4 hours, have abstained from alcohol and
caffeine for 12 hours and rigorous exercise for 24 hours. Before the start of the experiment,
the internal carotid and vertebral arteries are evaluated and in case the vessels can not be
visualized, e.g. because of high carotid bifurcation, the subject will not be able to
participate in the study. The subject rests in the supine position throughout the study.
Measurements A catheter is placed in the radial or brachial artery on the non-dominant arm
for evaluation of arterial pressure and gas variables. Total volume of blood sampled is less
than 25 ml. A long line is placed in a cubital vein and advanced to the subclavian vein for
infusion of sodium nitroprusside. The arterial pressure measurement is used for evaluation of
stroke volume, cardiac output, and total peripheral resistance by modified pulse contour
analysis. Heart rate is evaluated by electrocardiogram lead II. Forehead skin oxygenation and
blood flow is evaluated close to the hairline using Laser Doppler flowmetry with an
integrated oxygenation sensor at a depth of 1-2 mm in an area of approximately 9 mm^2.
Cerebral and biceps muscle oxygenation are evaluated using near-infrared spectroscopy .
Transcranial Doppler is used to evaluate MCA Vmean. At a constant diameter of the MCA,
changes in blood velocity reflect those of regional CBF, but the diameter may be affected by
changes in MAP and PaCO2.
Changes in central blood volume are evaluated by recording of thoracic electric admittance.
Central hemodynamics, MCA Vmean, electrocardiogram, and skin oxygenation and blood flow is
recorded at 100 hertz, cerebral and muscle oxygenation is recorded at 0.1 hertz, and thoracic
admittance at 0.25 hertz and saved on a pc.
Internal carotid and vertebral artery blood flow is evaluated unilaterally on the neck using
duplex ultrasound. Evaluation is in the longitudinal section 1-2 cm distal to the carotid
bifurcation and the vertebral artery is evaluated between the transverse processes of C2-5
with the head turned approximately 30⁰ to the contralateral side. In order to limit the
influence of ventilation, two recordings of approximately 20 s of both arteries are conducted
at each level of MAP and the mean is reported. A frequency of 8-12 megahertz is used and gain
is set as high as possible while vessel lumen is echo-free. Pulsed-wave Doppler at a stable
angle ≤ 60º determined the angle-corrected time averaged maximum flow velocity (TAVMAX), that
corresponds to twice the mean blood velocity. Diameter is assessed using automatic software
to track the vessel wall and blood flow is: 0.125 * 60 * TAVMAX * π * diameter^2 and CBF is
the sum of unilateral internal carotid and vertebral artery blood flow.
The CO2 reactivity of the internal carotid and vertebral artery is: change in blood flow *100
/ change in PaCO2 * baseline blood flow using individual linear regression for the
evaluations during normo-, hypo-, and hypercapnia. The CO2 reactivity of MCA Vmean and
cerebral oxygenation is evaluated similarly and measurements during sodium nitroprusside
infusion are corrected for changes in PaCO2 from baseline using the CO2 reactivity to
hypocapnia.
Procedures Baseline evaluation at rest is conducted at least 30 min after placement of
catheters. Subsequently, the CO2 reactivity is evaluated during hypo- and hypercapnia in
random order. Hypocapnia is attained by hyperventilation for 6 min to provoke a 0.7-1.2
kilopascal (kPa) reduction in PaCO2, and the evaluation is repeated if the reduction in PaCO2
is not within this interval. Hypercapnia is achieved by breathing 6% CO2 for 6 min.
Thereafter, sodium nitroprusside is infused to reduce MAP by 20% (15%-25%) and 40% (35%-45%
and minimally MAP 50 mmHg at a maximal infusion rate of 10 µg/(kg*min)). Sodium nitroprusside
is a short-acting, potent vasodilator that activates guanylate cyclase directly or by
production of nitric oxide, causing relaxation of smooth muscle cells in arteries and veins.
The effect of sodium nitroprusside is attained within 2 min, and the half-life is 2 min
whereby the effect is short lasting. Sodium nitroprusside has no direct effect on CBF.
Infusion of sodium nitroprusside is by an electronic infusion pump, at 0.25 µg/(kg*min) for
one minute and increased by 0.25 µg/(kg*min) each minute. The effect on MAP is evaluated each
minute before the infusion speed is increased. When a level of MAP is reached, MAP is
maintained for another minute where after measurements are conducted during 2-3 min. When
evaluations have been done at both levels of MAP, the infusion speed is reduced gradually in
order to avoid so-called "rebound hypertension". At this time the experiment is finished and
catheters are removed.
Statistics Trial size: In a similar study, sodium nitroprusside-induced reduction in MAP by
43% decreased CBF by 15% after correction for the decrease in PaCO2. A power calculation
indicates that at least 14 subjects are required to detect a 15% reduction in CBF with a
standard deviation of 18% when MAP is reduced by 40% by sodium nitroprusside with a 5%
significance level and a power of 80%.
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