Effect of Sodium Nitroprusside on Cerebral Blood Flow
Condition: Healthy Male Subjects
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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%.
    

Intervention name(s): Hyperventilation; 6% CO2 breathing; Infusion of sodium nitroprusside
Intervention type(s): Other; Other; Drug
Intervention description(s): The subject is instructed to hyperventilate for 6 min to provoke a 0.7-1.2 kPa reduction in PaCO2, and the evaluation is repeated if the reduction in PaCO2 is not within this interval. The order of hyperventilation and 6% CO2 breathing is randomized.; The subject breathes a mixture of 6% CO2 (with 21% O2 and 73% N2) from a bag and a face mask for 6 minutes. The order of hyperventilation and 6% CO2 breathing is randomized.; Using incremental intravenous infusion of sodium nitroprusside MAP is reduced by 20% (15%-25%) and then by 40% (35%-45%, MAP minimally at 50 mmHg).
Other intervention name(s): Evaluation of CO2 reactivity, hyperventilation; Evaluation of CO2 reactivity, 6% CO2 breathing
Intervention MeSH terms: Nitroprusside
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science