Erythropoietin Protect the Cerebral Blood Flow and Oxygenation During Simulated Dive?
Description:
Background
During facial cooling and especially during breath hold, can mammals – and also humans –
elicit a so called dive reflex, causing bradycardia, peripheral vasoconstriction and
centralization of blood flow to brain, lungs and heart (18 Foster et al 2005), but the reflex
is suppressed by physical activity. The dive reflex can be elicited by breath hold alone and
will be more pronounced during simultaneously facial cooling, but not by stimulation of other
skin receptors (19 Asmussen et al 1968).
Intrapleural pressure and lung volume affects the dive reflex in a way so that the less part
of vital capacity being used, the more pronounced bradycardia. This is explained by the fact
that the pulmonary stretch receptors are activated less by smaller lung volumes and thereby
sending a smaller vagal afferent output.
The dive reflex has an oxygen conserving effect, because of intense vasoconstriction in both
viscera and muscles, and simultaneously with reduction in cardiac output (CO). Therefore
plasma lactate will rise, to compensate for the lesser regional blood flow. If one
hyperventilates with 100 % oxygen, then the reflex can still be elicited, but it is more
pronounced during asphyxia. Experienced sports divers, who has been diving for more than 7-10
years have reduced post apnea acidosis and oxidational stress (18 Foster et al 2005), but
probably also less sensitivity for progressive hypoxia and hypercapnia, because these
individuals have a more pronounced dive reflex.
Persons with sleep apnea are, like trained breath hold divers, exposed for repetitive
episodes of hypoxia and hypercapnia during their sleep, of up to 30 to 60 seconds, and they
have developed a lesser sensitivity for this. These patients does typically have chronically
higher activity of the sympathetic nervous system, higher peripheral resistance and blood
pressure (18 Foster et al 2005).
SCUBA Sports divers, who dive more than 100 times a year, especially in cold water have
diminished cerebral blood flow and a cognitive deficit (20 Slosman et al 2003). Age and body
mass index (BMI) are associated to diminished cerebral blood flow and the cognitive deficit,
possibly because, SCUBA divers with higher BMI, have larger pools of nitrogen in their
adipose tissues, which then gives smaller non-symptomatic incidences of decompression
sickness (20 Slosman et al 2003). But is obvious to assume, that it could be caused by
diminished cerebral blood flow, because of the dive reflex.
Also climbing to high altitudes (between 54488 and 8848 m) is shown to give cognitive
deficit. Those who had the most pronounced symptoms, where very sensitive to hypoxia by
hyperventilation. It was suspected, that hypocapnia because of hyperventilation was causing
diminished cerebral blood flow (33 Hornbein TF et al 1989).
Transcranial Doppler ultrasonography (TCD) gives a reproducibly value for brain perfusion by
continuous non-invasive real-time sampling (14 Aslid et al 1982). A single piezo-electrical
transducer sends and collects ultrasound through the temporal region of the scull, where it
is the thinnest. Hereby can the blood flow of arteria cerebri anterior, media (MCA) and
posterior and basilaris be estimated.
With TCD it can be shown which parts of the brain, that are activated during static and
dynamic work (15 Colebatch et al 1991, 16 Dahl et al 1992). Also vasodilatation when CO2 is
high is seen as a rise in arterial blood flow, and small emboli sends a characteristic signal
during carotid surgery (17 Halsey et al 1986).
With Blood Oxygenation Level-Dependent functional Magnetic Resonance imaging, BOLD fMRI is it
shown that breath hold induced hypercapnia gives a higher cerebral blood flow in sensorimotor
cortex, frontal cortex, in ganglia basale, in visual cortex and in cerebellum (21 Kastrup et
al 1999). The largest changes are seen in cerebellum and the smallest in frontal cortex (21
Kastrup et al 1999).
With TCD it can be shown that the cerebral blood flow rises in MCA in healthy subjects during
facial cooling, with normal ventilation, when resting in a supine position without affecting
the systemic blood pressure (22 Browna et al 2003). Single Photon Emission Computerized
Tomography (SPECT)-scanning during normo-baric and hyperbaric pressure of professional divers
breathing 100% oxygen has shown to reduce the cerebral blood flow in several regions of the
brain (23 Di Pieroa et al 2002).
The brain metabolism depends on a continuously supply of glucose, which is suppressed during
the hypoglycemia induced by prolonged work (1 Nybo et al 2003). The brain is though capable
of using other substrates to a certain extent , like lactate which is absorbed in an amount
proportionally with the arterial concentration (2 Dalsgaard et al 2003). So it seems that the
brain during prolonged work is capable of having an absorption of lactate to the same amount
as glucose. Also it seems that lactate is being metabolized, since it is not accumulated in
spinal fluid or brain tissue (3 Madsen et al 1999). At rest the brain absorption of glucose
is balanced by a proportional oxygen absorption (approximately 1:6). When the brain is
activated, this equilibrium is disturbed regionally (4 Fox Raichle et al 1986) and globally
(5 Madsen 1995). At rest, where the concentration of lactate in serum is low, is the
importance of lactate for brain metabolism minimal, but during physical activity, where
plasma lactate rises, is the absorption increasing and it contributes to the lowering in
brain metabolic ratio.
The underlying cause for the fall in brain metabolic ratio during physical activity is not
known. But the excessive amount of carbohydrate (in proportion to oxygen ) can reach a level,
comparable to the total amount of brain glycogen (6 Dalsgaard et al 2004).
Also the activated brain seems to free IL-6 and HSP-72 (7 Nybo et al 2002). On the other hand
only a small amount of ammonium is absorbed by the brain (8 Nybo et al 2005), which partly –
besides a rise in temperature (9 Nybo et al 2002) – explains, why brain autoregulation is
less stable during especially intense physical activity (10 Ogoh et al 2005), as known from
patients in coma caused by hepatic failure (11 Larsen et al 1996).
A possible explanation for the fall in brain metabolic ratio during physical activity is that
this mechanism can be overruled in rat brain after administration of the non-specific
beta-blocking drug propanolol (12 Schmalbruch et al 2002), while the cardioselective drug
metoprolol does not have the same effect in humans (13 Dalsgaard et al 2004).
But it is yet unknown how brain blood flow and metabolism are affected by an "face immersion
dive" and simultaneously prolonged physical activity, and hence a rise in lactate under
hyperbaric pressure (3 m dybde), breathing atmospheric air, similar to the circumstances for
trained scuba divers work.
Presumably it will cause a fall in brain blood flow and in time cognitive deficits.
Erythropoietin (rhEPO) is a well known drug, used as doping in sports for about 15 years (24
Parisotto R et al, 2001). So far the only known enhancement in athletic achievement by rhEPO
is caused by peripheral improvements and especially blood capability to transport oxygen to
the working muscles (25 A Gaudard et al, 2003); this has been documented by a rise in
haematocrit (25 A Gaudard et al, 2003). rhEPO has also a neuroprotective effect on neurones
in patients with neuron damage caused by cerebral hypoxic ischeamia (26, HH Marti 2004).
rhEPO work also on a series of cerebral mechanisms, including enhanced motor and spatial
learning, increased dopamine production and improved neural function through activation of
calcium-channels (26, HH Marti 2004). Enhanced motor learning may improve the professional
divers choices during work and may be also physical performance and mechanical efficiency.
Less dopamine-concentration in the brain can cause enhanced fatigue, and increased dopamine
production caused by treatment with rhEPO may delay fatigue during physical activity.
Intravenous injection of rhEPO will increase rhEPO in cerebrospinal fluids, since rhEPO is
capable of crossing blood brain (26, HH Marti 2004). All together this may indicate that
rhEPO, not only works on physical performance, but also has effects on the brain. An enhanced
concentration of rhEPO could improve brain function by stimulating neural function and
thereby induce increased release of dopamine, reduce mismatch between oxygen and glucose
absorption, improve voluntarily activation and increase effect through improved motor
learning. rhEPO has also an effect on the condition of cancer and dialysis patients, not only
explained by merely increased heamocrit (27, W Jelkmann, 2004).
This project will add new knowledge in the understanding of the mechanisms of clinical use of
rhEPO.
Erythropoietin (EPO) is a heamatopoietic growth factor primarily synthesized in the kidneys.
It stimulates erythropoiesis. New investigations has shown that EPO can be neuroprotective in
cerebral ischaemia, brain trauma, autoimmune encephalomyelitis and kainattoksicitet (26, HH
Marti 2004)). The pathophysiology is yet unknown, but may secondarily to gene induction,
through suppression of the inflammatory response, such as inducible nitrogen oxide synthesis
(iNOS) and mitogen activated protein kinase (MAPK), to suppress apoptosis. Also it may be
plausible, that EPO upregulates antioxidants. In rats rhEPO has increased survival after
circulatory shock, induced by total ischemia / reperfusion of the splanchnicus (28 F
Squadrito et al, 1999). Treatment with rhEPO suppressed activity of endotoxin mediated
increase in NO. rhEPO suppresses the production of iNOS in smooth muscle cells after
stimulation of the proinflammatory IL-1. These effects of rhEPO are expressed from hours to
days after treatment with rather high solitary doses and seems to be independently mediated
by the erythropoietic effect, which can only be achieved after weeks continuous treatment
with rhEPO (29 E Kusano et al, 1999, 30 Brines ML et al, 2000).
Purpose of this study The purpose of this study is to investigate, how brain blood flow and
metabolism are affected by face immersion dive and simultaneously breath hold during
normo-baric and hyperbaric pressure (3 m depth) when breathing atmospheric air in trained
sports divers. IL-6, HSP-72, lactate, ammonium and body-temperature will be measured. Brain
and muscle oxygenation will be measured by near-infrared spectroscopi (NIRS). Furthermore we
will investigate whether a small dose of rhEPO affects mentioned parameters during simulated
dive in pressure chamber with facial cooling.
Hypothesis Brain blood flow in trained divers will be diminished during prolonged physical
activity during simultaneously face immersion dive and breath hold under hyperbaric pressure
when breathing atmospheric air.
There will be a release of IL-6 and HSP-72. Pretreatment with a small amount of rhEPO before
prolonged physical activity during simulated dive has a protective effect on brain blood flow
and oxygenation.
Condition:
Healthy
Treatment:
Recombinant human Erythropoietin
Start Date:
August 2005
Sponsor:
Rigshospitalet, Denmark
For More Information:
https://clinicaltrials.gov/show/NCT00265486