Pulsatile Perfusion Therapy Phase II
Condition: Hemorrhage
MeSH terms: Hemorrhage
Study type: Interventional

Summary: 
      Individuals who suffer from a stroke, cardiac arrest, or traumatic bleeding (hemorrhage)
      injuries often have compromised blood flow and oxygen to the brain which can lead to the
      death of brain cells, and if the patient survives, subsequent difficulty in thinking and
      performing tasks of daily living. Traditionally, delivery of a constant flow of blood to the
      brain has been thought to be the most important factor for the survival of brain cells. In
      this study, a novel intervention will be assessed called "pulsatile perfusion therapy",
      delivering blood flow in a slow pulsing pattern. It is anticipated this intervention will
      improve brain blood flow and oxygenation during these serious clinical events.

      There is a specific interest in whether delivery of brain blood flow with a slow pulsatile
      pattern will improve oxygenation of brain tissue, particularly when the brain is challenged
      under low oxygen (hypoxia) and low volume (hypovolemia) conditions, simulating stroke,
      cardiac arrest, and hemorrhage. A technique called oscillatory lower body negative pressure
      (OLBNP) will be used in healthy human participants, facilitating delivery of blood flow to
      the brain with different pulsing patterns. This technique will allow for determination of the
      ideal pattern of brain blood flow that improves oxygenation of the brain tissue. Measurements
      will be made of substances in the blood that may be released with pulsatile flow which act on
      the blood vessels to increase flow and delivery of oxygen.
    

Detailed description: 
      Hemorrhage due to trauma is one of the leading causes of morbidity and mortality worldwide in
      both the civilian and military settings. A major factor contributing to death and disability
      from severe blood loss is poor tissue perfusion and oxygenation of the vital organs.
      Traditionally, protection of absolute cerebral blood flow (CBF) has been deemed the most
      important factor in maintaining perfusion and oxygenation. In recent years, it has been shown
      that low frequency (LF, ~0.1 Hz) pulsatile CBF is associated with increased tolerance to
      simulated hemorrhage in healthy human subjects, despite ≥30% reductions in absolute CBF. The
      underlying mechanism for this improvement in tolerance is unclear; the proposed study aims to
      address this knowledge gap. The central hypothesis is that LF oscillations (~0.1 Hz) will
      improve CBF and tissue oxygenation under hypoxic and/or hypovolemic conditions, due to
      increased shear stress and the release of vasoactive mediators that facilitate vasodilation
      and enhanced tissue perfusion. This hypothesis will be addressed in two Specific Aims under
      hypoxic and hypovolemic conditions: 1) determine if inducing oscillations in arterial blood
      pressure and CBF at 0.1 Hz elicits shear stress-induced vasodilation, subsequently increasing
      CBF and oxygenation; and, 2) assess the effect of 0.1 Hz oscillations on the release of shear
      stress-induced vasoactive mediators. Twenty human subjects (males and females) will be
      recruited to address these aims using oscillatory lower body negative pressure (OLBNP) to
      induce 0.1 Hz oscillations. Measurements will include CBF (intracranial & extracranial
      arteries), shear stress, cerebral oxygenation, arterial pressure, and venous blood samples
      for assessment of nitric oxide, prostaglandin E2, 6-keto-PGF1α (a metabolite of prostacyclin,
      PGI2), histamine, and endothelin-1. The rationale for the proposed research is to identify a
      mechanism for the previously observed increase in tolerance to simulated hemorrhage with
      increases in LF oscillations in arterial pressure and CBF. The approach is innovative as it
      challenges the traditional association of hemodynamic variability with negative clinical
      outcomes using a novel methodological approach in human subjects. This contribution is
      significant as the findings may provide an alternative approach to maintaining cerebral
      perfusion and oxygenation under conditions of hypovolemia and/or hypoxia.
    

Intervention name(s): 0 Hz Control; 0.1 Hz PPT; 0.05 Hz PPT
Intervention type(s): Other; Other; Other
Intervention description(s): Lower body negative pressure (LBNP) applied to -60 mmHg for 10-min; Lower body negative pressure (LBNP) applied at a frequency of 0.1 Hz from -30 mmHg to -90 mmHg; Lower body negative pressure (LBNP) applied at a frequency of 0.05 Hz from -30 mmHg to -90 mmHg
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science