Pulsatile Perfusion Therapy Phase II

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.

Inclusion criteria

• Aged 18 to 40 years
• Non-tobacco/nicotine users (e.g., cigarettes (including electronic cigarettes), chewing tobacco, nicotine gum or patches)
• Systolic arterial pressure <140 mmHg; diastolic arterial pressure <90 mmHg
• Normal 12-lead ECG (reviewed by a physician)
• Normal clinical results from a medical exam reviewed by a board certified physician (e.g., General Health Questionnaire - see attached document)
• Easily visualized internal carotid and vertebral arteries (via Doppler ultrasound) for accurate measurement of velocity and diameter.
• Body mass index (BMI) <30 kg/m2 unless athletic/muscular build; calculation = body weight (kg)/height (m2); this criteria is used to ensure subjects will fit inside the LBNP chamber
• Females only: documentation of a negative pregnancy test prior to the familiarization and experimental sessions

Exclusion criteria

• Age <18 or >40 years
• Use of tobacco/nicotine within the last 6 months (e.g., cigarettes (including electronic cigarettes), chewing tobacco, nicotine gum or patches)
• Body mass index (BMI) >30 kg/m2 unless athletic/muscular build; calculation = body weight (kg)/height (m2)
• Not abstaining from the following 24 hours prior to the experimental session: exercise, alcoholic substances, prescription or non-prescription medications (unless cleared by the medical screener), dietary supplements, herbal medications, caffeinated substances (including coffee, tea (iced or hot), caffeinated energy drinks or sodas).
• Inability to visualize the internal carotid and vertebral arteries (via Doppler ultrasound) for accurate measurement of velocity and diameter.
• Positive pregnancy test
• Post-menopausal females
• Females with an erratic/irregular menstrual cycle
• Use of prescription drugs, non-prescription drugs or herbal medicines known to alter cardiovascular, autonomic, or cerebrovascular function unless cleared prior to the study
• Use of anti-hypertensive medications
• Use of beta blockers
• Frequent use of bronchodilators (occasional use, i.e. seasonally, is allowable)
• Use of anti-coagulant therapy
• Use of non-contraceptive related hormone therapy
• Current or past history of hyperthyroidism, or other thyroid hormone-related disease
• Signs of cardiovascular abnormalities (e.g., resting systolic blood pressure >140mmHg or diastolic blood pressure >90mmHg; abnormal 12-lead ECG)
• History of cerebrovascular abnormalities (e.g., prior stroke, transient ischemic attacks, epilepsy)
• Known history of atherosclerosis of the carotid arteries (i.e., plaque formation)
• History of concussion and or other loss of consciousness within the preceding month
• Autonomic dysfunction (e.g., Shy-Drager Syndrome, Bradbury-Eggleston syndrome, sinus arrhythmia, idiopathic orthostatic hypotension, fainting disorder)
• Respiratory illnesses (e.g., chronic asthma (including exercise-induced asthma), Chronic Obstructive Pulmonary Disease, Reactive Airway Disease)
• History of anaphylaxis
• Known allergies to medications or other substances (e.g. latex) unless cleared prior to the study
• History of pre-syncopal/syncopal episodes or orthostatic hypotension
• Donated blood within the last 60 days
• History or family history of abnormal blood clotting, clots in deep veins in the legs or pelvis, or blood clots to the lungs aa) Known or suspected abdominal hernia bb) History of alcohol or drug abuse which inhibits the subject's ability to complete this study cc) Known depression, anxiety, or any other mental health issue which inhibits the subject's ability to complete this study dd) Known claustrophobia ee) Previous positive diagnosis of COVID-19