The ability to quickly diagnose hemorrhagic shock is critical for favorable patient outcomes. Therefore, it is important to understand the time course and involvement of the various physiological mechanisms that are active during volume loss and that have the ability to stave off hemodynamic collapse. This review provides new insights about the physiology that underlies blood loss and shock in humans through the development of a simulated model of hemorrhage using lower body negative pressure. In this review, we present controlled experimental results through utilization of the lower body negative pressure human hemorrhage model that provide novel insights on the integration of physiological mechanisms critical to the compensation for volume loss. We provide data obtained from more than 250 human experiments to classify human subjects into two distinct groups: those who have a high tolerance and can compensate well for reduced central blood volume (e.g. hemorrhage) and those with low tolerance with poor capacity to compensate.We include the conceptual introduction of arterial pressure and cerebral blood flow oscillations, reflex-mediated autonomic and neuroendocrine responses, and respiration that function to protect adequate tissue oxygenation through adjustments in cardiac output and peripheral vascular resistance. Finally, unique time course data are presented that describe mechanistic events associated with the rapid onset of hemodynamic failure (i.e. decompensatory shock). Impact Statement: Hemorrhage is the leading cause of death in both civilian and military trauma. The work submitted in this review is important because it advances the understanding of mechanisms that contribute to the total integrated physiological compensations for inadequate tissue oxygenation (i.e. shock) that arise from hemorrhage. Unlike an animal model, we introduce the utilization of lower body negative pressure as a noninvasive model that allows for the study of progressive reductions in central blood volume similar to those reported during actual hemorrhage in conscious humans to the onset of hemodynamic decompensation (i.e. early phase of decompensatory shock), and is repeatable in the same subject. Understanding the fundamental underlying physiology of human hemorrhage helps to test paradigms of critical care medicine, and identify and develop novel clinical practices and technologies for advanced diagnostics and therapeutics in patients with life-threatening blood loss.

Vital signs historically served as the primary method to triage patients and resources for trauma and emergency care, but have failed to provide clinically-meaningful predictive information about patient clinical status. In this review, a framework is presented that focuses on potential wearable sensor technologies that can harness necessary electronic physiological signal integration with a current state-of-the-art predictive machine-learning algorithm that provides early clinical assessment of hypovolemia status to impact patient outcome. The ability to study the physiology of hemorrhage using a human model of progressive central hypovolemia led to the development of a novel machine-learning algorithm known as the compensatory reserve measurement (CRM). Greater sensitivity, specificity, and diagnostic accuracy to detect hemorrhage and onset of decompensated shock has been demonstrated by the CRM when compared to all standard vital signs and hemodynamic variables. The development of CRM revealed that continuous measurements of changes in arterial waveform features represented the most integrated signal of physiological compensation for conditions of reduced systemic oxygen delivery. In this review, detailed analysis of sensor technologies that include photoplethysmography, tonometry, ultrasound-based blood pressure, and cardiogenic vibration are identified as potential candidates for harnessing arterial waveform analog features required for real-time calculation of CRM. The integration of wearable sensors with the CRM algorithm provides a potentially powerful medical monitoring advancement to save civilian and military lives in emergency medical settings.

The inability to compensate for acute central hypovolemia underlies the clinical development of orthostatic hypotension and instability (e.g., syncope). Although neuro-humoral control of both cardiac output and peripheral vascular resistance contributes to hemodynamic stability during orthostasis, a notion has been proposed that the failure of adequate peripheral vascular constriction rather than cardiac responses represents the primary mechanism the development of orthostatic intolerance. This review article provides an opportunity to present compelling evidence captured over the past 30 years in our laboratory to support the concept that neural-mediated tachycardia during orthostasis in healthy individuals represents a critical response to tolerating acute reduction in central blood volume in addition to, and independent of, peripheral vascular constriction. In this review paper, data are presented from experiments using graded lower body negative pressure (LBNP) as a method to induce orthostatic intolerance in two experimental human models: 1) comparison of heart rate and autonomic responses in individuals with relatively high and low tolerance to LBNP; and 2) vagal and sympathetic blockade of cardiac neural control. These experiments revealed that: 1) greater elevations in heart rate are associated with higher orthostatic (LBNP) tolerance; 2) higher orthostatic heart rate is associated with greater sympathetic nerve activity and withdrawal of vagally-mediated cardiac baroreflex response; and 3) nonspecific sympathetic blockade causes a pronounced reduction in heart rate and LBNP tolerance. Cardiac parasympathetic withdrawal contributes to protection against development of hypotension during the initial seconds of transition to an orthostatic challenge, while the primary mechanism by which tachycardia defends orthostatic stability in healthy subjects for extended durations is mediated predominantly through sympathetic adrenergic control.

The objective of this minireview is to describe the physiology and potential clinical benefits derived from inspiration. Recent animal and clinical studies demonstrate that one of the body’s natural mechanisms associated with inspiration is to harness the respiratory pump to enhance circulation to vital organs. There is evidence that large reductions in intrathoracic pressure (>20 cmH₂O) caused by some inspiration maneuvers (e.g., Mueller maneuver) or pathophysiology (e.g., heart failure, chronic obstructive lung disease) can result in adverse hemodynamic effects. However, the respiratory pump can improve cardiovascular functions when a “sweet spot” for generation of negative intrathoracic pressure during inspiration can be maintained at or less than 10 cmH₂O below normal inspiration. These beneficial physiological effects include greater cardiac filling and output, lower intracranial pressure, cardiac baroreflex resetting, greater cerebral blood flow oscillatory patterns, increased vascular pressure gradients, and promoting sustained feedback between sympathetic nerve activity and arterial pressure. In addition to promoting gas exchange, data obtained from numerous animal and human experiments have provided new insights into “the other side of breathing”: the modulation of circulation by reduced intrathoracic pressure generated during inspiration. The translation of these physiological relationships form the basis for the development and application of technologies designed to optimize the intrathoracic pump for treatment of clinical conditions associated with hypovolemia including cardiac arrest, orthostatic hypotension, hemorrhagic shock, and traumatic brain injury. Harnessing these fundamental mechanisms that control cardiopulmonary physiology provides opportunities to use inspiration as a potential tool to help treat significant and often life-threatening circulatory disorders.

Based on evidence extracted from a cross-sectional review of the literature, we sought to advance a novel conceptual framework that the physiology of hemorrhagic shock from exsanguination and maximal oxygen uptake ([ ]O₂max), induced by physical exercise, shares key common features. As such, this review focuses on the notion that intolerance to inadequate oxygen delivery (DO₂) resulting from associated states of hypovolemia appears to be a common physiological link that “connects” hemorrhagic shock to the physiology that limits maximal aerobic capacity. Our approach focuses on the similarities in a complex cascade of cardiopulmonary, metabolic and autonomic compensatory responses during hemorrhage and maximal physical exertion that ultimately function to avoid critical levels of DO₂ (DO_2crit) and are manifested by elevation in blood lactate levels. We introduce a paradigm of absolute (i.e. hemorrhage) versus relative (i.e. exercise) hypovolemia as a primary physiological factor that contributes to reaching DO_2crit, and define the concept of “O₂ deficit” to replace the clinical concept of O₂ debt. Using the peer-reviewed literature, we provide human data obtained from patients who suffered hemorrhagic shock from severe blood loss and compare it to healthy subjects who performed maximal exercise. We include a novel conceptual framework of the continuum of metabolic relationship between DO₂ and [ ]O₂ that is manifested as the final step during both progressive blood loss leading to hemorrhagic shock and at [ ]O₂max. We present evidence to support the contribution of utilizing “O₂ extraction reserve” as the initial mechanism for developing an O₂ deficit, and the notion of individual variability in compensatory responses. In the absence of reversing inadequate DO₂, an increased reliance on O₂ extraction reserve, cellular anaerobic glycolysis, and phosphocreatine stores to supplement the energy required by the tissues for normal function will deplete a finite capacity for compensation. In the end, acidity reflected by a blood pH ≤ ∼7.0 leads to disturbance of normal cell functioning of metabolic machinery manifested by irreversible shock in the case of hemorrhage or physical exhaustion when [ ]O₂max is reached. Impact statement: Disturbance of normal homeostasis occurs when oxygen delivery and energy stores to the body’s tissues fail to meet the energy requirement of cells. The work submitted in this review is important because it advances the understanding of inadequate oxygen delivery as it relates to early diagnosis and treatment of circulatory shock and its relationship to disturbance of normal functioning of cellular metabolism in life-threatening conditions of hemorrhage. We explored data from the clinical and exercise literature to construct for the first time a conceptual framework for defining the limitation of inadequate delivery of oxygen by comparing the physiology of hemorrhagic shock caused by severe blood loss to maximal oxygen uptake induced by intense physical exercise. We also provide a translational framework in which understanding the fundamental relationship between the body’s reserve to compensate for conditions of inadequate oxygen delivery as a limiting factor to [ ]O₂max helps to re-evaluate paradigms of triage for improved monitoring of accurate resuscitation in patients suffering from hemorrhagic shock.