The physiology of blood loss and shock: New insights from a human laboratory model of hemorrhage

Abstract

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.

Keywords: Tissue oxygenation; lower body negative pressure; resuscitation; trauma; vital signs.

Figure 1

(a) Human subject undergoing lower body negative pressure (LBNP). (b) Depiction of standard protocol with definition of high tolerant and lower tolerant subjects. (c) Representative figure of an arterial pressure waveform during LBNP leading to decompensation. (d) Percent change in stroke volume from baseline during four steps of hemorrhage () and LBNP (•) in baboons corresponding to 6.25% (n = 14), 12.5% (n = 14), 18.75% (n = 14) and 25% (n = 12) total blood volume loss. Human responses to six levels of LBNP are superimposed (). Data are expressed as mean ± SD. Modified from Convertino et al. and Hinojosa-Laborde et al.

Figure 2

Kaplan–Meier analysis of healthy human subjects undergoing LBNP until symptoms of presyncope are evident. Both panels utilize the same data. (a) Analysis of time to presyncope in minutes in subjects categorized as high tolerant or low tolerant. (b) Analysis of time to presyncope (minutes) in subjects categorized as male or female. (A color version of this figure is available in the online journal.)

Figure 3

(a) Real-time Transcranial Doppler (TCD) recording (top panel) of cerebral blood flow velocity (CBFV) in a human subject at rest (∼80 cm·s⁻¹) and during progressive LBNP who decompensates at −70 mmHg LBNP (lower panel recording) at a CBFV of ∼5 cm·s⁻¹. (b) Mean medial cerebral artery blood flow velocity (MCAv) during progressive reductions in central blood volume in high-tolerant and low-tolerant subjects. †P < 0.05 compared with corresponding LT value. Modified from Rickards et al. (A color version of this figure is available in the online journal.)

Figure 4

(a) Mean arterial pressure (MAP), (b) cardiac output, (c) peripheral vascular resistance (PVR), (d) stroke volume, (e) heart rate, (f) baroreflex sensitivity (BRS), and (g) muscle sympathetic nerve activity (MSNA) at baseline (open bars) and at decompensation (closed bars) in high-tolerant (HT) and low-tolerant (LT) subject groups. Bars and lines represent mean ± 1 sem. †P < 0.001 compared with corresponding LT value. Modified from Convertino et al. (h) MSNA recordings at baseline (BL), sub-maximal LBNP (SM), and presyncope (PS) in HT (top panel) and LT (bottom panel) subjects

Figure 5

(a) Plasma renin-angiotensin activity, norepinephrine, and vasopressin levels at decompensation in high-tolerant (open bars) and low-tolerant (lined bars) subject groups. Bars and lines represent mean ± 1 sem. † P < 0.05 compared with corresponding LT value. Modified from Convertino and Sather. (b) LBNP tolerances during placebo (open bar), atropine (closed bar), and propranolol (lined bar) treatments in low (LT, n = 5) and high (HT, n = 6) LBNP-tolerant individuals. Symbols are mean ± 1 sem. †P < 0.05 compared with corresponding LT value. Modified from Convertino and Sather. (c) Changes (Δ) in peripheral vascular resistance and heart rate during placebo (open bar) and atropine (closed bar) treatments in low (n = 5) and high (n = 6) LBNP-tolerant individuals. Symbols are mean ± 1 sem. Modified from Convertino. (d) Changes (Δ) in peripheral vascular resistance and heart rate during placebo (open bar) and propranolol (closed bar) treatments in low (n = 5) and high (n = 6) LBNP-tolerant individuals. Symbols are mean ± 1 sem. †P < 0.05 compared with corresponding LT value. Modified from Convertino.

Figure 6

(a) Continuous recordings demonstrating the tight coupling between arterial diastolic blood pressure oscillations (DBP; upper tracing) and muscle sympathetic nerve activity (MSNA; lower tracing) that act to provide alternating perfusion to the brain and peripheral tissue under conditions of low circulating blood volume. Modified from Convertino. (b) Arterial waveform recordings demonstrate that pronounced oscillatory patterns are associated with high tolerance to progressive reduction in central blood volume (bottom recording) compared to low tolerance (top recording). Modified from Convertino et al.

Figure 7

(a) Arterial waveform recordings of the medial cerebral artery blood flow velocity (MCAv) demonstrate that pronounced oscillatory patterns are associated with high tolerance to progressive reduction in central blood volume (bottom recording) compared to low tolerance (top recording). Modified from Convertino et al. (b) Individuals with high tolerance to central hypovolemia (closed bars) display greater oscillations in mean medial cerebral artery blood flow velocity (MCAv) at the onset of decompensation (right panel) compared to individuals with low tolerance (open bars), but tolerate lower levels of mean MCAv (left panel). Symbols are mean ± 1 sem. †P < 0.05 compared with corresponding LT value. Modified from Rickards et al. (A color version of this figure is available in the online journal.)

Figure 8

(a) Results from experiments conducted using an animal (porcine) model of 40% controlled hemorrhage demonstrate that reduced intrathoracic pressure lowers right atrial pressure, which in turn pulls more venous blood back into the thorax and increases arterial pressure and reduces intracranial pressure, which together increase cerebral perfusion. Modified from Convertino et al. (b) Arterial waveform recordings demonstrate that a delay in the onset of symptoms and hemodynamic decompensation is associated with increases in CBFV oscillations when intrathoracic pressure is reduced by breathing against resistance (bottom recording) compared to breathing with normal intrathoracic pressure in the same subject (top recording). Modified from Convertino et al. (c) Individuals with high tolerance to central hypovolemia (closed bars) display greater oscillations in mean medial cerebral artery blood flow velocity (MCAv) at the onset of decompensation (right panel) compared to individuals with low tolerance (open bars) despite similar levels of mean blood flow (left panel). Symbols are mean ± 1 sem. Modified from Rickards et al. (A color version of this figure is available in the online journal.)

Figure 9

Systemic peripheral vascular resistance (top panel), heart rate (middle panel), and mean arterial pressure (bottom panel) during progressive LBNP time (seconds) in individuals with low tolerance (LT, n = 59, open Δ) and high tolerance (HT, n = 113, closed •). The first phase of hypotension is associated with a sudden reduction in peripheral vascular resistance (vertical lines 1 and 3 for LT and HT) followed by the second phase of hypotension that is associated with a sudden reduction in heart rate (vertical lines 2 and 4 for LT and HT). Data extracted from Ryan et al. (A color version of this figure is available in the online journal.)

Figure 10

Conceptual figure depicting the key interactions from a physiological stimulus that elicits hypovolemia, such as hemorrhage, that results in hemodynamic decompensation and ultimately shock. Note that LT individuals compared to HT individuals have a reduced physiological and compensatory response, and thus reach a threshold of decompensation at a faster rate.