Physiological comparison of hemorrhagic shock and $\dot{V}$O₂max: A conceptual framework for defining the limitation of oxygen delivery

Short abstract

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 ($\dot{V}$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 $\dot{V}$O₂ that is manifested as the final step during both progressive blood loss leading to hemorrhagic shock and at $\dot{V}$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 $\dot{V}$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 $\dot{V}$O₂max helps to re-evaluate paradigms of triage for improved monitoring of accurate resuscitation in patients suffering from hemorrhagic shock.

Introduction

Maintaining a balance between delivery and utilization of oxygen in various organs of the body represents a fundamental premise for sustaining “adequate” tissue oxygenation and cell function. As the requirement for oxygen uptake and utilization ($\dot{V}$O₂) to meet cellular energy demand overwhelms the capacity of the respiratory and circulatory systems to deliver oxygen (DO₂), the cells must rely increasingly on the metabolic transformation of glycogen to lactate known as anaerobic glycolysis, as well as tissue oxygen and phosphocreatine stores. Systemic DO₂ is the product of cardiac output and arterial oxygen content.¹ Mitigating the potential impact of failure to maintain an adequate DO₂ on disrupting normal metabolic functioning at the cellular level relies on the integration of numerous compensatory mechanisms.

“Shock” has been described as a pathophysiological condition of “inadequate tissue oxygenation”^1,2 that ensues when DO₂ fails to meet the tissue $\dot{V}$O₂ required to maintain aerobic energy production.^2,3 In the context of this definition, maximal intensity exercise could be described as a type of “shock” in individuals, including endurance-trained athletes, whose $\dot{V}$O₂max is limited by a failure of DO₂ to meet the energy demand of working muscles.^4–8 Within this context, progression of tissue acidity indicates failure to sustain a balance in oxygen supply and cellular energy demand that underlies the onset of both hemorrhagic shock and $\dot{V}$O₂max. Although the magnitude of compensatory responses can differ between these two physiological states, we recognize that both hemorrhagic shock and $\dot{V}$O₂max display qualitatively many similar hemodynamic, autonomic, metabolic, and compensatory patterns. Figure 1 represents our conceptual framework to illustrate the cascade coupling of ventilation, circulation, tissue metabolism, and energy balance in the mitochondria. Within this construct, an inability to maintain adequate DO₂ to the cells can lead to disturbance of normal cellular metabolic functioning that defines a common pathway in both hemorrhagic shock and $\dot{V}$O₂max. In this mini-review, we used this model in the context of young healthy humans, trained fit individuals, and/or athletes where, in general, DO₂ sets the upper limit for $\dot{V}$O₂max. Our primary comparison population from a conceptual perspective is young trauma victims, especially battlefield casualties. Our index populations are generally similar, so we explored relevant literature in an attempt to gain insight about the limiting factors that lead to hemorrhagic shock in bleeding patients by comparing the pathophysiological mechanisms of exsanguination to the physiological limits of individuals whose $\dot{V}$O₂max is limited by inadequate DO₂.

Figure 1.

Conceptual model to illustrate the cascade coupling of ventilation, circulation, tissue metabolism, and energy balance in the mitochondria to cell function that defines common pathways to hemorrhagic shock and V̇O₂max. VI: inspiratory volume; TV: tidal volume; Rf: respiratory frequency; DO₂: oxygen delivery; CO: cardiac output; CaO₂: oxygen carrying capacity; V̇O₂: oxygen uptake; OER: oxygen extraction ratio; StO₂: tissue oxygen saturation; PCr: phosphocreatine. Conceptually adopted from Wasserman.⁹ (A color version of this figure is available in the online journal.)

Absolute vs. relative hypovolemia

Central hypovolemia represents another common fundamental physiological state that underlies the inadequate DO₂ resulting from both hemorrhage and many instances of physical exertion at $\dot{V}$O₂max. Hypovolemia is defined as a reduction in circulating blood volume relative to the capacitance of the cardiovascular space. Figure 2 provides an illustration of the difference in the hypovolemic state caused by hemorrhage from that resulting from an acute exercise. During hemorrhage, an “absolute” hypovolemia occurs as a consequence of reduced circulating blood volume within the same vascular space (or smaller as ongoing compensatory vasoconstriction occurs).^10,11 In contrast, increased vascular capacitance due to significant vasodilation in working muscles during acute exercise results in a “relative” hypovolemia defined by vascular space expansion with no or negligible change in circulating volume.^10,11 Consequently, we can think of assessing limitations in compensatory adjustments to hemorrhage and $\dot{V}$O₂max in DO₂-limited individuals as a comparison in physiological differences in DO₂ associated with absolute and relative hypovolemic conditions that eventually lead to under-perfused tissue.

Figure 2.

Conceptual comparison of normal circulating blood volume (normovolemia) with absolute and relative hypovolemia. Orange indicates circulating blood volume; Pink indicates capacitance of vascular space. Adopted from M.N. Sawka with permission. (A color version of this figure is available in the online journal.)

Clinical concepts of oxygen deficit and debt

The terms oxygen “deficit” and or “debt” are routinely used in emergency and critical care medicine to reflect a mismatch between cellular energy requirement and $\dot{V}$O₂.^2,12–14 The conceptual use of the terms O₂ deficit or debt by clinicians can be linked to the concept of a cumulative deficiency of DO₂ needed to support cellular energy demands through oxidative metabolism that was initially described by A.V. Hill from experiments using strenuous physical activity performed by healthy individuals.¹⁵ Hill’s research included the measurement of $\dot{V}$O₂ responses during steady-state and maximal exercise, laying the foundation for defining systemic $\dot{V}$O₂ dynamics and the emergence of the concepts of O₂ deficit and O₂ debt.¹⁵ Subsequently, O₂ deficit and or O₂ debt have been used repeatedly in the clinical literature to describe the ultimate pathophysiological factor leading to shock.^2,12,13,16 However, the use of “O₂ debt” can be misleading and confusing to physiologists who recognize it as referring to a post-exercise $\dot{V}$O₂ phenomenon that is quantitatively and physiologically different than O₂ deficit.^17,18 In an effort to alleviate confusion in terminology between clinicians and physiologists, we will use the term O₂ deficit as a more appropriate term to describe cellular $\dot{V}$O₂-energy requirement mismatch and “O₂ extraction reserve” to reflect various sources of O₂ available to cells to support their energy requirements (e.g. hemoglobin, myoglobin). Within this context, it is conceptually transparent that reduced total O₂ availability resulting from lowered DO₂ during severe blood loss or $\dot{V}$O₂max will result in increased O₂ deficit because O₂ is “barrowed” from the O₂ extraction reserve. Thus, O₂ deficit represents a mechanism of compensation designed to avoid reaching the DO₂crit. As such, we use this review to focus on lowered DO₂ as the underpinning of progressive reduction in O₂ extraction reserve in an effort to support increased O₂ deficit that leads to failure in meeting cellular energy demands during either hemorrhagic shock (absolute hypovolemia) or $\dot{V}$O₂max (relative hypovolemia).

Inadequate DO₂ created by $\dot{V}$O₂max

Inadequate DO₂ can be defined as inability of O₂ delivery to tissues to meet cellular energy demand. Figure 3 provides a conceptual schematic of the continuum of DO₂ moving from normal rest. Moving to the right of resting baseline $\dot{V}$O₂ (yellow bar in Figure 3) with the initiation of physical exercise, DO₂ is progressively increased as a result of increased systemic blood flow (cardiac output). Despite higher absolute DO₂ during exercise, there is an immediate development of an O₂ deficit due to the time delay between immediate energy requirement and systemic $\dot{V}$O₂. It is noteworthy that during the mismatch between energy requirement and $\dot{V}$O₂ in the working muscle, blood lactate usually does not appear until the individual reaches a physiological work capacity above ∼50% of $\dot{V}$O₂max.¹⁹ As such, an O₂ deficit during physical exertion is initiated by two compensatory mechanisms that work in concert to mobilize O₂ from the O₂ extraction reserve in the presence of inadequate DO₂: (1) increased extraction of hemoglobin-bound oxygen delivered through increased blood flow to the tissue (i.e. higher oxygen extraction ratio, OER in Figure 3) with a subsequent reduction in measured oxygen saturation of venous blood (SvO₂); and (2) utilization of local tissue and O₂ bound to myoglobin (SmO₂) in addition to reserves of phosphocreatine (PCr) (Figure 3, right pink area).²⁰ When increased DO₂ and utilization of PCr/O₂ reserves fail to support the cellular energy requirement, DO_2crit is reached resulting in the production of energy through initiation of the transformation of glucose or glycogen to lactate. With limited amounts of oxygen available for aerobic glycolysis, an accumulation of lactate gradually appears in the blood in the presence of inadequate lactate clearance.^4,21,22 When increasing energy demand can no longer be supported in the presence of accumulated O₂ deficit, physical exhaustion is manifested by reaching $\dot{V}$O₂max. In the end, the prevailing evidence indicates that $\dot{V}$O₂max in healthy exercising humans is ultimately limited by inadequate DO₂.^4,23

Figure 3.

Conceptual representation of the continuum of metabolic relationship of oxygen delivery (DO₂) to utilization (V̇O₂) responses from hemorrhagic shock (left of Normal Resting State) to exertion at V̇O₂max (right of Normal Resting State). OER: oxygen extraction ratio; SvO₂: venous oxygen saturation; StO₂: tissue oxygen saturation; PCr: phosphocreatine; DO_2crit: critical oxygen delivery. Responses to progressive hemorrhage modified from Hooper et al.¹³ See text for explanations.

Inadequate DO₂ created by hemorrhage

The extrapolation of metabolic events that lead to $\dot{V}$O₂max induced by intense physical exercise to severe blood loss is reflected by a final common pathway that an inadequate DO₂ limits tolerance of the body’s organs to sustain cellular energy requirements after reaching DO_2crit. Similar to inadequate DO₂ that limits the healthy exerciser from performing more physical work beyond $\dot{V}$O₂max, is the arrival at a threshold of intolerable reduction in O₂ extraction reserve with blood loss. This is due to the reduced DO₂ that is not restored over time, which will lead to irreversible shock and death.^13,14 Moving to the left from resting baseline $\dot{V}$O₂ along the continuum with the initiation of hemorrhage (Figure 3), DO₂ is reduced as a result of a loss of oxygen-carrying red blood cells and lower circulating volume for cardiac filling and output. Despite the progressive reduction in DO₂ during the early stages of bleeding, $\dot{V}$O₂ can be maintained at baseline levels by the capacity to utilize the O₂ extraction reserve (i.e. increased OER); a cascade of events that is reflected by lowered SvO₂. This notion of an early delivery-independent $\dot{V}$O₂ in the presence of reduced DO₂ was best illustrated by Weiskopf et al.²⁴ who demonstrated no change in $\dot{V}$O₂ or blood lactate (i.e. failed to reach DO_2crit) following an experimentally-induced reduction in hemoglobin concentration (i.e. >60% lower DO₂). Like the condition of physical exercise, it might be expected that the cells can draw upon tissue PCr and O₂ extraction reserves (i.e. O₂ deficit) during hemorrhage. If O₂ extraction reserves contribute to the initial burden of an O₂ deficit during the delivery-independent $\dot{V}$O₂ phase of hemorrhage, higher O₂ extraction (OER) and lower tissue O₂ saturation (StO₂) would be expected before an appearance of lactate in the blood. Consistent with this hypothesis is an immediate and progressive reduction in StO₂ and elevation in OER during simulated human hemorrhage (Figure 4) while blood lactate remained within baseline levels (0.95 to 1.1 mmol/l) during lowered DO₂.²⁶

Figure 4.

Time course of responses of systemic oxygen delivery (DO₂; Panel A), systemic oxygen uptake (V̇O₂; Panel B), tissue oxygen saturation (StO₂; Panel C), and oxygen extraction ratio (Panel D) during progressive central hypovolemia induced by lower body negative pressure (LBNP). Data are means ± SD; n = 18. Modified from Ward et al.²⁵

Within this construct of timing, the clinical description of an onset of O₂ deficit as the point in time at which tissue metabolism converts to anaerobic glycolysis to produce lactate in an effort to sustain the total energy requirement of the cell during hemorrhage has been misleading.^1,13,14 Contrary to this hypothesis, failure to reach DO_2crit in the presence of reduced O₂ extraction reserves (Figure 4) supports the concept that O₂ deficit, defined by reduced O₂ extraction reserve, must occur in advance of reaching DO_2crit. As such, the onset of O₂ deficit during hemorrhage, like exercise, is initiated by a compensatory utilization of the O₂ extraction reserves before there is increased anaerobic glycolysis. As such, we propose a revision in the biphasic relationship between DO₂ and $\dot{V}$O₂¹³ to include stores of tissue PCr and O₂ extraction reserve prior to the appearance of lactate in the blood (i.e. DO_2crit; Figure 3, left pink area). In the end, the burden of a cellular O₂ deficit beyond DO_2crit must be “repaid” to restore adequate metabolic function and prevent organ dysfunction or injury at the cellular level whether describing DO₂-limited strenuous physical activity that requires working at $\dot{V}$O₂max or life-threatening exsanguination.

Physiologic similarities between hemorrhagic shock and $\dot{V}$O₂max

The ultimate challenge of the cardiopulmonary and metabolic systems in both conditions of hemorrhagic shock and $\dot{V}$O₂max is to maintain a sustainable DO₂ so that a threshold of intolerable cellular O₂ deficit and disturbance of normal cell functional metabolism can be avoided. This challenge requires a physiological capacity to recruit a complex network of compensatory mechanisms with the ultimate function of defending against inadequate DO₂. A summary of compensatory responses and their outcomes is presented in Table 1 and described below.^27,28

Table 1.

Similarities in qualitative and quantitative cardiopulmonary, metabolic and autonomic responses for hemorrhagic shock and exertion at $\dot{V}$O₂max.

Physiological responses	Directional change	Baseline rest	Hemorrhagic shock	References	Exertion @ V̇O2max	References
O2 deficit, mL kg−1 VO2	↑	0	104a	Siegel et al.16	50–80	Linnarsson et al. 20Joyner and Coyle 19
StO2, %	↓	75	29–50	Convertino and Sawka10	29–44	Martin et al. 29
PtO2, mmHg	↓	∼34	5	McKinley et al.30b	3	Richardson et al.31
Heart rate, bpm	↑	60–70	120–180	Cloutier et al.32 Gutierrez et al.1	140–200	Joyner and Casey33Tanaka et al. 34
SNA, pg/mL	↑	200–500	5–10 fold	Woolf 35	> 7-fold	Engelke and Convertino 36
OER, %	↑	20–30	> 50	Ward et al. 25	85–90	Joyner and Casey33Bassett and Howley23
SvO2, %	↓	65–75	< 30	Kasnitz et al. 37	< 20	Mortensen et al. 38
Blood pH	↓	7.4	≥ 7.0	Cloutier et al. 32	≥ 7.0	Osnes and Hermansen 39Goodwin et al.40
Blood [LA], mmol/l	↑	1–2	> 3–13	Bonanno et al. 41Vitek et al.27	15–25	Osnes and Hermansen 39Ferguson et al.4
Blood BD, mmol/l	↑	0	> 5–15	Eastridge et al. 42	∼ 7	Osnes and Hermansen 39
Rf, breaths/min	↑	10–20	> 35	Gutierrez et al.1	> 40	Forster et al. 43
Vt, liters	↑	0.5	> 0.7	Convertino et al.44	> 2.5	Forster et al. 43Younes and Burkes 45
EtCO2, mmHg	↓	35–40	< 35	Stone et al.46McManus et al.28	< 35	Hagberg et al. 47
Compensatory Reserve, %	↓	90–100	< 15	Convertino et al. 48	< 20	Convertino and Sawka 10

StO₂: tissue oxygen saturation; PtO₂: partial pressure of tissue oxygen; SNA: sympathetic nerve activity; OER: oxygen extraction ratio; SvO₂: venous oxygen saturation; [LA]: lactate concentration; BD: base deficit; R_f: respiration frequency; V_t: tidal volume; EtCO₂: end-tidal carbon dioxide.

^aData from animal experiments.^bCase study of one trauma patient.

Hemodynamic mechanisms

Despite stark differences in systemic arterial blood flow, blood pressure, DO₂, and $\dot{V}$O₂, one of the most obvious features between exercise and hemorrhage is pronounced elevation of heart rate that represents a compensatory attempt to maintain adequate DO₂ in the face of a hypovolemia-induced accumulating O₂ deficit. Indeed, inadequate systemic DO₂ is viewed as the primary factor that ultimately leads to development of O₂ deficit that limits $\dot{V}$O₂max in most healthy exercising humans.^5–8,24 as well as the onset of shock for bleeding patients.^1,13,14

Similar to exercise, the cardiac response to hemorrhage relies on optimizing cardiac output in an effort to maintain perfusion (arterial blood) pressure. Despite vast differences in cardiac filling, severe hemorrhage can elicit tachycardia greater than 120–180 beats per minute (bpm) in shock^1,32,49 similar to the pronounced elevation in heart rate of 140–200 bpm during exercise requiring maximal effort.^33,34 Whether supporting the low cardiac filling states of acute hemorrhage or high cardiac filling during physical exercise, increased cardiac rate represents a common compensatory mechanism for optimizing cardiac output.

Autonomic mechanisms

Autonomically mediated elevations in heart rate are controlled by a combination of cardiac vagal withdrawal and sympathetic nerve activation.³³ Although the direct measurement of parasympathetic nerve activity is not readily accessible in humans, the use of frequency-domain analysis R-R interval variability has provided an indirect metric for changes in cardiac vagal activity by demonstrating nearly complete elimination of the high-frequency spectra (0.15–0.40 Hz) during muscarinic receptor blockade.⁵⁰ Calculating heart rate variability (HRV) from frequency-domain analysis has revealed that significant vagal withdrawal is an underlying mechanism of increased heart rate during both hemorrhagic shock⁵¹ and maximal exercise.^33,52,53

Hypovolemia is a very potent stimulus for activation of sympathetic activity. Catecholamine levels in the blood have been used as an indicator for adrenergic response to hemorrhage and exercise since the relationship between HRV measures and sympathetic activity is not as established as that for cardiac vagal activity.⁵² In addition to vagal withdrawal, significant elevations in heart rate can be explained by blood levels of norepinephrine (NE) that become several times normal during both physical exercise at $\dot{V}$O₂max and hemorrhagic shock (Table 1). Within minutes of the onset of hemorrhagic shock, blood levels of NE can reach as much as 10 times basal (>1800 pg/mL), enough to produce compensatory elevations in pulse rate and blood pressure.³⁴ Likewise, maximal heart rate responses have been associated with average elevations in plasma NE from 183 to 1337 pg/mL during graded exercise that elicited $\dot{V}$O₂max.³⁶

The underlying mechanisms that elicit increased sympathetic nerve activation during physical exertion may provide insight to sympathetic control in conditions of blood loss. During exercise, heart rate can increase in the face of elevated arterial blood pressure because of a resetting of the cardiac baroreflex to a higher operating set point.⁵⁴ In contrast, the elevation in sympathetic nerve activity and heart rate associated with the central hypovolemia of hemorrhage is accompanied by reduced cardiac baroreflex sensitivity.⁵⁵ Since the pressure stimulus to arterial baroreceptors differs in direction between the hypotension associated with blood loss and the hypertension of exercise, metabolic stimuli that elicit activation of chemically-sensitive nerves in the tissues may represent a more likely common mechanism for activation of sympathetically mediated heart rate effects at $\dot{V}$O₂max and in conditions of hemorrhagic shock. There is compelling evidence that an elevated sympathetic efferent response to activation of these so-called “metaboreflexes” results in increased perfusion (arterial) pressure as a consequence of chronotropic effects on the heart, acting to increase cardiac output as well as constriction of the vasculature.⁵⁶ The end result of activating metaboreflexes in combination with baro- and chemoreflexes can result in similar magnitudes of sympathetic activation reflected by similar elevations in circulating catecholamines during hemorrhagic shock³⁵ and maximal exercise.³⁶

Oxygen extraction ratio and tissue oxygenation

Utilizing the O₂ extraction reserve (e.g. hemoglobin bound O₂, myoglobin-bound O₂) represents a compensatory mechanism from which O₂ can be provided to cells during hemorrhage and physical exercise when DO₂ cannot meet the cellular requirement of $\dot{V}$O₂. This lowering of the O₂ extraction reserve inherently represents an O₂ deficit. In this context, measurements of the oxygen extraction ratio (OER) and tissue oxygen saturation (S_tO₂) can provide insights into the dynamics of O₂ deficit as a compensatory mechanism during intense exercise or severe hemorrhage.

OER represents the ratio of $\dot{V}$O₂ to DO₂ as the fraction of oxygen delivered to the microcirculation that is taken up by the tissues (OER = $\dot{V}$O₂/DO₂ – Figure 1).⁵⁷ Despite differences between hemorrhage and exercise in $\dot{V}$O₂ magnitude and direction, both conditions require increased OER as a contributing compensatory mechanism for maintenance of adequate $\dot{V}$O₂ in the face of inadequate DO₂. This was best demonstrated by Weiskopf et al.²⁴ when they found that the failure to reduce $\dot{V}$O₂ or elevate blood lactate in healthy humans who underwent >65% reductions in O₂–carrying capacity with whole blood withdrawal. The Weiskopf observation actually supports the contention that the only way that $\dot{V}$O₂ and lactate could remain constant in the face of reduced DO₂ was to incur an O₂ deficit by borrowing from the O₂ extraction reserve.²² The insight to be gained from exercise is that significant O₂ deficit can be incurred without inducing significant injury in the form of organ damage or failure. In this context, O₂ deficit is indeed an adaptive and protective response as part of the compensatory reserve measurement.

The premise that DO₂crit occurs well after the onset and accumulation of O₂ deficit is a fundamental relationship that evolved from the early work in exercise physiology that demonstrated an immediate development of an O₂ deficit because of the difference between energy requirement and $\dot{V}$O₂ at the onset of exercise. It is the O₂ kinetics data obtained from physical exercise that provides the evidence that an O₂ deficit is defined by the immediate reduction in O₂ extraction reserve. Given that fact, the data in Figure 4 clearly demonstrate that, like exercise, O₂ deficit resulting from a “borrowing” of oxygen from the O₂ extraction reserve is increased immediately upon the onset of absolute central hypovolemia (e.g. hemorrhage) in the form of reduced StO₂ with concurrent reduction in DO₂.²⁵ As such, the early increase in O₂ deficit represents the compensatory part of hemorrhagic shock defined as Class I and II shock by the American College of Surgeons⁵⁸ well before the onset of decompensatory Class III shock (i.e. DO₂crit).

The reliance on elevations in OER is reflected by normal resting levels of 20% to 30%⁵⁷ rising to as high as >50% during blood loss²⁵ and > 85–90% at $\dot{V}$O₂max.^23,33 The increase in OER estimated for hemorrhagic shock is most likely underestimated since it does not represent any reported measurements made near the point of death when OER would be maximal (far left in Figure 3). Low mixed venous oxygen saturation (SvO₂= DO₂–$\dot{V}$O₂) has been proposed to identify anaerobic glycolysis and global tissue hypoxia.⁴¹ As a result of increased OER, SvO₂ is precipitously reduced from its normal resting value of 65–75%⁵⁹ to less than 20% to 30% in both hemorrhage³⁷ and exercise.³⁸

S_tO₂ represents the amount (%) of myoglobin-bound O₂. The myoglobin disassociation curve requires a significant reduction in the partial pressure of oxygen (pO₂) in the tissue before O₂ will be disassociated from myoglobin. Indeed, tissue pO₂ has been reported to be as low as ∼5 mmHg compared to a baseline level of ∼34 mmHg in both hemorrhage³⁰ and maximal exercise.³¹ A reduction in S_tO₂ reflects a compensatory increase in the availability of O₂ to support cellular $\dot{V}$O₂ in the presence of inadequate DO₂. This was best illustrated in humans undergoing progressive central hypovolemia without changing systemic $\dot{V}$O₂ or blood lactate despite significant reductions in DO₂ because of mobilization of myoglobin-bound O₂ (i.e. decreased S_tO₂) and hemoglobin-bound O₂ (Figure 4).²⁵ This compensatory mechanism for increasing cellular O₂ availability is reflected by a dramatic reduction in S_tO₂ from normal resting levels of ∼70% to as low as ∼30% during progressive central hypovolemia similar to blood loss¹⁰ and at $\dot{V}$O₂max.²⁹

Glycolysis and lactate

When $\dot{V}$O₂ can no longer meet the cellular energy demand alone, the cell becomes more reliant on energy sources of phosphocreatine and glycolysis to meet its ATP demand. Consequently, increased levels of blood lactate in the absence of adequate clearance are common to both hemorrhage and intense physical exercise. Although blood lactate is commonly measured by clinicians as a metric of shock, study of the physiology of $\dot{V}$O₂max has revealed that glycolysis and lactate production per se rarely accumulate because of inadequate DO₂.⁴ The benign presence of blood lactate is best reflected by the observation that a high risk of shock and death is associated with elevated arterial blood lactate levels of only > 4 mmol/L during hemorrhage,⁴¹ while blood lactate levels have been reported to be >15–25 mmol at $\dot{V}$O₂max.⁴⁰ The mechanism underlying the physiological tolerance to higher levels of blood lactate accumulation during muscle contraction compared to hemorrhage is reflected by the use of lactate as an oxidizable fuel during intense exercise, i.e. increased lactate clearance.^4,22 As such, the dynamics of lactate metabolism during intense exercise challenges the paradigm that measures of systemic blood lactate fail to provide an accurate assessment of cellular O₂ deficit in a patient with severe hemorrhage. During the absolute hypovolemia of hemorrhage, blood flow is redirected away from tissues with high mass but low energy demand (e.g. skeletal muscle) to support DO₂ to critical organs like the brain, heart, gut, liver, and kidney. Significant levels of lactate can accumulate in the brain during hemorrhage and diffuse into the blood.⁶⁰ However, the dilution of highly concentrated blood lactate leaving the brain in blood from other less metabolically-active tissues will lead to underestimation of brain lactate as an accurate measure of hemorrhagic shock. Thus, local measures of blood lactate in blood leaving specific tissues may prove to provide a more accurate clinical measure of hemorrhagic shock. Ultimately, it is not the amount of accumulated systemic blood lactate that reflects the limitation of tolerance to severe blood loss or intense exercise, but rather emergence of intolerable O₂ deficit that results from inadequate DO₂.

Acid–base buffering

In contrast to lactate, the ultimate challenge during hemorrhagic shock and $\dot{V}$O₂max is impaired removal of accumulated H⁺ created by a complex number of metabolic byproducts⁶¹ in the cells and blood that are associated with increased acidity (reduced pH). It is tissue acidity that may define the common critical factor emerging from inadequate DO₂ that leads to intolerable disturbance of cellular metabolic function. The deleterious effect of reduced cellular pH may be best reflected by the similarity in maximal arterialized blood pH of ≤ 7.0 that has been reported during bot hemorrhagic shock³² and exercise at $\dot{V}$O₂max^39,40,61 despite a large discrepancy in accumulated blood lactate. Thus, the ability to sustain acid-base balance during progressive blood loss or intense physical exercise depends on the capacity to buffer accumulated H⁺.

Another sensitive means of assessing tissue oxygenation and O₂ deficit is by measuring the base deficit, which represents the number of millimoles of base required to correct the pH of one liter of whole blood to 7.4.^41,49 Indeed, the capacity to buffer blood acidity is reflected by a high correlation between increased base deficit and reduced arterialized blood pH,³² with base deficits > 5 mmol/L being associated with both hemorrhagic shock^32,42 and $\dot{V}$O₂max.³⁹

Relatively small base deficits of only 6 to 10 mmol/L observed during hemorrhagic shock have been associated with “metabolic decompensation” when there is increasing requirements for blood transfusion⁴² and the probability of death rises exponentially.¹² Although the reliance on tissue oxygen extraction reserves, phosphocreatine, and glycolysis exists with inadequate DO₂ during both hemorrhage and $\dot{V}$O₂max, it is important to recognize that intense physical activity can result in metabolic acidosis with base deficits three to five times higher than those associated with hemorrhagic shock. This disparity of higher base deficits created by exercise is an indication that extreme changes in the acid-base balance seem to be well tolerated in healthy exercising subjects³⁹ compared to patients with severe blood loss. These comparisons reaffirm the notion that high levels of blood lactate are not by themselves detrimental as long as cellular metabolism is high enough to oxidize the lactate as a source of energy.⁴ Thus, it is the reduction in $\dot{V}$O₂ as a consequence of lowered DO₂ during severe hemorrhage that leads to inadequate blood lactate clearance after reaching DO_2crit that can result in circulatory shock in the presence of relatively low blood lactate levels.

Mechanisms of pulmonary ventilation

Pulmonary ventilation is usually associated with gas exchange and is critical to the maintenance of adequate DO₂ by maintaining optimal hemoglobin saturation of the blood in both hemorrhagic shock and exercise at $\dot{V}$O₂max. However, pulmonary ventilation function also contributes significantly to acid–base balance and hemodynamics necessary for enhancing DO₂ and attenuating the accumulation of O₂ deficit at the cellular level.

Comparisons of pulmonary ventilation responses during hemorrhagic shock and $\dot{V}$O₂max are presented in Table 1. Respiration rate (breaths per minute) increases from a resting level ranging from 10 to 20 to more than 35–40 in conditions of hemorrhagic shock¹ and $\dot{V}$O₂max.⁴³ This hyperventilatory response acts to create a respiratory alkalosis by removing carbon dioxide (CO₂) from the blood as a way to buffer the accumulation of H⁺ and reduction in pH.⁶¹ The respiratory alkalosis is reflected by concomitant reductions in end-tidal CO₂ below a threshold of 35 mmHg in both individuals in hemorrhagic shock⁴⁶ and exercising at $\dot{V}$O₂max.⁴⁷

Like respiration rate, the time kinetics of the tidal volume (V_T) response to progressively increasing intensity of exercise leading to $\dot{V}$O₂max^44,45 is similar to that reported during progressive reductions in central blood volume associated with hemorrhage and leading to decompensation.⁴⁴ In both physiological conditions, V_T remains relatively unchanged until a level >80% of tolerance is reached, at which time there is an exponential increase in V_T characterized by deeper inspirations. Inspiration lowers intrathoracic pressure.⁶² The greater vacuum created in the thorax by this “respiratory pump” increases venous return, cardiac filling, and cardiac output⁶² which in turn may prove instrumental in sustaining systemic DO₂ through elevations in perfusion pressure during conditions of hypovolemia¹⁰ represented by both blood loss and $\dot{V}$O₂max. Perhaps it is no surprise that patients with severe conditions of hypovolemia who gasp (i.e. the so-called “last gasp”) to increase V_T have better mortality outcomes than those who do not.⁴⁸

Compensatory reserve

The physiological parameters listed in Table 1 represent responses of compensation to the combination of accumulated tissue O₂ shortfall and inadequate DO₂ associated with hypovolemic states of hemorrhage or exercise at maximal intensity. The capacity for compensation that “protects” against low tissue perfusion during states of compromised DO₂ is known as the compensatory reserve.^10,63–65 A historical challenge has been to develop a capability to measure the integration of compensatory mechanisms, particularly as it relates to DO₂, rather than their physiological outcomes (e.g. blood pressure, SpO₂, blood pH). Novel monitoring technologies have been developed that include the application of advanced real-time signal analysis and machine learning of hundreds of thousands of photoplethysmographic waveforms during progressive states of central hypovolemia. Application of such advanced computer processing algorithms has demonstrated that measures of arterial waveform features reflect the integration of all compensatory mechanisms recruited to sustain adequate DO₂ during conditions of progressive hypovolemia with greater specificity and sensitivity compared to standard vital signs and metabolic markers.^66–70 Specifically, changing features of the ejection wave reflect the sum of all compensatory mechanisms that control myocardial function, while reflected wave features reflect the sum of all mechanisms associated with compensation for compromised cellular energy requirements.⁶³

From the initial onset of hemorrhage or exercise (illustrated in Figure 3, broken lines), recruitment of the entirety of all compensatory mechanisms (e.g. autonomically-mediated tachycardia and blood flow redistribution, O₂ extraction reserve, respiration, etc.) is required to maintain adequate DO₂. With progression along the DO₂ time continuum (Figure 3), the reserve capacity to compensate would be expected to gradually deplete until energy requirements for oxygen at the cellular level can no longer be sustained during progressively severe hypovolemia. This concept is supported by a linear relationship between compensatory reserve and DO₂ (Figure 5). Ultimately, it is the depletion of compensatory reserve that leads to an inability to sustain energy requirements of the cells in the face of inadequate DO₂ that leads to impending hemodynamic decompensation from blood loss^63,72 or failure to continue muscular work at $\dot{V}$O₂max.¹⁰

Figure 5.

Linear regression of the relationship between systemic oxygen delivery (DO₂) and compensatory reserve measurement (CRM) expressed by DO₂ (mL O₂·kg⁻¹ ·min⁻¹) = 0.08 × CRM (%) + 5.3. Open circles represent extension of the regression line to 0% and 100% CRM. Data, collected from non-human primates, are expressed as mean ± SEM; N = 12. Modified from Koons et al.⁷¹

Individual variability in compensatory responses: A different perspective

Although the physiological responses listed in Table 1 represent generalizable direction and magnitude of changes in both conditions of hemorrhagic shock and physical work at $\dot{V}$O₂max, it is recognized that there exists significant individual variability in tolerance to tissue deoxygenation and O₂ deficit. This variability is most apparent from the data presented in Figure 6 that illustrates large differences in tissue oxygen saturation across levels of hypovolemia, making it impossible to distinguish some individuals with >85% of compensatory reserve from some individuals with <5% reserve to compensate. The data presented in Figure 6 also indicates that there remains >30% of tissue oxygen saturation in most individuals who have very little remaining capacity to compensate. Consistent with these data, actual measured $\dot{V}$O₂max has been reported to be only ∼90% of the theoretical $\dot{V}$O₂max calculated from mitochondrial oxidative capacity with significant individual variability.⁷³ Taken together, these observations support the notion suggested by others⁴ that tissue oxygen per se is not necessarily a primary limiting factor in development of intolerable O₂ deficit.

Figure 6.

Relationship between tissue oxygen saturation and compensatory reserve. Symbols are average (±95% CI) values generated from 55 healthy volunteer subjects exposed to 0, −15, −30, −45, −60, −70, −80 and −90 mmHg LBNP. Amalgamated r² = 0.965. Modified from Convertino and Sawka.¹⁰

One approach to test this hypothesis is to compare individual variability in global compensatory response to hypovolemia in normal sedentary people to exercise-trained individuals and world class endurance athletes who have extraordinarily high blood volume, capillary density, cellular mitochondrial content, and aerobic enzyme activities.^19,23 If tissue capacity for storing and utilizing oxygen contributes to mitigating the accumulation of O₂ deficit, it might be expected that the endurance athlete’s physiology designed to support high $\dot{V}$O₂max would be reflected by high tolerance to absolute central hypovolemia such as severe hemorrhage. Contrary to this notion, there is consistently reported observations in the literature that individuals who participate in endurance exercise activities (e.g. marathon runners) demonstrate some degree of physiological compromise to their blood pressure regulation leading to a higher incidence of symptomatic syncope in conditions of central hypovolemia compared to non-athletes.^74–76 This observation is reasonable when consideration is given to the evidence that endurance-trained athletes demonstrate a steeper slope of the Frank–Starling relation that translates to greater reductions in stroke volume for equal falls in left ventricular filling volume.⁷⁵ Consequently, the steep Frank–Starling curve that provides endurance athletes a great physiological advantage during competitive running can predispose them to decompensation in the face of severe central hypovolemia such as during hemorrhage by compromising DO₂. The comparison of physiological functions in endurance athletes, sedentary individuals, and chronic heart failure patients support the notion that, in the end, the limiting factor to reaching hemorrhagic shock or $\dot{V}$O₂max is inadequate DO₂ to meet the need to maintain cellular O₂ demand.^4,73 Thus, it is not enough to measure either tissue oxygen or DO₂, but individual variability demands measurements that reflect both factors to assure a most accurate assessment of which combination of compensatory mechanisms dictates either hemorrhagic shock or $\dot{V}$O₂max in each individual. It is for this reason that measurements of arterial waveform features provide the most accurate assessment of either hemorrhagic shock or $\dot{V}$O₂max since features of the ejected wave represent the sum total of all mechanisms that dictate systemic DO₂, while features of the reflected wave represent the impact of metabolism that influences cellular $\dot{V}$O₂ and accumulated tissue O₂ deficit.⁶³

Hemorrhagic shock vs. $\dot{V}$O₂max conceptual framework: Other factors to consider

In addition to sharing key common physiological features, it is important to consider that reaching the threshold of hemorrhagic shock or $\dot{V}$O₂max will depend on the rate of accumulated O₂ deficit during blood loss or maximal oxygen uptake. For instance, a patient suffering from a slow venous bleed may sustain a progressively increasing acidotic state for an extended period of time without succumbing to hemorrhage. This slow hemorrhage condition would be physiologically equivalent to a healthy individual who performs a prolonged period of submaximal exercise above the threshold for blood lactate accumulation. On the other hand, an injury to a major artery that results in rapid exsanguination and imminent death would be analogous to a sprint exercise that reaches $\dot{V}$O₂max in a short time period, both conditions resulting in rapid imbalance between oxygen demand and oxygen supply that cannot be resolved because of a limitation to DO₂. The physiology of hemorrhagic shock is also complicated by the notion that individual tissues (e.g. gut, brain, muscle) during blood loss varies in their tolerance to low DO₂, which may be analogous to the varying patterns of tissue oxygen demands during physical exercise that are defined by the inverse relationship between power and speed duration.

Clinical translation from the exercise experience

Accurate guidance for resuscitation of patients suffering from hemorrhagic shock represents a significant challenge to emergency medicine caregivers in their efforts to avoid the sequela associated with over- or under-resuscitation. A metric of inadequate DO₂ reflects the most sensitive quantifier of the degree of shock,¹³ but accurate assessment of DO₂ has been limited by technology gaps in the ability to measure a bleeding trauma patient’s O₂ shortfall and repayment O₂ extraction reserve in real time.¹³ As a result of this monitoring limitation, use of devices in pre-hospital critical care medicine that provide measures of blood lactate or tissue oxygen saturation has been proposed.^13,77 However, challenges associated with the use of blood lactate or tissue oxygen as surrogate measures of compromised DO₂ for guidance to clinical intervention are numerous. First, blood lactate levels do not necessarily reflect pathophysiology since their rise at $\dot{V}$O₂max in young healthy individuals is multiple times that observed with hemorrhagic shock (Table 1) without clinical consequence. Second, DO₂ during hemorrhage can be decreased during the early stages of compensatory shock in the absence of elevated blood lactate. Third, although tissue oxygen is reduced during hemorrhage and at $\dot{V}$O₂max, there remains adequate cellular O₂ levels indicated by ∼30% to 50% of resting baseline (Table 1). As such, clinical and exercise evidence indicates that it is likely that measures of blood lactate or tissue oxygen saturation may misrepresent the DO₂ status of a patient with hemorrhagic shock.

The key to effective resuscitation in patients with hemorrhagic shock is an appreciation “that it is not enough to simply halt the accumulation of oxygen debt (i.e. shortfall); it (O₂ shortfall) must be repaid.”¹³ The challenge, however, is that the clinical community has not realized a way to assess O₂ shortfall in real time.¹³ Figure 5 provides data obtained from experiments conducted on healthy baboons illustrating that measurement of the capacity to compensate (i.e. compensatory reserve) during whole blood resuscitation is closely correlated to DO₂.⁷¹ These results reflect the ability of changing features of the arterial waveform to provide a real-time measurement of integrated mechanisms that contribute to control of physiological factors that influence the development of O₂ deficit. As such, it is compensatory reserve data collected with measures of exercise O₂ deficit during exercise that provide a basis for using such technology for early identification of bleeding patients with hemorrhagic shock and for guiding accurate fluid or whole blood resuscitation leading to O₂ deficit repayment.

Summary

Evidence provided by a cross-sectional review of the literature supports our conceptual framework that hemorrhagic shock in bleeding patients and $\dot{V}$O₂max of endurance athletes shares similar physiological responses initiated by a requirement to avoid critical levels of accumulated tissue O₂ deficit in response to inadequate DO₂ associated with states of hypovolemia (Figure 1). In both physiological conditions, hypovolemia initiates a similar complex cascade of compensatory responses that include (but are not limited to) vagally- and sympathetically-mediated tachycardia, increased oxygen extraction from the blood and tissue O₂ extraction reserves, and hyperventilation acting to optimize acid–base balance and central hemodynamics. With a finite capacity to maintain adequate DO₂, the sum total of all compensatory responses eventually can be depleted without repayment of the O₂ deficit. With this progression of events, and individual variability, a critical threshold of DO₂ is reached, requiring a marked increase in the energy contribution from glycolysis to supplement the energy required by the tissues for normal function that can no longer be provided by aerobic metabolism alone. The resulting impairment in removal of accumulated H⁺ leads to a reduction in pH (cellular acidity) that, if not reversed, will lead to a disturbance of normal cell metabolic function as reflected by irreversible shock in the case of hemorrhage or physical exhaustion when $\dot{V}$O₂max is reached.

Authors’ contribution

All authors contributed to parts of the conceptualization, drafting or revising the article critically for important intellectual content, and final review and approval of the version submitted for publication.

DECLARATION OF CONFLICTING INTERESTS

The authors have no conflict of interests to report. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

FUNDING

Funding for this work was provided in part by appointments to the Internship/Research Participation Program at the United States Army Institute of Surgical Research, administered by the Oak Ridge Institute for Science and Education (KRL, NJK) through an interagency agreement between the U.S. Department of Energy and Environmental Protection Agency, and grants from the US Army Medical Research and Materiel Command Combat Casualty Care Research Program (D-023–2011-USAISR; D-009–2014-USAISR; STO R.MED.2016.20).