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Review Article

ASSESSING SHOCK RESUSCITATION STRATEGIESBY OXYGEN DEBT REPAYMENT

Robert Wayne Barbee,*†§ Penny S. Reynolds,*§ and Kevin R. Ward*†‡§

Departments of *Emergency Medicine, † Physiology, ‡ Biochemistry, and § Virginia Commonwealth

University Reanimation Engineering Shock Center, Virginia Commonwealth

University Medical Center, Richmond, Virginia

Received 23 Apr 2009; first review completed 5 May 2009; accepted in final form 10 Jul 2009

ABSTRACT—Identification of occult shock is a major clinical problem compounded by inadequate criteria for assessing

the efficacy of fluid resuscitation. We suggest that these problems may be resolved in part by understanding both the

physiological mechanisms underlying oxygen debt accumulation and, more importantly, the debt repayment schedule

during resuscitation. We present a simplified tutorial that incorporates the concept of the oxygen supply-delivery

relationship with that of oxygen debt and show how this is relevant to the understanding of shock and resuscitation. Use of

oxygen debt metrics as end points for shock have been controversial; however, much of the controversy may have been

due to incomplete understanding of basic physiology of shock and semantic confusion between the various metrics

proposed as end points. Here, we provide working definitions for the frequently misunderstood concepts of oxygen deficit

and oxygen debt and discuss the relatively novel concept of oxygen debt repayment schedule. We introduce predictions

made on the basis of data derived from animal models of hemorrhagic shock. Our calculations suggest that the amount of

debt repaid in the first 2 h of resuscitation, rather than the restoration of volume per se , influences the likelihood of organ

damage. Because of difficulties inherent in measuring oxygen debt in the prehospital and emergency settings, various

metabolic end points such as lactate and base deficit have been proposed as surrogates. We demonstrate the heuristic

value of this model in providing a predictive framework for both the optimum therapeutic time window and optimum fluid

loadings before critical transitions to an irreversible shock state can occur. The model also provides an unambiguous and

objective standard for quantifying the behavior of various postulated shock ‘‘markers.’’

KEYWORDS—Hemorrhagic shock, reperfusion, oxygen deficit, fluid resuscitation, trauma, multiple organ failure, lactate,

base deficit

INTRODUCTION

The identification of both occult and inadequately resusci-tated shock in critically ill and injured patients continues to be

a major clinical problem. Occult shock (that is, shock that is

not immediately clinically apparent) is of particular concern in

the care of elderly trauma patients (who may be in early sepsis

and are frequently characterized by multiple comorbidities

and/or medications that may mask the conventional signs and

symptoms of shock), and wounded war fighters (where diag-

nostic and treatment resources are limited). Shock occurring

in even the relatively young and healthy victim of blunt

trauma (the classical trauma patient) may be difficult to rec-

ognize because of occult hemorrhage occurring in the thorax,

abdomen, retroperitoneum, pelvis, or soft tissue.

Part of the difficulty inherent to shock assessment is thatthere is still considerable controversy as to what criteria

determine the most appropriate end points for assessing shock

depth and duration. Conventional vital signs are clearly

inadequate (1), and attempts to gauge the extent of shock

and resuscitation using more physiologically relevant mea-

sures of perfusion such as oxygen delivery (2) have led to

equivocal results (3, 4). Most resuscitation strategies seem to

be heavily weighted toward efforts to restore normal oxygen

delivery to the tissues (5), whereas much of current resusci-

tation research has centered on methods of controlling

inflammation or coagulopathy (6 Y 10). Perhaps what has been

lost in translation is the fact that inflammatory and coagu-

lation systems (once thought separate) are instead a single

system that is uniformly and rapidly activated and modulated

by tissue injury and hypoperfusion (6, 11). The degree to

which this system is activated and subsequent occurrence of

complications are unlikely to be simply corrected either by

using oxygen delivery as an end point in itself or by

modulation of certain specific pathways. We suggest that allthese efforts have lost sight of the major physiological

underpinnings of the shock state. Instead, we propose a return

to three fundamental physiological principles underlying

shock and shock treatment: 1) prevention of further oxygen

debt accumulation, 2) repayment of oxygen debt, and 3)

minimization of the time to oxygen debt resolution.

There is a considerable literature on the subject of oxygen

debt and shock V the reader is referred to an excellent review

on the topic (12) V so we provide only an outline of the

relevant information required to understand the next two

principles. Principle 2 is an obvious extension of principle 1,

but there have been very few experimental or clinical

investigations concerning this concept, and we expand on this

113

SHOCK, Vol. 33, No. 2, pp. 113 Y 122, 2010

Address reprint requests to Penny S. Reynolds, PhD, Department of Emergency

Medicine, AD Williams Bldg, 2nd Fl. Central Wing, Virginia Commonwealth

University Medical Center, 1201 East Marshall St., Richmond, VA 23298. E-mail:

[email protected].

Order of the first two authors is alphabetical; both authors contributed equally

to this work.

Supported by the Surviving Blood Loss program (grant no. N66001-02-C-8052

to R.W.B.) and Prolong Pharmaceuticals (grant no. AM 10274 to K.R.W.).

DOI: 10.1097/SHK.0b013e3181b8569d

Copyright Ó 2010 by the Shock Society


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topic below. Principle 3 is more novel and will be the

emphasis of this review. The time to oxygen debt resolution

will be referred to hereafter as the oxygen debt repayment

schedule.

THE PHYSIOLOGY OF SHOCK AND

REPERFUSION: THE BASICS

Shock is a state of hypoperfusion at the cellular level that

occurs when the delivery of oxygen (DO2) to the tissues falls

below the tissue oxygen consumption (VO2) requirements,

and thus represents an imbalance or mismatch between tissue

DO2 and VO2. Oxygen delivery is dependent on blood flow

(traditionally assessed globally by cardiac output) and arterial

oxygen content. Clinically, multiple organ dysfunction is

associated with a persistent inadequate balance of DO2 and

VO2 of specific tissue or organ beds. Conventionally, perfu-

sion status is assessed by whole-body end points such as

mental status and the standard cardiovascular parameters of

heart rate, palpable pulses, and systemic blood pressure (5).However, data from both animal models and clinical studies

indicate that these measures are very poorly correlated with

perfusion of specific tissue beds (1). Thus, organ beds may

have inadequate DO2 even if gross systemic hypotension has

been corrected. As a result, even if the subject is normoten-

sive, unequal distribution of DO2 to various tissue beds may

result in isolated organ ischemia before the occurrence of

whole-body ischemia. The gut in particular seems to be

especially susceptible to ischemic injury; there is increasing

evidence to suggest that ischemic changes in the gut drive the

systemic activation of inflammatory cascades (13). Continu-

ing systemic hypoperfusion has been implicated in ischemic

cellular injury and cell death, which, unless corrected, leads tosystemic inflammatory response syndrome and irreversible

multiple organ dysfunction syndrome (MODS). Although the

total incidence of MODS has decreased over the last several

decades, MODS remains a leading cause of late morbidity and

mortality in trauma, and the mortality rate still remains high

(50% Y 80%) (14).

Both animal and clinical data support the findings that first,

late outcome is strongly related to both the severity and

duration of shock, and second, oxygen debt and its metabolic

surrogates are the best predictors of outcome (12). To un-

derstand the concept of oxygen debt, it is useful to describe

the relationship between oxygen delivery and oxygen con-sumption during normal perfusion and in shock. In the normal

healthy subject, whole-body oxygen consumption (VO2) is

independent of cardiac output (and, hence, DO2) because of

the ability of the tissues to modulate oxygen extraction from

the blood at the level of the microcirculation. However, if

DO2 is decreased below a certain threshold (critical oxygen

delivery, DO2crit), extraction is no longer adequate, and VO2

declines in proportion to the reduction in DO2; ischemic

metabolic insufficiency then follows. A marker of this

insufficiency is the increase in the concentration of metabo-

lites such as lactate in the peripheral blood (Fig. 1).

Approximately 20 years ago, it was suggested that organ

failure resulted from the subject crossing this critical DO2

threshold to a prolonged and often unrecognized state of flow-

dependent VO2 (15). Accordingly, it was proposed that

resuscitation should involve Bpushing[ DO2 back over this

threshold so that VO2 reaches the flow-independent Bplateau[

(15, 16) (Fig. 1). In the clinical setting, DO2crit cannot be

measured easily and will vary widely among patients; as a

result, the concept of Bsupranormal[ resuscitation as a

therapeutic goal soon followed. Supranormal resuscitation

involved provision of fluid and inotropic support to ensure

that DO2crit could be exceeded, and therefore the patient could

be maintained at an oxygenation level commensurate with theflow-independent plateau. Supranormal levels were defined

a priori as the median values of hemodynamic and oxygen

transport variables values observed for survivors in a previous

clinical evaluation of critically ill, high-risk surgical patients

(17). The use of supranormal oxygen delivery as a metric was

at one time particularly widespread in treatment of septic

patients; this approach was subsequently applied to both

sepsis and trauma patients who had in all probability already

accumulated substantial oxygen debt but for whom debt could

not be readily measured or quantified (3, 18). Although initial

data indicated patient outcomes improved with early optimi-

zation to supranormal DO2 (15), subsequent studies have notshown any advantage over more conventional resuscitation

protocols (3, 4). A further concern was that, in practice, the

volume of crystalloid administered during shock resuscitation

did not seem to be closely coupled to the levels of DO2

actually measured in patients. Supranormal delivery protocols

were characterized by substantially larger amounts of crys-

talloid required to achieve the higher DO2 end point, with

subsequent risks of fluid overloading, volume shifts (3), and

inflammatory responses (19). Possible reasons for these

failures will be discussed in the following sections. It seems

that driving resuscitation DO2 to supranormal values is

now less popular as a widespread resuscitation goal. In cases

of traumatic hemorrhagic shock, current Advanced Trauma

FIG. 1. Schematic of the relationship between oxygen delivery (DO2)and whole-body oxygen consumption (VO2). VO2 represents oxygendemand; the inflection point is the critical oxygen delivery (DO2crit) whereoxygen extraction by the tissues is no longer sufficient to meet demand.Above DO2crit, oxygen demand is met and VO2 is independent of DO2; belowthis point, VO2 becomes directly dependent on DO2 when oxygen extractioncannot meet demand. Critical oxygendelivery is also indicated by increases inlactate (indicated by the dotted line) and other metabolic end products, as

oxygen delivery to the tissues is reduced and metabolism shifts to anaerobicpathways. The concept of ‘‘supranormal’’ resuscitation postulates that‘‘pushing’’ DO2 past the critical threshold A should boost VO2 to the‘‘plateau’’ where oxygen debt no longer accumulates.

114 SHOCK VOL. 33, NO. 2 BARBEE ET AL.



Life Support guidelines (5) state that the goal of resuscitation

is a Bbalance[ between restoration of organ perfusion via fluid

infusion and minimization of the risk of rebleeding; suggested

end points are blood pressure and recommendations for the

serial monitoring of base deficit and/or lactate. Preload-

directed resuscitation with sequential fluid boluses remains

the standard of care for trauma resuscitation in the intensive

care unit (20). These strategies, although nominally based on

principles of oxygen transport, often are inadequate in

practice, as will be demonstrated below.

OXYGEN DEFICIT AND OXYGEN DEBT

Clearly, oxygen delivery alone is still not an ideal indicator

of either perfusion status or the adequacy of resuscitation. To

resolve this problem, we must consider what is actually being

measured during the trajectory of shock and resuscitation.

When DO2 is reduced below DO2crit, an oxygen deficit is

incurred because the amount of oxygen demanded by the

tissues is inadequately matched by supply; this is the standarddefinition of shock. Therefore, oxygen deficit can be cal-

culated as the difference between baseline Bnormal[ oxygen

consumption VO2, and the VO2 measured at a given time

during the shock period. However, because there is a sig-

nificant associated time dimension, shock cannot be evaluated

merely by the oxygen deficit Bsnapshot[ of perfusion status

at any one time; the shock state must account for the amount

of deficit accumulated over time from the point of injury.

Deficit accumulated over time is debt . In other words, oxygen

debt is the accumulation of multiple oxygen deficits over

time and thus represents the sum of all deficits incurred. As

an example, suppose that baseline VO2 (an estimate of tissue

oxygen demand) is 200 mL minj1 and is followed by a reduc-tion in VO2 by slightly more than one third to 134 mL min

j1.

Because oxygen deficit is the change in VO2 from base-

line, oxygen deficit is therefore equal to the difference be-

tween baseline VO2 (VO2,0) and the VO2 at this new time

point t , or

Oxygen deficit ¼ VO2;0 j VO2;t

In this example, the reduction in VO2 results in an oxygen

deficit of (200 j 134) = 66 mL minj1. If this deficit is

sustained for a period of 1 h, the resulting oxygen debt will

be equal to the product of the oxygen deficit integrated over

time (66 mL min

j1Â

60 min) or 3.96 L. Figure 2 further illustrates the distinction between oxygen deficit and oxygen

debt and how there may be little correlation between deficit

at any one time and the amount of debt already accumulated.

At time point 1, the deficit is 30 mL minj1

, and debt incurred

to that point is 359 mL. At time point 2, deficit is at a max-

imum (48 mL minj1

), and debt is increasing. At time point 3,

deficit is beginning to resolve with resuscitation and is equiv-

alent to that measured at t 1; however, debt is still increasing,

although the rate at which it is accumulating is declining. At

time point 4, deficit is 0, and no more debt is being incurred;

however, the overall oxygen debt is still substantial (1,871 mL).

The concept of oxygen debt has been known since the early

1960s but has not been applied uniformly in the clinical

setting. Oxygen debt has been shown to be the only

physiological variable that can quantitatively predict survival

and the development of multiple organ failure after hemor-

rhage (17, 21, 22). Implicit in the concept of oxygen debt isthat the probability that multiple organ dysfunction and death

are influenced primarily by the accumulated debt. Early

animal experiments indicated that there was a minimum

threshold of oxygen debt below which all animals survived

and above which mortality increased until a universally lethal

threshold of debt was attained (23). Subsequent animal and

clinical studies showed that increasing probability of mortality

was directly associated with total oxygen debt, and this debt

could be estimated from key metabolic markers, namely, base

deficit and lactate (12, 22, 24). It follows that if resuscitation

is initiated before a clinically significant oxygen debt is in-

curred and the debt is then repaid, cellular damage will beslight or nonexistent. Conversely, the likelihood of cellular

damage and subsequent organ failure is substantially in-

creased if the period of increased oxygen debt is prolonged

and/or resuscitation is inadequate (i.e., failure to repay oxygen

debt) (12, 21). Although there are limited data as to the

precise sequence of cellular events that occur during debt

repayment in the clinical setting, evidence of shock resolution

should consist, at a minimum, of the complete repayment of

oxygen debt.

Unfortunately, none of the original oxygen debt studies

made any assumptions as to the timeframe within which

accumulated debt is to be Bforgiven[ or repaid. In theory,

morbidity and/or mortality should not be affected by the

FIG. 2. Schematic of the relationship between oxygen deficit andoxygen debt. Oxygen deficit is the difference between baseline oxygenconsumption VO2 (indicated by the dashed line) and VO2 measured at agiven time point (indicated by numbered arrows) during the shock period; themagnitude of deficit is indicate by the length of the arrow. Oxygen debt isthe accumulated sum of all oxygen deficits incurred and is represented bythe area under the curve. See text for details.

SHOCK FEBRUARY 2010 OXYGEN DEBT REPAYMENT AND SHOCK RESUSCITATION 115



repayment schedule as long as no more debt is allowed to

accumulate. However, in practice, it is likely that debt

repayment will be slower when lower volumes of resuscita-

tion fluid are administered or if there is a delay in the onset of

definitive resuscitation. It has been observed that prolonged

hemorrhagic shock coupled with inadequate resuscitation

causes a relatively small proportion of immediate deaths but

nevertheless accounts for more than one fourth of hospital

deaths, primarily from organ failure (25). There is now

evidence that outcome from traumatic brain injuries is greatly

worsened if resuscitation is inadequate (26). This has pro-

found implications for war fighters because traumatic brain

injury is the signature injury of the current military conflicts

in Iraq and Afghanistan. The recent push toward both low-

volume (and hypotensive) and delayed resuscitation in the

prehospital environment means that it is even more important

that we reevaluate these resuscitation strategies in terms of

debt repayment schedule.

CASE STUDY: A CANINE MODEL OF OXYGENDEBT REPAYMENT

There are few data that pertain to the potential effects of

oxygen debt repayment schedule on mortality and morbidity

resulting from hemorrhagic shock. The only systematic

experimental study of which we are aware is a previously

reported canine model of hemorrhagic shock described by

Siegel et al. (27). This study represents a unique effort to

characterize oxygen debt repayment during early resuscitation

at the level of the whole organism. In brief, this model was

essentially an Bassay[ of different volumes of colloid fluid

(5% albumin) administered during the immediate posthemor-

rhage period and their relative effectiveness for maximizing

survival and minimizing organ damage. This model was

relatively severe: dogs were hemorrhaged to a predicted

mortality of 50%. The resulting oxygen debt of approximately

104 mL O2 kgj1

resulted in a realized mortality of 40%

within the first 3 days postshock. Fluids were administered

postshock according to one of five randomly assigned

resuscitation regimes: Bfull[ resuscitation (120% of shed

blood volume [SBV] replaced by fluid during a 20-min

period), no fluid (0% SBV) for 2 h postshock, followed by

full resuscitation, or by three Bpartial[ resuscitation regimes

(8.4%, 15%, and 30% SBV during a period of 10 min,

followed by the remaining SBV as colloid at 2 h posthemor-

rhage). Outcome was scored according to the amount of

physiological compromise incurred at 7 days posthemorrhage,

as determined by organ function and histological examination;

a good outcome indicated recovery at 7 days with intact motor

and neurological function, stabilization of vital signs, and

minimal to no cellular damage. Although survivors did not

differ appreciably in visible clinical signs of impairment,

cellular damage in liver and kidney was most severe in

surviving animals receiving the lowest partial immediate

resuscitation volumes (8.4% and 15% SBV) and minimal to

absent in animals receiving at least 30% SBV immediately

postshock. None of the animals in the 0% immediate

resuscitation group survived.

IMPLICATIONS FOR RESUSCITATION TIMINGAND FLUID VOLUMES

If oxygen debt repayment alone determines mortality and

morbidity, there should have been no differences in outcome

between groups of animals receiving 15%, 30%, or 120%

SBV immediately after the shock period. This is because these

volumes of fluid were sufficient to prevent additional debt

accumulation, and any remaining volume was returned at 2 h so

that debt was eventually repaid in all groups. However, his-

tological and organ function data showed that there was instead

a graded response in outcomes; cell and organ damage was

successively minimized with each volume increment returned

immediately posthemorrhage. Accordingly, we determined the

cell damage threshold by estimating the percent of oxygen debt

repaid for each hemorrhage group from the reported values and

comparing to the chart of histological outcomes (Table 1). The

TABLE 1. Colloid volumes estimated to achieve a given repayment of oxygen debt in a canine model of severe controlled hemorrhagic shock

Posthemorrhage resuscitation fluid volume, % SBV

0 8.4 15 30 120

SBV, % TBV* 71.0 73.7 72.1 69.8 69.3

Body mass, kg* 26.4 23.6 22.3 21.3 22.7

SBV, mL† 1,631 1,513 1,399 1,293 1,369

Oxygen debt incurred, mL oxygen kgj1* 101.3 105.6 102.2 108.8 103.5

Oxygen debt repaid, mL oxygen kgj1* 0 30.0 65.0 80.0 103.5

Oxygen debt repaid, % 0 28 64 74 100

Immediate resuscitation fluid total bolus, mL N/A 127 210 388 1,642

Mass-specific fluid bolus, mL kgj1 N/A 5 9.4 18.2 72.3

Outcome Early death Early death, severe focal

cellular injury

Moderate cellular injury Mild to moderate

cellular injury

Normal to mild

cellular injury

Data indicated by an asterisk are reported in Ref. (27). Resuscitation groups described in that study are based on the volume of fluid (as % SBV) givenduring the immediate postshock initial resuscitation phase: 0 indicates no fluid given for 2 h; 8.4 is 8.4% SBV returned, etc. See text for details of fluidrequirement estimates (milliliters per kilogram).†Assuming total blood volume is equivalent to 8.7% body mass.




percentage of oxygen debt repaid over 2 h for each group was

estimated from the ratio of oxygen debt repaid to that incurred.

For example, animals in the 30% SBV group incurred a debt

of 108.8 mL kgj1

by the end of hemorrhage. They received

approximately 30% SBV immediately posthemorrhage, which

repaid approximately 80 mL kgj1

, which is approximately 80/

108.8 or 74% of the accumulated debt over 2 h.

Two deductions can be inferred from this study. First, our

calculations suggest that it was in fact the amount of debt

repaid within a restricted time window, rather than the

absolute repayment of debt over a prolonged period of time,

which had a major impact on organ damage (Table 1).

Animals receiving 120% SBV repaid all of the debt within

2 hours and incurred no cellular damage (Fig. 3A). Animals

receiving 30% SBV were still able to repay approximately

three fourths of the sustained debt in a 2-h period, although

they incurred minimal to moderate organ damage (Fig. 3B).

Animals receiving an immediate resuscitation volume equal to

15% of SBV repaid less than a third of the accumulated debt

in 2 hours, with more severe organ damage (Fig. 3C). In allthese groups, all of the incurred oxygen debt was eventually

repaid, and no additional debt was incurred. In contrast,

animals receiving an immediate resuscitation volume equal to

only 8.4% of SBV continued to accrue debt for a short period

and then repaid less than a third of the accumulated debt in

2 hours, resulting in subsequent organ failure and death. In

summary, assessment of our calculated debt repayment

proportions in the context of the reported histological data

suggested that at least 30% of the shed blood volume, and

approximately 75% of oxygen debt, had to be repaid within

2 h of the hemorrhagic injury to prevent or minimize organ

damage. These data suggest that there is in fact a relatively

short time window (probably less than 2 h) within which aminimum proportion of oxygen debt must be repaid to avoid

mortality and major morbidity after moderate to severe shock.

The second consideration relates to the minimum volume of

resuscitation fluid required for oxygen debt repayment. For

the animals in the study of Siegel et al., we estimated the

minimum immediate fluid volume requirements that permit-

ted survival with at least an Bacceptable[ amount of organ

dysfunction. As previously discussed, this cutoff was equiv-

alent to a 75% oxygen debt repayment or approximately 30%

of the SBV (Table 1). Approximate SBV for each group was

estimated by assuming that total blood volume (TBV) was

approximately equivalent to 8.7% body mass (27). Mass-specific fluid volumes were then estimated as the fraction of

SBV returned divided by body mass. Therefore, estimated

TBV for animals in the 30% SBV group was approximately

0.087 mL gj1Â 21,300 g = 1,853 mL. The SBV removed to

incur an oxygen debt of 108.8 mL kgj1

in this group was

69.8% of TBV or 0.698 Â 1,853 mL = 1,293 mL. The volume

of fluid returned immediately posthemorrhage was 30% of

SBV or 0.3 Â 1,293 mL = 388 mL. Thus, the estimated min-

imum mass-specific volume associated with minimal organ

damage was (388 mL/21.2 kg) or 18.2 mL kgj1

. In summary,

these data suggest a fluid bolus of approximately 20 mL kgj1

may be necessary to avoid mortality and major morbidity af-

ter moderate to severe shock.

The canine model previously described is obviously not an

ideal representation of the clinical situation V albumin was

used for the resuscitation fluid, hemorrhage was controlled,

there was no additional trauma imposed, animals were anes-

thetized and heparinized, and only a single level of oxygen

debt was characterized. Despite these limitations, our deduc-

tions from these data have several major implications for

current resuscitation protocols and for the design of subse-

quent clinical trials. First, to minimize the probability of both

death and organ damage after moderate to severe shock, the

immediate repayment of at least two-thirds to three-fourths of the incurred oxygen debt within a relatively short period of

time (approximately 2 h) may be warranted. In some circum-

stances, this will not be an achievable goal. For example, in

the combat arena, delayed evacuation to definitive resuscita-

tion is almost inevitable given the reality of hostile urban,

austere, and/or remote environments. However, so-called

Bdelayed[ resuscitation strategies for civilian victims of

penetrating trauma have been advocated by the apparent

necessity to prevent clot dislodgment and the subsequent

increase in blood loss caused by immediate and/or excessive

fluid administration before hemorrhage control (28, 29). To

our knowledge, none of the published rationales for delayed

administration have considered implications for the oxygen

FIG. 3. Relationship between oxygen debt repayment and the like-lihood of significant organ damage and/or death. Oxygen debt isrepresented by the area under the basal VO2 dashed line; oxygen debtrepayment is the area above the basal VO2 dashed line. In all cases, oxygen

debt repayment is fixed (e.g., as in targeted fluid resuscitation protocols),but varying amounts of debt will be repaid in the first 2 h depending on theproportion of SBV immediately returned as resuscitation fluid. Resuscitationis marked by the dotted line between the shock and postshock sections. A,Oxygen debt rapidly paid off within an estimated 2 h of severe injury shouldincur little or no long-term ischemic damage. Here, oxygen debt repaymentequals oxygen debt incurred (100% repayment). B, Oxygen debt with im-mediate repayment of 75% of the accumulated debt. C, Oxygen debt withimmediate repayment of 30% of the accumulated debt. Continued accu-

mulation of oxygen debt and subsequent risk of organ damage, MODS,and death are highest in this scenario.




debt repayment schedule. Our calculations suggest that resus-

citation protocols must balance minimization of blood loss

and clotting failure with the need to resolve oxygen debt as

soon as possible after injury.

A second consideration is that Badequacy[ of fluid

resuscitation must be gauged by the extent to which oxygen

debt has been repaid within a given time window, rather than

in terms of a set fluid volume. Current Advanced Trauma Life

Support and PHTLS protocols deemphasize the amount of

fluid to be administered until hemorrhage can be controlled.

Both PHTLS and Tactical Combat Casualty Care guidelines

(30) recommend partial (hypotensive) resuscitation with

titration of fluid to maintain SBP at approximately 80 to

90 mmHg or MAP of 60 to 65 mmHg until definitive care is

reached. The stated goal of so-called low-volume resuscitation

strategies is the provision of enough fluid after severe blood

loss to raise blood pressure sufficiently to maintain adequate

oxygen delivery to tissue but not high enough to dislodge

clots and increase blood loss (31, 32). To meet current resus-

citation goals, relatively small volumes of hypertonic crys-talloids or synthetic colloid solutions have been promoted for

use in-theater (33). Low-volume resuscitation with hypertonic

fluids and/or colloids has the obvious physiological advan-

tages of volume expansion and hyperosmotic vasodilation

(which promotes reperfusion of ischemic tissues) (34) while

minimizing the absolute volume of fluids to be administered

(35). Small volume requirements also result in considerable

logistic advantages, such as the minimization of weight car-

ried by medics and conservation of scarce fluid resources in

austere environments (30, 33, 36, 37). Tactical Combat Casu-

alty Care volume guidelines suggest administration of colloids

up to two boluses of 500 mL each (30). This is equivalent to

approximately 7 to 14 mL kgj1 for a 70-kg subject. However,weight-based recommendations predicated on the assumption

of the hypothetical 70-kg male subject are themselves mislead-

ing because many recent potential military recruits have greatly

exceeded this weight (http://www.armytimes.com/news/2009/

01/ap_fat_camp_recruits_011209/ ), with the result that even

lower volumes will be provided. More extreme fluid goals

have been proposed by the DARPA Surviving Blood Loss

Program (http://www.darpa.mil/DSO/thrusts/bio/mainhuman/

sbl/index.html ) with the objective of reducing fluid loads to

4 mL kgj1

(the equivalent of a 250-mL bag of fluid for a

70-kg subject) before definitive resuscitation. However, our

calculations indicate the minimum colloid requirements torepay even moderate debt may be substantially higher than

these suggested volumes. Based on our analysis of oxygen

debt repayment kinetics, the minimum fluid requirements of

18 mL kgj1

estimated here with a colloid (albumin) as the

primary fluid were somewhat higher than the Tactical Combat

Casualty Care Y recommended maximum, and more than four

times greater than the DARPA/Surviving Blood Loss target;

volume requirements with Hextend would likely be no less. In

contrast, use of crystalloid would dramatically increase the

fluid needed to repay even a minimal amount of oxygen debt.

Our calculations regarding debt repayment schedule also

indicate why many prior historical values of critical oxygen

delivery as an end point (e.g., 600 mL minj

1 mj

2) gave such

equivocal results. Critical oxygen delivery marks the tran-

sition at which oxygen debt may accumulate, but without an

estimate of how much oxygen debt was actually incurred

beforehand and how much repaid on a per patient basis,

historical target values are essentially an arbitrary end point.

In many studies, the actual duration of the shock state was

either unknown or unreported. Therefore, the time at which

resuscitation was initiated relative to the insult, and con-

sequently the rate of oxygen debt repayment, will also be

unknown. In the original studies using hospitalized high-risk

surgical patients, it is possible that the surviving patients with

targeted oxygen delivery may never have passed the critical

DO2 threshold or, alternatively, the level of oxygen debt was

considerably less than expected so that resuscitation was

adequate to repay debt and thus favor a positive outcome.

Alternatively, critical illness may induce an increase of VO2

from baseline (38), thus resulting in a threshold DO2 occur-

ring at higher levels of DO2 compared with those produced

by nonsurgical insults or injuries. In this scenario, attempts to

restore oxygen delivery to threshold by a fixed-volume loadwould fail in that critical threshold would not be achieved,

and the individual subject would be underresuscitated. For a

third subset of patients, no resuscitation will be adequate

either because the initial incurred oxygen debt was lethal or

the debt repayment was so delayed that death or MODS was

inevitable. In trials designed to evaluate patient end points, it

is the patient-specific end point that is relevant. Because use

of a fixed oxygen delivery target will result in some patients

being underresuscitated, and some grossly overresuscitated,

we argue that Bone-size-fits-all[ guidelines are not useful and

do not allow for individualization of care. Basing resuscitation

protocols on specified end points without regard to the phys-

iological status of the individual patient may do more harmthan good. Clearly, time relative to injury must be accounted

for when assessing efficacy of resuscitation protocols. In

practice, however, determining this time point will be a prob-

lem especially for sepsis patients where the point of insult is

unknown.

SOME MODEST PROPOSALS AND A CAVEAT

A reevaluation of current experimental approaches to the

problem of adequate fluid resuscitation is clearly warranted.

In 1999, the Committee on Fluid Resuscitation for Combat

Casualties concluded that hemorrhagic shock researchconcentrating on correction of either hemodynamics or single

biochemical abnormalities associated with hemorrhage was

Bunlikely to be successful because multiple pathways lead to

the cell death result from severe hemorrhagic shock. Rather,

novel therapies should be aimed at the multiple metabolic and

cellular derangements that accompany traumatic shock[ (39).

We propose that resuscitation to correct immediate volume

deficits and hypoperfusion, and to control inflammation,

should involve not only a consideration of anti-inflammatory

adjuvants but also place increased emphasis on clinical

strategies to rapidly estimate and repay oxygen debt.

Methods of directly measuring oxygen debt in the prehos-

pital setting are not currently feasible. However, various




biochemical correlates such as lactate and base deficit have

been proposed as indices of posttraumatic hypovolemic shock,

postinjury resolution or deterioration, and the probability of

mortality (12, 40). Serum lactate levels have been used for

many years to identify and manage patients in shock

secondary to trauma and sepsis. Elevated lactated levels

(94 mM) are associated with increased patient mortality

(41). However, single time-point measurements are limited in

their use unless measured very soon after injury; this is

because a single lactate measurement either prior to, or some

time after, institution of resuscitation cannot provide the

information necessary to quantitatively estimate the extent of

shock. Therefore, it has been suggested that sequential values

will be of much greater clinical use as an index to patient

condition and response to fluid resuscitation (5, 42 Y 44).

Because the estimated half-life of serum lactate is approxi-

mately 20 min, persistently high or elevated lactate levels

have been considered to be a good indicator of persistent

impairment of oxygen delivery, early activation of inflamma-

tion, and subsequent development of MODS (45). Severalstudies have shown an association between rates of lactate

reduction and outcome (41 Y 43, 46, 47). Other studies have

indicated that lactate kinetics, or time to lactate clearance,

discriminated between survivors and nonsurvivors of trauma,

sepsis, burns, and cardiac arrest (41 Y 44, 47, 48). In an animal

trial of acute severe hemorrhage shock followed by low-

volume resuscitation, survivors could be discriminated from

nonsurvivors by lower absolute lactate concentrations at the

end of hemorrhage and during resuscitation, and sequential

lactate measurements obtained even over very short time

frames (minutes to hours) provided a useful rapid indication

of subject response to resuscitation (49). Therefore, given the

importance of oxygen debt repayment during the earlypostshock period, rapid sequential assessment of oxygen debt

repayment markers could increase the effectiveness of early

resuscitation especially in the prehospital or battlefield

setting. The recent evolution of point-of-care lactate/base

deficit monitors indicates that rapid sequential assessment of

metabolic markers in the field will be feasible in the very

near future.

The studies previously cited implicitly assume a close

association between high levels of marker concentration on

the one hand and the extent of the shock state on the other. In

one sense, use of a surrogate marker is essentially a problem

of calibration; that is, the magnitude of the surrogatemeasurement is assumed to vary in a predictable fashion with

that of the Bstandard.[ However, unlike a true calibration

problem, the requirements for determining a calibration

standard for shock are not met; that is, the Bstandard[

condition (shock) is still poorly understood, and there are

few objective measures of the shock state presented in the

literature that can be used to predict mortality and morbidity

in the laboratory or clinical setting. The mechanisms under-

lying oxygen debt at the cellular level have not been well

characterized. Most investigators would agree that Bshock[

likely represents the integration of the degree and duration of

tissue ischemia from multiple tissue beds (50). Nevertheless,

cellular mechanisms underlying the progression from low to

high death probability (loss of high-energy phosphate pools,

failure of membrane pumps, etc) have received far less

attention than simpler models of ischemia/reperfusion. Con-

sequently, it is unknown how changes in surrogate markers

may be expected to vary with changes in patient condition

during shock and resuscitation. If the change in marker

concentration with the degree of ischemia is in fact intrinsi-

cally nonlinear (as might be expected because the debt mor-

tality is logarithmic), and without indications of either limits

to detection or areas of insensitivity, there will be difficulty in

interpreting the absolute magnitude of the marker and its rel-

evance to clinical condition. For instance, lactate levels in-

crease not only in response to hypoxia but are also modulated

by skeletal muscle ATPase activity (51, 52). Therefore, it is

important to assess how well a given surrogate marker tracks

changes in oxygen deficit and/or debt in real time.

As part of a larger trial performed at our institution, we

examined the extent to which changes in lactate levels

correspond to changes in oxygen debt in a swine model of

hemorrhagic shock and resuscitation (approved in advance bythe Virginia Commonwealth University Institutional Animal

Care and Use Committee). In these trials, swine were

subjected to controlled hemorrhage under anesthesia to a

fixed oxygen debt of approximately 80 mL kgj1

. At the end

of hemorrhage, animals were resuscitated with a single bolus

of a given resuscitation fluid (such as whole blood, lactated

Ringer, hypertonic saline, and colloids, e.g., Hespan).

Sequential arterial lactates were measured simultaneously

with oxygen debt. As demonstrated with other models of

oxygen debt (24), the level of debt was not closely associated

with hemorrhage volumes and hemoglobin levels. Figure 4

demonstrates several oxygen debt-lactate response curves

observed for three animals selected to illustrate (A) a poor response to resuscitation, (B) near-complete resolution of

shock, and (C) an intermediate or partial resolution of shock

with failure to completely repay oxygen debt. It is apparent

that during the hemorrhage phase, each animal showed

increases in lactate corresponding to an increase in oxygen

debt. However, responses to resuscitation were variable. In

Figure 4A, both oxygen debt and lactate continued to

accumulate; fluid resuscitation (with lactated Ringer) was

clearly inadequate, and the animal died shortly before the end

of the prescribed 3-h postresuscitation period. In Figure 4B,

fluid resuscitation (with whole blood) seemed to be adequate

to completely repay oxygen debt, and lactate was reduced tonear-baseline levels. However, in the intermediate case

(Fig. 4C), oxygen debt was not fully repaid; lactate had begun

to resolve but still remained above baseline.

It is apparent from these examples that any two individuals

may start resuscitation from the same level of initial oxygen

debt and yet may end up on either extreme of the resuscitation

response continuum. Here, resolution of oxygen debt and

lactate clearly depend on the relative response to a given

resuscitation fluid. Second, although not perfect indicators of

oxygen debt status, sequential lactate determinations clearly

give promise of the first real calibration of a surrogate marker

with the shock condition. In this study, because the period of

shock was relatively short, two of these fluid regimens were




sufficient to partially or completely repay oxygen debt in the

short term. By Bpushing[ oxygen delivery back to the flow-

independent portion of the VO2 curve, it is assumed that an-

aerobiosis, and therefore the accumulation of further oxygen

debt, would be halted. Similarly, lactate levels are assumed to

track oxygen debt because the cessation of anaerobiosis would

result in the return of lactate production to normal, with sub-

sequent clearing of accumulated lactate, most likely by the

liver and renal cortex (53, 54). However, if the shock state

was sufficiently severe or prolonged beyond a certain point,

the ensuing ischemic damage to liver and kidney would result

in an inability to clear lactate. Further loss of high-energy

phosphate pools, mitochondrial disruption, and disruption of

ionic gradients would lead to cellular damage generated in

multiple organ beds (55), driving the progression of shock that

would in turn influence potential responses to subsequent

resuscitation efforts. As illustrated in Figure 4C, this implies

that in certain cases significant oxygen debt may remain de-

spite lactate returning to clinically normal levels. This creates

a practical difficulty in determining if patients whose lactate

levels are apparently normalized with resuscitation have in

fact repaid their oxygen debt. There are some clinical data for

sepsis patients suggesting that lactate levels may normalize

without oxygen debt resolution (56).

Crucial from the standpoint of managing the individual

patient is the question as to how much accumulated oxygen

debt can be tolerated while avoiding the transition to an

irreversible state of cell damage. The intermediate conditions

previously described represent the greatest problem for

personnel charged with the initial resuscitation of the

critically ill and injured because at present, there are no

useful clinical methods for fully tracking debt accumulationand clearance. Even if VO2 could be measured (as is the case

for the ventilated sedated patient in the intensive care unit

setting), both baseline VO2 and the actual duration of the

shock state before treatment V essential components of the

oxygen debt calculation V will still be unknown for a given

individual. Furthermore, hypothermia, sedation, anesthesia,

and other factors that serve to reduce VO2 will make it dif-

ficult to assess baseline VO2 relative to levels of VO2 at the

time of injury. Therefore, both the time at which resuscitation

was actually initiated relative to initiation of debt accumu-

lation and the absolute rate of oxygen debt repayment will

also be unknown. Further investigations of potential surrogate

markers and serial correlates for oxygen debt repayment maybe a good start. However, because organ blood flow is

determined by perfusion pressure and vascular resistance, we

need to investigate other tissue oxygenation variables (such as

oxygen extraction ratios of accessible tissue beds) for moni-

toring the relative persistence of oxygen debt during the post-

resuscitation period. Tissue oxygenation, although thought to

be an important determinant of organ dysfunction (57), could

be an unreliable end point if VO2 is decreased, not because

of a reduction in DO2, but because mitochondria are unable

to use available oxygen, a state known as cytopathic hypoxia

(58). Potential areas for future study could include determi-

nations of patterns of organ system Y

specific accumulation of oxygen debt during hemorrhage, debt repayment upon re-

suscitation, and the consequences for long-term organ func-

tion during the postresuscitation period.

Use of low-volume expanders in the treatment of trauma

and combat casualties may require the addition of pharmaco-

logic adjuncts to enhance repayment of debt, especially those

that promote microcirculatory blood flow, reduce VO2 re-

quirements of tissues, or provide alternative substrate use

until such time that adequate DO2 is assured. In the military

context, repayment of minimal oxygen debt requirements

within the modest volume constraints currently proposed will

likely require a combination of colloid, hypertonic saline, and

possibly hemoglobin or a non Y hemoglobin-based oxygen

FIG. 4. Relationship between lactate (:) and oxygen debt (&) for threeindividual animals in a swine model of hemorrhage and fluid resusci-tation. Animals were hemorrhaged (H) to a fixed oxygen debt of 80 mL kgj1,administered a single bolus of a given resuscitation fluid (R), then monitoredfor up to 180 min postresuscitation (PR). Baseline levels are represented (B).A, Animal administered lactated Ringer shows no resolution of debt with fluidresuscitation; lactate levels track increasing debt. B, Animal administeredwhole blood shows complete repayment of debt; lactate levels return to near-baseline levels. C, Animal administered Hespan shows partial repayment of

oxygen debt (50%) and near resolution of lactate.




carrier. Single administrations of hypertonic saline combined

with dextran (HSD) not exceeding 4 mL kgj1

seem to be safe

(35, 59), although in vitro coagulopathic changes have been

noted at higher loadings (60). HSD has been used clinically for

several years in Europe as RescueFlow (www.rescueflow.com).

Higher concentrations of sodium and colloids may serve as ef-

fective resuscitation agents even at levels less than 4 mL kgj1

(35, 59). Dilutional anemia resulting from repeated dosing

could be overcome, in theory at least, by combining HSD (or

other hypertonic saline/colloid cocktails) with a hemoglobin-

based oxygen carrier. Data from animal studies indicate that

incorporation of hemoglobin-based oxygen carrier into colloid

solutions result in improved short-term survival (61, 62), com-

pared with colloid alone.

CONCLUSIONS

In this article, we first review the concept of the oxygen

supply-delivery relationship with that of oxygen debt and

show how this is relevant to the current understanding of shock and resuscitation. We then build on this overview to

introduce the concept of oxygen debt repayment schedule.

There is obviously a great need for appropriate clinical data to

assess this concept for hemorrhagic shock patients. However,

we used some of the only available data from a canine model

of shock and resuscitation (27) to argue that this metric for

shock resuscitation provides a more rigorously defined and

clinically relevant end point for assessing the therapeutic

benefit of various resuscitation strategies. The concept of the

oxygen debt repayment schedule also provides an unambig-

uous and potentially objective standard for quantifying the

behavior of various postulated shock Bmarkers[ in response to

resuscitation. We demonstrate its heuristic value in providinga predictive framework for both the optimum therapeutic time

window and optimum fluid loadings before critical transitions

to an irreversible shock state can occur. A quantitative metric

such as oxygen debt should allow more rigorous assessment

of potential associations between the shock state and the

various physiological and biochemical alterations induced by

hemorrhage, such as the degree of inflammation, immune sup-

pression, and coagulopathy. Future work should be directed

toward the correlation of downstream injuries with oxygen debt

repayment kinetics. For the clinician who normally cannot

know absolute oxygen debt, the practical application of the

oxygen debt model will be manifested primarily as the pre-vention of additional debt accumulation. Normally, this would

be accomplished first by control of bleeding, and second, by

initial resuscitation to increase oxygen delivery to a point suf-

ficient to support baseline oxygen consumption. Once defini-

tive resuscitation can occur, we argue that repayment of debt

should occur as quickly as possible. As the canine data suggest,

the Bgolden hour [ may in reality consist of Btwo silver hours[;

that is, in moderate to severe shock, approximately three

fourths of the accumulated oxygen debt must be repaid within

2 h. Finally, although our discussion has concentrated on hem-

orrhagic shock and its resuscitation, oxygen debt repayment

kinetics may find wider applicability in other types of shock

and resuscitation protocols.

ACKNOWLEDGMENTS

The authors thank John Siegel, M.D., F.A.C.S., Emeritus Professor, New Jersey

Medical School (retired), for valuable comments on the manuscript.

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