REVIEW ARTICLE

“Blood failure” time to view blood as an organ: how oxygen debt contributes to blood failure and its implications for remote damage control resuscitation

Christopher K. Bjerkvig,1,2 Geir Strandenes,1,3 Ha˚kon S. Eliassen,3 Philip C. Spinella,4,5 Theodor K. Fosse,1,2 Andrew P. Cap,7 and Kevin R. Ward6

Hemorrhagic is both a local and systemic disorder. INTRODUCTION In the context of systemic effects, blood loss may lead to lmost 100 years ago, Robertson and Watson levels of reduced oxygen delivery (DO2) sufficient to cause tissue . Similar to other physiologic debts such as described the degenerative changes that take sleep, it is not possible to incur a significant oxygen debt place in the organism when the exsanguinated 1 and suffer no consequences for lack of timely repayment. A condition persisted for more than a few hours. They recommended to be cautious with the use of While the linkage between oxygen debt and traditional and warned not to wait too long before resorting to blood organ failure (renal, hepatic, lung, and circulation) has transfusion to improve the chances of successful surgery been long recognized, we should consider failure in two and recovery. This apt description of hemorrhagic shock is additional linked and very dynamic organ systems, the no less relevant today where identification and treatment endothelium and blood. These systems are very sensitive of hemorrhagic shock continues to represent a serious to oxygen debt and at risk for failing, having further implications on all other organ systems. The degree of 1 damage to the endothelium is largely modulated by the From the Norwegian Naval Special Operations Command and 2 degree of oxygen debt. Thus hypoperfusion is believed to Department of Anesthesia and Intensive Care and 3 begin a cascade of events leading to acute traumatic Department of Immunology and Transfusion Medicine, 4 coagulopathy (ATC). This combination of oxygen debt Haukeland University Hospital, Bergen, Norway; the Division driven endothelial damage and ATC might be considered of Pediatric Critical Care, Department of Pediatrics, collectively as “blood failure” due to the highly connected Washington University in St Louis, St Louis, Missouri; the 5 networks between these drivers. Coagulation and Blood Research, US Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas; the This article presents the implications of oxygen debt for 6Michigan Center for Integrative Research in Critical Care; remote damage control resuscitation strategies, such as Department of Emergency Medicine, University of Michigan, permissive and hemostatic resuscitation. Ann Arbor, Michigan; and the 7Blood Research Program, U.S. We review the impact of whole blood resuscitation and Army Institute of Surgical Research, Fort Sam Houston, Texas. red blood cell efficacy in mitigation of oxygen debt. Address reprint requests to: Kevin R. Ward, Michigan At last, this article recognizes the need for simple and Center for Integrative Research in Critical Care, NCRC: Bldg 10: durable, lightweight equipment that can detect the Office A103, 2800 Plymouth Rd, Ann Arbor, MI 48109; e-mail: adequacy of tissue DO and thus patient needs for 2 [email protected]. resuscitative care. The opinions or assertions contained herein are the pri- Point-of-care lactate measuring may be a predictive tool vate views of the authors and are not to be construed as offi- for identifying high-risk trauma patients and occult shock cial or as reflecting the views of the Norwegian Armed Forces, because it provides information beyond that of vital signs U.S. Department of the Army or the U.S. Department of and mechanism of injury as it may help predict the level Defense. of oxygen debt accumulation and need for resuscitation. Received for publication October 4, 2015; revision Serial measurements may also be valuable as a tool in received December 22, 2015; and accepted December 22, 2015. guiding resuscitative efforts. doi:10.1111/trf.13500 VC 2016 AABB TRANSFUSION 2016;56;S182–S189

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gen (VO2) is not limited by the DO2. The global DO2 to the

tissues can be derived from Fick’s equation, where DO2 is the product of cardiac output, hemoglobin oxygen satura-

tion and the hemoglobin concentration. DO2 at the tissue level is, of course, affected by other variables that can be adversely affected by low flow states, such as vasoregula-

tion and capillary patency, making tissue DO2 and its maintenance more complex.

As tissue DO2 decreases through hemorrhage, com- pensation occurs through greater oxygen extraction at the

level of microcirculation to meet tissue VO2. However, when oxygen extraction is not enough to meet demand Fig. 1. Biphasic relationship between oxygen consumption (tissue DO2 falls below the tissue VO2), an inflection point

(VO2) and oxygen delivery (DO2) (Solid line). As noted, DO2 called critical DO2 is reached (Fig. 1). This inflection point can vary widely without a drop in VO2 as extraction of deliv- represents the transition from mass aerobic metabolism ered oxygen can increase to continue to meet tissue VO2 and to mass anaerobic metabolism where VO2 now becomes thus lactate levels do not rise (Dashed line). However, when directly dependent on DO2. This metabolic transition

DO2 drops to a point where extraction of delivered oxygen moves tissues into an ischemic state where oxygen deficit cannot meet tissue VO2 (critical DO2), VO2 becomes directly exists. Because there is a significant associated time dependent on DO2 and anaerobic metabolism increases, dimension, shock cannot be fully evaluated by the deficit leading to increasing levels of lactate. This signals the begin- at any given time period (snapshot). The shock state ning of shock and the accumulation of oxygen deficit, the should account for the deficit accumulated over time degree of which is determined by the magnitude of VO2 since the point of injury. The oxygen deficit accumulated below its aerobic threshold. The accumulated oxygen deficit over time is thus termed oxygen debt. As the DO2/VO2 over time is oxygen debt. ratio falls, a greater deficit accumulates, and when multi- plied by time, a greater cumulative debt also accumulates. challenge in prehospital trauma care, especially when Thus shock and oxygen debt are synonymous, but with definitive care is delayed. oxygen debt being a more quantitative descriptor of the Robertson’s and Watson’s description of the exsangui- state over time. nated condition over time encompasses the concept of An often overlooked physiologic principle in regards oxygen debt, a well-known driver of survival from hemor- to oxygen debt is the need for timely repayment of critical 4,5 rhagic shock and an increasingly recognized initiator and portions of this debt as soon as possible. Similar to sustainer of important intermediary physiologic processes other physiologic debts such as sleep, it is not possible to 2 incur a significant oxygen debt and suffer no consequen- such as coagulopathy and inflammation. The fact that ces for lack of timely repayment. It is simply not enough Robertson and Watson recommended early use of blood to stop incurring a deficit. So, in addition to restoring DO and less reliance on saline also recognizes and under- 2 to meet the basal metabolic demands of the body (on scores the importance of developing strategies that limit mean 200-250 cc/min), thus halting additional deficit the development of oxygen debt. accumulation, as much as 10 L of additional consumption may be required to replenish such critical cellular ener- THE PHYSIOLOGY OF OXYGEN DEBT AND getic processes as the phosphogen and glycogen-lactic THE QUANTIFICATION OF SHOCK acid system, which can be significantly depleted in shock.6 The ability to repay decreases with increasing lev- Hemorrhagic shock is both a local and systemic disorder. els of debt. In the context of systemic effects, blood loss may lead to The accumulations of critical levels of oxygen debt levels of reduced oxygen delivery (DO2) sufficient to cause and failure to repay in a timely manner have consequen- tissue ischemia. Oxygen debt can be viewed as another ces. Rixen and others have shown a correlation between term for whole body ischemia. While stroke and myocar- oxygen debt and the amount of reperfusion and inflam- dial infarction are examples of ischemia in isolated organ matory injury.3 Again, if we look at stroke or acute myo- systems, shock is the example for whole body ischemic cardial infarction (AMI), the greater the ischemic burden, events during hemorrhage. To understand the concept of the worse the tissue will do on reperfusion. Several patho- oxygen debt, one must look at the biphasic relationship physiological mechanisms ranging from free radicals and 3 between the oxygen consumption (VO2)andDO2 (Fig. 1). oxidative damage, calcium influx, necrosis, and apoptosis

In a normal resting state, VO2 is independent of DO2.Or, lead to further multiorgan dysfunction syndrome in other terms, the whole body metabolic demand of oxy- (MODS). Capillary leakage will lead to activation and

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infiltration of neutrophils into the parenchyma. As the gut lation and oxygen debt repayment should be a primary starts leaking bacteria, endotoxins may enter the systemic goal in prehospital trauma care. Resuscitation guidelines circulation and initiate an aggregated inflammatory reac- and strategies should adopt these principles to develop tion. Much of the final organ damage and failure in the logical strategies that optimize outcomes in the challeng- end will be due to irreversible mitochondrial damage. ing prehospital care environment. The pathophysiological course of hemorrhagic shock is also reflected in mortality data. Current knowledge THE GREAT CHALLENGE OF AVOIDING points at three cohorts in which death can be caused by BLOOD FAILURE: OXYGEN DEBT AND either intractable rapid exsanguination, irreversible shock REMOTE DAMAGE CONTROL in the acute phase refractory to resuscitation measures RESUSCITATION (when oxygen debt proves lethal), or subacute MODS in patients who survive surgery and die in the ICU.7,8 Remote damage control resuscitation (RDCR) is a treat- While the linkage between oxygen debt and tradi- ment strategy for the severely injured trauma patient tional organ failure (renal, hepatic, lung, etc.) has been designed to limit hemorrhage and to produce or preserve long recognized, we should consider two additional linked an adequate level of physiologic reserve to deliver a and very dynamic tissues that are very sensitive to oxygen patient that can be salvaged with the follow-on strategy of debt and are at risk for failing, having implications for all damage control surgery.11 Since definitive control of hem- other organ systems. These two tissues, endothelium and orrhage can rarely be guaranteed in the prehosptial set- blood, can be thought of as an integrated organ system, ting, the doctrine of permissive hypotension has been both from a developmental standpoint and from the per- adopted as a strategy for RDCR to limit ongoing hemor- spective of shock. The microcirculation with its endothe- rhage by reducing hydrostatic pressure while maintaining lial lining is estimated to represent an area of 4000- a “critical level” of vital organ . The practice is, 7000 m2 and thus might be considered, along with the in theory, an overall component of hemostatic resuscita- blood it envelops, the body’s largest integrated functional tion. This strategy is not new. In 1945, Emerson suggested organ system. With over 1013 cells, the endothelium is a an approach to combat casualties in hemorrhagic shock major target of damage from trauma, hemorrhage, hypo- using resuscitation that avoids excessive hemodilution perfusion, and reperfusion injury. Recent attention to the with plasma (not more than 1000 cc) and restoring the endothelium’s glycocalyx structure and function are now systolic pressure to 100 mmHg before surgery. This providing important insights into its role in the develop- approach, based on whole blood (WB) and plasma only, ment of response to trauma.9 allowed a slightly higher pressure and thus a higher flow 12 The degree of damage to the endothelium is largely and DO2. Very general physiologic parameters have modulated by the degree of hypoperfusion experienced, been suggested to guide permissive hypotension, such as which is believed to begin a cascade of events leading to maintenance of a palpable radial pulse, mental status, acute traumatic coagulopathy (ATC). ATC is characterized and an systolic (SBP) of 80-100 mmHg. by a systemic combination of fibrinolysis and to some Recently, Eastridge et al. published data suggesting that extent anticoagulation driven by the protein C pathway. an SBP of 100 mmHg should define hypotension and Platelet dysfunction also occurs through mechanisms that impending hypoperfusion, at least for the battlefield casu- have yet to be fully elucidated. Evidence indicates that the alty.13 Systolic blood pressures below 100 mmHg were degree of hypoperfusion and resulting oxygen debt is the associated with increased base deficits (indicating greater main driver behind ATC and that significant coagulopathy oxygen debts) and mortality. Data are lacking to support can occur before fluid resuscitation.2 New evidence indi- the use of other physical resuscitative endpoints such as a cates that reperfusion injury may damage fibrinogen and palpable radial pulse or mental status. fibrin, thus making for weaker clots and further exacerbat- There are, of course, many challenges to the use of ing ATC.10 Further blood loss, crystalloid-induced hemo- permissive hypotension, including the desire to titrate dilution, acidosis, , occurring during the blood pressure to a level that limits hemorrhage but at the course of continued hemorrhage and treatment only serve same time halts the continued accumulation of oxygen to exacerbate ATC, creating conditions favorable for more debt. Obviously, factors such as prolonged transport times, and worsening of oxygen debt. This combination limited monitoring tools, and limited availability of blood of oxygen debt-driven endothelial damage and ATC might products make widespread and precise adoption of such be considered collectively as “blood failure” due to the strategies very complicated. In this context, and according highly connected networks between these drivers. to Fick’s equation, resuscitation with clear fluids to increase

Both animal and clinical data support that late out- cardiac output to sustain adequate DO2 will lead to dilution come is correlated with the severity and duration of shock, of hemoglobin levels. Over time, and following repeated and that metabolic correlates are the best predictors of boluses, this will leave the patient in a downward spiral in outcome. This is why mitigation of oxygen debt accumu- relation to DO2. Thus, early transfusion of erythrocytes is

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reasonable. Concomitant (TBI) adds This approach represents the best chance to avoid or cor- additional complexities, as permissive hypotension will fur- rect blood failure and its underlying drivers. Recent data ther decrease cerebral perfusion pressure and thus exacer- demonstrating the endothelium-restoring capacity of bate TBI through secondary ischemic injury. Use of plasma, for example, help to underscore that the benefit analgesics and sedatives make the use of mental status as of all products together are greater than the sum of their an indicator of adequate perfusion less practical. parts. However, implementing such strategies far-forward Studies on prolonged permissive hypotension are where they would have their greatest benefit is logistically mostly limited to animal studies, case reports, in-hospital challenging. The ideal approach may be to consider a studies, or prehosptial studies with short transport times wider use of WB. to definitive care and with the use of crystalloid resuscita- A mixture of red blood cells (RBCs):plasma:platelets tion.14-17 No study exists to our knowledge that would in a 1:1:1 ratio contains a hemoglobin concentration of resemble the combat or even civilian setting where pro- around 9 g/dL due to the anticoagulants and RBC additive longed transport times (>1 hr) are routine. solutions. WB (approximately 450 mL blood 1 63 mL pres- Thus, while permissive hypotension should be viewed ervation solution) has a mean hematocrit of 40%-45%, as a potentially valuable RDCR hemostatic strategy, the which gives a mean hemoglobin level of 13-14 g/dL (using resulting potential accumulation of additional oxygen healthy young individuals as donors). According to Fick’s debt is important to take into consideration given its equation, the WB approach gives a DO2 30% higher than impact on the development of ATC (blood failure), other the component approach in a volume replacement trans- organ failure and finally depletion of physiologic reserve fusion. This may be crucial for mitigating oxygen debt adequate to ensure near-term survival. during ongoing bleeding and delayed evacuation. Further- As outlined above, the balance between allowing the more, the practical resuscitative efforts in the context of patient to be hypotensive and simultaneously avoiding workload should be easier with the WB approach com- development of additional oxygen debt will be critical for pared to 1:1:1 therapy, simply because it is easier to trans- survival of hemorrhagic shock. The goal is to maintain the fuse one bag instead of three. highest possible DO2 at the lowest possible hydrostatic Fibrinogen levels should also be taken into considera- driving pressure. Improvement of flow (cardiac output) at tion. With the 1:1:1 component approach, the patient will a given perfusion pressure is obtained by reducing sys- soon reach a critical fibrinogen level due to low levels in temic vascular resistance (SVR), allowing a higher flow at freeze dried and fresh frozen plasma, and extra fibrinogen the same pressure threshold. This may be possible in the concentrate must be considered. WB fibrinogen levels anesthetized and monitored patient with titration of anes- from healthy young donors levels mean about 3 g/L, miti- thetics (reducing SVR while refilling the vascular bed), gating fibrinogen depletion in the patient during ongoing resulting in increased DO2 if the hemoglobin and oxygen bleeding. saturation level are maintained at adequate levels. How- The impact of the platelet contribution from WB ever, accomplishing this with any precision in a nonse- resuscitation in the preshospital setting also has to be dated and spontaneously breathing battlefield casualty evaluated because there exist clinical studies showing under maximal sympathetic tone resulting from injury improved survival with early use of platelets in combina- and pain would require the development and implemen- tion with RBCs and plasma.18 tation of transformative monitoring and therapeutic The current Tactical Combat Casualty Care (TCCC) technologies. guidelines now recommend WB as the number one pre- This leaves us with limited options for implementing ferred fluid for hemorrhagic shock resuscitation in combat permissive hypotension as a hemostatic RDCR strategy, casualties.19 Mitigating oxygen debt with WB may be particularly in the setting of prolonged transport. Based superior to component therapy and easier to implement on the physiology of oxygen debt and its linkage to blood than initially believed.20 Both cold-stored WB, and warm failure and survival, it appears that we need to “fast- fresh WB drawn from a walking donor pool or an emer- forward” to the past and strongly consider the approach gency donor panel are feasible.21,22 Simple use of RBC suggested by Emerson. units (discussed below) does not represent an adequate solution to the problem. HEMOSTATIC RESUSCITATION TO LIMIT OXYGEN DEBT IMPORTANT CONSIDERATIONS REGARDING THE EFFICACY OF RBC- Today, aggressive hemorrhage control with hemostatic CONTAINING BLOOD PRODUCTS IN dressings and tourniquets, together with hemostatic REVERSING OXYGEN DEBT resuscitation using blood products provided in a 1:1:1 ratio and early administration of tranexamic acid, is con- Most physicians consider RBCs in either RBC or WB units sidered to be the gold standard of care in trauma centers. as the optimal resuscitative solution to treat hemorrhagic

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shock. It is commonly believed that because transfused such as loss of 2,3-DPG and ATP concentrations (e.g., akin RBC units increase hemoglobin content and blood oxygen to improved function of transplanted organs over time).33 content, that DO2 to tissue is likewise improved. Some Human trials are needed to evaluate the efficacy of data suggest, however, that with increasing storage dura- RBCs to reverse shock in patients with traumatic hemor- tion, DO2 may be in fact progressively impaired by altered rhagic shock. Clinical measures of efficacy in future oxygen affinity, disfavorable rheology and adhesion, as trauma trials can be measured, such as improvement in well as by abnormal vascular signaling by RBCs that lactate concentrations, tissue DO2 and consumption, increases regional vascular resistance (and diminishes functional hemostatic measures, organ function, and regional blood flow despite adequate perfusion pres- other morbidity measures, as well as mortality. sure).23 This is of particular concern because these RBC storage lesions are generally believed to increase over MONITORING: THE MISSING LINK time and are coupled with the routine practice of trans- fusing the oldest units from the blood bank into trauma Identification, quantification, and monitoring of shock patients.24 represent the greatest clinical challenges in the treatment Recent large RCTs in nontrauma patients have not of traumatic shock, especially in the prehospital setting. indicated a clinical benefit from the use of “fresher” In this phase, decisions are largely based on recognition of RBCs.25-27 These trials, however, were in critically ill the mechanism of injury and clinical evaluation of vital patients that were not in hemorrhagic shock, which limits signs. Occult shock (shock in the presence of a normal their generalizability to this population. In addition, there range of vital signs, or accumulating oxygen debt) is a sig- is increasing awareness that donor variability in RBC qual- nificant problem because healthy young individuals have ity is high. This donor variability in RBC quality causes the great compensatory reserves. Resuscitation decisions are based on uncertainty regarding the anatomic source of stored RBCs to “age” differently, and as a result the use of bleeding and the volume and duration of hemorrhage. In RBC age as a measure of quality may not be accurate.28 part due to the lack of advanced diagnostic tools in the Investigators are examining whether there are other RBC field, management of shock is a difficult task even for the quality measures that can be used as more accurate surro- most experienced of clinicians. In the combat theatre, one gates for RBC quality. also has to remember that most front-line providers have Clinicians need to appreciate that native RBC func- medical care as a secondary task. Senior policymakers tion in increasing DO may be altered or diminished in 2 attempt to compensate for this by developing and relying stored RBC-containing blood products. There are in vitro, on protocols to overcome this gap. animal, and nonrandomized studies in adult trauma Many protocols rely solely on systolic blood pressure, patients that indicate that RBCs of increased storage dura- heart rate, and mental status, despite the fact that none of tion are associated with reduced DO , reduced perfusion, 2 these are optimal surrogates for cellular perfusion. Pro- and perturbed vasoregulation, as well as impaired spective research suggests that while casualties with hypo- immune and coagulation function.24,29,30 Arecentstudy tension have greater base deficits and mortality, these by Kiraly and colleagues in adult trauma patients indi- measures lack specificity that would optimize the use of cated that RBCs stored for more than 21 days reduced therapeutic resources to significantly improve out- 31 DO2 compared with those stored for less than 21 days. comes.4,34,35 In this context, there is an obvious need for Another prospective study performed in a severe pneumo- simple and durable, lightweight equipment that can nia model in canines indicated that transfusion of older detect the adequacy of tissue DO2 and thus patient needs RBCs was associated with impaired vasoregulation and for resuscitative care. 32 increased mortality. With the preponderance of animal Given the importance of addressing the development and human data indicating reduced efficacy and safety of of oxygen debt, the ability to leverage a metabolic signal older RBCs in critically ill populations, particularly in to identify, track, and guide therapy to reduce oxygen debt trauma patients, it is appropriate, if possible, to preferen- should be desirable. To this end, the use of lactate moni- tially use RBCs or WB of reduced storage duration (<15 toring is attractive. Many studies have correlated lactate days) until there is evidence that older RBCs are equiva- levels in trauma to outcomes, including its measurement lent to fresher ones. If fresher RBCs are not available, it is in the prehospital setting.36-38 Guyette et al. found that still important to transfuse available RBC or WB units lactate is superior to other early surrogates of hypoperfu- because impaired regulation of regional blood flow is a sion (systolic blood pressure and shock index) in predict- moot point if overall cardiac output and hemodynamics ing the need for resuscitative care in trauma patients are inadequate to generate regional perfusion pressure. presenting with a systolic blood pressure between 70 and Also, if the patient survives the acute resuscitation, some 100 mmHg.39 The linkage of lactate levels to base deficit of the adverse effects associated with the storage lesion values as indicative of hypoperfusion (oxygen debt) and appear to reverse in the 48 hours following transfusion, development of ATC also underscores its potential value.

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Studies have demonstrated the ability of serial lactate lev- to supranormal levels has been associated with adverse els to quantify oxygen debt and even identify an LD50 in events such as overresuscitation, leading to abdominal animals.40 Given these data and the availability of small, compartment syndrome and other complications.41 lightweight point-of-care lactate (P-Lac) devices, the use Lastly, casualties who are physically active before of serial field lactate monitoring may serve as a valuable injury may have significantly elevated lactate levels ini- tool in guiding RDCR and in optimizing scarce resources tially, since oxygen debt can be incurred through strenu- such as the use of WB. ous activity. However, hyperlactatemia from this alone Thus P-Lac may be a predictive tool for identifying should clear rapidly. Persistently elevated lactate levels, high-risk trauma patients and occult shock because it pro- especially after transfusion, would indicate oxygen debt vides information beyond that of vital signs and mecha- from hemorrhage. nism of injury, predicting the level of oxygen debt accumulation and need for resuscitation. An isolated lac- tate measurement above 4-5 mmol/L has been demon- A MORE PERSONALIZED AND PRECISE strated to predict the need for resuscitative care.39 APPROACH TO RDCR Furthermore, trends in lactate levels such as lactate clear- Based on the facts discussed above, we propose a more ance will be useful in understanding the true effectiveness personalized and precise approach to RDCR, using a com- of resuscitation even in patients with normal vital signs. bination of mechanism of injury, SBP tracking, and P-Lac A few caveats and possibilities should be noted to monitoring in triage as well as in monitoring resuscitative maximally leverage P-Lac monitoring. First, serial meas- efforts. Mechanism of injury may be the most important ures and not singular measures are most important. It is initial trigger for resuscitative care in the field. This notion the degree of lactate elevation over time that will be most has been supported by Benfield et al., who showed an valuable in understanding an individual’s accumulating association between the pattern of injury and the total oxygen debt, position on the DO /VO curve, likely out- 42 2 2 number of blood products needed for resuscitation. comes, and optimal therapy. Monitoring P-Lac every However, we must be cognizant of the need for additional 30-60 minutes is recommended as a strategy to guide triggers to either continue or modify resuscitations therapy. It is difficult to overstate the potential value of because of the resource limitations imposed by RDCR. We this, especially if multiple casualties are encountered and thus recommend mechanism of injury as a primary resources such as blood products are scarce and evacua- decision-making foundation. Together with trending lac- tion times are prolonged. For example, a casualty with a tate and SBP, enough parameters may be available to persistently elevated lactate above 10 mEq/L for 2-3 hours develop a logical approach to a more personalized RDCR might not be considered a candidate for additional blood that limits oxygen debt, avoids blood failure and maxi- products, because the accumulated oxygen debt is likely mizes utilization of resources.39 For example, an SBP of 90 not consistent with survival.40 mmHg in the face of lactate clearing in one individual A second important caveat is that while lactate clearance in the hemorrhaging casualty is a sign that would pose different resource allocation and ongoing the continued accumulation of oxygen debt has been resuscitation strategy options than an SBP of 110 in an halted, it is not an indication that oxygen debt has been individual with a climbing lactate. repaid to any significant extent. The reason for this can be seen in Fig. 1. Due to the biphasic nature of the rela- CONCLUSION tionship between DO2 and VO2,DO2 can be pushed up Because of its essential role in survival and resuscitative just past the point of DO2crit where VO2 is not DO2 dependent. At this stage, anaerobic metabolism has complications, mitigation of oxygen debt accumulation in shifted to aerobic metabolism, and lactate production is the prehospital phase is imperative to reduce the inci- reduced. The previously produced lactate will be metab- dence of blood failure and improve outcome in hemor- olized by the liver and kidney. However, one cannot rhagic shock. Ideally, this should be accomplished by know if debt has been adequately repaid. Thus, while rapid, aggressive hemorrhage control when possible, fol- lactate monitoring can be used to quantify accumulat- lowed by a resuscitation strategy based on blood products. ing debt, it is a poor guide in debt repayment. There are WB is the preferred product in optimizing DO2 to a point currently no technologies available in or out of hospital proximal to critical DO2, sufficient to support tissue VO2 that can be used in a practical sense to know if debt is in a delivery independent manner, thereby halting the being or has been adequately repaid. It should also be accumulation of oxygen debt. Permissive hypotension has stressed that moving the casualty to a state of VO2 that to be further evaluated in the context of oxygen debt accu- is independent of DO2 to halt the accumulation of oxy- mulation, especially in the case of delayed evacuation. gen debt is not to be confused with resuscitating to After surgical hemorrhage control, repayment of debt supranormal levels of DO2. The practice of driving DO2 should occur as quickly as possible.

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Today, prehospital care providers are challenged to 13. Eastridge BJ, Salinas J, Wade CE, et al. Hypotension is perform under extreme conditions. There is a “gap” where 100 mm hg on the battlefield. Am J Surg 2011;202:404-8. providers, sometimes with medical care as a secondary 14. Garner J, Watts S, Parry C, et al. Prolonged permissive hypo- task, have to carry out advanced resuscitation procedures tensive resuscitation is associated with poor outcome in pri- with minimal equipment and limited experience. This gap mary blast injury with controlled hemorrhage. Ann Surg must be filled with reliable, simple protocols and proce- 2010;251:1131-9. dures focusing on the principles of oxygen debt repay- 15. Skarda DE, Mulier KE, George ME, et al. Eight hours of hypo- ment and thus mitigation of blood failure. Use of tools tensive versus normotensive resuscitation in a porcine such as P-Lac monitoring in combination of monitoring model of controlled hemorrhagic shock. Acad Emerg Med of SBP could bring tremendous value in guiding RDCR 2008;15:845-52. and leveraging permissive hypotension as a hemostatic 16. Doran CM, Doran CA, Woolley T, et al. Targeted resuscitation strategy. Lastly, it is also important to remember that improves coagulation and outcome. J Trauma Acute Care management recommendations are guidelines rather Surg 2012;72:835-43. than definitive standards of care. 17. Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994;331:1105-9. CONFLICT OF INTEREST 18. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 The authors have disclosed no conflicts of interest. ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015;313:471-82. REFERENCES 19. Butler FK, Holcomb JB, Schreiber MA, et al. 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Tarasev M, Alfano K, Chakraborty S, et al. Similar donors - 11. Holcomb JB. Damage control resuscitation. J Trauma 2007; similar blood? Transfusion 2014;54:933-41. 62:S36-7. 29. Hess JR. Red cell changes during storage. Transfus Apher Sci 12. Emerson CP,Ebert RV. A study of shock in battle casualties: 2010;43:51-9. measurements of the blood volume changes occurring in 30. Spinella PC, Perkins JG, Grathwohl KW, et al. Risks response to therapy. Ann Surg 1945;122:745-72. associated with fresh whole blood and red blood cell

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transfusions in a combat support hospital. Crit Care Med 37. Tobias AZ, Guyette FX, Seymour CW, et al. Pre-resuscitation 2007;35:2576-81. lactate and hospital mortality in prehospital patients. Pre- 31. Kiraly LN, Underwood S, Differding JA, et al. Transfusion of hosp Emerg Care 2014;18:321-7. aged packed red blood cells results in decreased tissue oxy- 38. Guyette F, Suffoletto B, Castillo JL, et al. Prehospital serum genation in critically injured trauma patients. J Trauma lactate as a predictor of outcomes in trauma patients: a ret- 2009;67:29-32. rospective observational study. J Trauma 2011;70:782-6. 32. Solomon SB, Wang D, Sun J, et al. Mortality increases after 39. Guyette FX, Meier EN, Newgard C, et al. A comparison of massive exchange transfusion with older stored blood in can- prehospital lactate and systolic blood pressure for predicting ines with experimental pneumonia. Blood 2013;121:1663-72. the need for resuscitative care in trauma transported by 33. Heaton A, Keegan T, Holme S. In vivo regeneration of red ground. J Trauma Acute Care Surg 2015;78:600-6. cell 2,3-diphosphoglycerate following transfusion of DPG- 40. Dunham CM, Siegel JH, Weireter L, et al. Oxygen debt and depleted as-1, as-3 and CPDA-1 red cells. Br J Haematol metabolic acidemia as quantitative predictors of mortality 1989;71:131-6. and the severity of the ischemic insult in hemorrhagic shock. 34. Wo CC, Shoemaker WC, Appel PL, et al. Unreliability of Crit Care Med 1991;19:231-43. blood pressure and heart rate to evaluate cardiac output in 41. Balogh Z, McKinley BA, Cocanour CS, et al. Supranormal emergency resuscitation and critical illness. Crit Care Med trauma resuscitation causes more cases of abdominal com- 1993;21:218-23. partment syndrome. Arch Surg 2003;138:637-42, discussion 35. McGee S, Abernethy WB III, Simel DL. The rational clinical 42-3. examination. Is this patient hypovolemic? JAMA 1999;281: 42. Benfield RJ, Mamczak CN, Vo KC, et al. Initial predictors 1022-9. associated with outcome in injured multiple traumatic limb 36. Broder G, Weil MH. Excess lactate: an index of reversibility amputations: a Kandahar-based combat hospital experience. of shock in human patients. Science 1964;143:1457-9. Injury 2012;43:1753-8.

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