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Intravascular Volume Expansion: Which Surrogate Markers Could Help the Clinician to Assess Improved Tissue Perfusion?

Vallet, Benoit MD, PhD

doi: 10.1213/ANE.0b013e3182066299
Editorials: Editorials

From the Department of Anesthesiology and Intensive Care Medicine, University Hospital of Lille, Lille, France.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the author.

Address correspondence to Pr. Benoit Vallet, Department of Anesthesiology and Intensive Care Medicine, University Hospital of Lille, F-59037 Lille, France. Address e-mail to

Accepted October 12, 2010

The primary goal of intravascular volume replacement therapy is to maintain stable hemodynamics by correcting hypovolemia. At present, there is no evidence that mortality rates can be influenced by the choice of replacement strategy. Although volume replacement seems logically to be essential in the hypovolemic patient, this has never been proven in large multicenter trials and is therefore not evidence based. Many of our therapeutic strategies in the critically ill are not based on proven evidence but rather on applied physiology. Therefore, when looking for the “ideal” volume replacement strategy, we should consider not only effects on hemodynamics, but also possible effects on additional properties such as organ perfusion, microcirculation, tissue oxygenation, or even inflammation or endothelium injury-related parameters.

Crystalloids, especially saline solution, have often been recommended as the fluid of choice for treating the hypovolemic critically ill patient. Their so-called “physiological” properties have often been overemphasized, and they seem, in fact, less likely to be appropriate for resuscitation of the intravascular space and for restoration of the microcirculation. Indeed, resuscitation with colloids showed more beneficial effects on the microcirculation than resuscitation with saline in experimental models.1,2 Although hydroxyethyl starch (HES) prevents vascular leakage, crystalloids do not; thus, fluid shifts to the interstitial space and produces edema.3 Hypertonic saline with HES (HHES), which is not only hypertonic but also hyperoncotic, was also proposed as a new approach to intravascular volume replacement and as the initial treatment of posttraumatic hypotension, with the strong suggestion that the fluid-saving properties of HHES would also avoid crystalloid-induced fluid overload.

In this issue of Anesthesia & Analgesia, using a classic experimental hemorrhagic modified Wiggers' model, Barros et al.4 hypothesize, therefore, that HHES would prolong volume expansion through endogenous fluid redistribution by osmotic-dependent absorption of interstitial fluid. They believe that this should prove to be more beneficial for hemodynamics and oxygen transport than 6% HES alone. Mongrel dogs were submitted to pressure-guided hemorrhage (mean arterial blood pressure between 40 and 50 mm Hg for 45 minutes). According to the type of solution used for resuscitation, the authors observed that lactated Ringer (LR) solution (in a 3:1 ratio to shed blood volume) and HES (6% 130/0.4 in a 1:1 ratio to shed blood volume), through different mechanisms, resulted in early and larger intravascular volume expansion, and consequently, better hemodynamic performance than HHES (7.5% NaCl in 6% HES 130/0.4 solution). The smaller intravascular volume expansion from HHES after fixed volume resuscitation indeed provided worse systemic oxygenation recovery compared with LR solution and HES.

As emphasized by the authors, the 30 mL · kg−1 hemorrhage performed (approximately 40% of total blood volume) limits the extrapolation of their results to severe hemorrhagic shock. It must nevertheless be underscored that this experimental study could influence our clinical practice because it effectively describes the pathophysiology of shock and its resuscitation by fluids. It should also influence our decision to use better markers of improved perfusion than macrohemodynamics. Indeed, the key variables investigated in this study were carefully collected and put into perspective: blood and plasma volume, hematocrit, blood volume expansion and volume expansion efficiency, hemodynamics, plasma sodium and chloride, acid-base balance, and lactate concentration. Global oxygenation as assessed by venous oxygen saturation was used as a surrogate of the balance between oxygen delivery and oxygen consumption. Tissue perfusion was estimated through assessment of gastric tonometered tissue-to-arterial CO2 difference (PCO2 gap). The authors clearly demonstrate that HHES did not improve the splanchnic perfusion, as indicated by a higher tonometered tissue-to-arterial PCO2 gap, during resuscitation, in comparison to LR solution and HES.

This regional hypoperfusion certainly explains the significantly lower mixed venous O2 saturation observed 90 minutes after fluid resuscitation with HHES (venous oxygen saturation was 72% with HES and 75% with LR solution), and the significantly lower arterial pH (7.24 vs 7.33 and 7.37, respectively) and arterial bicarbonates (17 vs 20 mmol · L−1). The PCO2 gap after 90 minutes of fluid replacement remained <15 mm Hg with LR solution and HES, but was much larger than 20 mm Hg with HHES, a value indicative of risk of tissue dysoxia, organ failure, and death in critically ill patients.5 It must be emphasized that the lactate concentration was not different between the groups, suggesting that either the dysoxic threshold for gut O2 delivery was not yet reached or that lactate would take longer to show a tissue energy crisis. Indeed, because CO2 is highly diffusible and because CO2 tissue accumulation is strictly related to hypoperfusion,6 the PCO2 gap provides a sensitive and quite easily collected marker of hypoperfusion.

Today, determination of the gastric tonometered PCO2 gap remains the unique clinical monitoring tool for assessing the efficacy of fluid loading or the effect of catecholamine infusion on tissue perfusion. The mixed or central venous-to-arterial carbon dioxide difference [P(v-a)CO2] can, to some extent, be proposed as an elegant surrogate for tissue perfusion assessment.79 In the experimental model described by Barros et al., it appears that P(v-a)CO2 offered a good estimate of residual tissue hypoperfusion when dogs were resuscitated with HHES. P(v-a)CO2 values remained much larger than 6 mm Hg, a threshold found to be associated with poorer outcome and organ dysfunction.810

A last notable result from this experimental work pertains to the use of a “balanced” crystalloid in 1 of the 3 groups. Indeed LR solution, which provides bicarbonates through lactate metabolism, might explain the better acid-base balance observed in that group. One may regret that the strong ion gap calculation was not included in that study, because it is an important aspect of recent developments in fluid resuscitation. It is also interesting that lactate concentration in these animals was not increased through the treatment effect. One may also regret that the HES used was not diluted in a “balanced” crystalloid as well, favoring an even better effect on arterial pH or bicarbonates and gastric PCO2.

To conclude, in contrast to conventional plasma expanders and contrary to what was anticipated by the authors, the smaller volemic expansion from HHES solution in hemorrhagic shock caused lesser systemic oxygen delivery and tissue perfusion. These results clearly emphasize the importance of using physiologically driven studies to explore significant differences in volume replacement strategies and of establishing quality surrogate markers to test improved tissue perfusion before implementing large randomized clinical trials assessing fluid therapy. These trials should be able to link global outcome with perfusion markers and acid-base balance assessment.

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Name: Benoit Vallet, MD, PhD.

Conflicts of Interest: Professor Vallet received consulting fees from Fresenius Medical, Baxter, and B. Braun.

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1. Kupper S, Mees ST, Gassmann P, Brodde MF, Kehrel B, Haier J. Hydroxyethyl starch normalizes platelet and leukocyte adhesion within pulmonary microcirculation during LPS-induced endotoxemia. Shock 2007;28:300–8
2. Hoffmann JN, Vollmar B, Laschke MW, Inthorn D, Schildberg FW, Menger MD. Hydroxyethyl starch (130 kD), but not crystalloid volume support, improves microcirculation during normotensive endotoxemia. Anesthesiology 2002;97:460–70
3. Dieterich HJ, Weissmuller T, Rosenberger P, Eltzschig HK. Effect of hydroxyethyl starch on vascular leak syndrome and neutrophil accumulation during hypoxia. Crit Care Med 2006;34:1775–82
4. Barros JMP, do Nascimento P, Marinello JLP, Braz LG, Carvalho LR, Vane LA, Castiglia YMM, Braz JRC. The effects of 6% hydroxyethyl starch–hypertonic saline in resuscitation of dogs with hemorrhagic shock. Anesth Analg 2011;112:395–404
5. Levy B, Gawalkiewicz P, Vallet B, Briancon S, Nace L, Bollaert PE. Gastric capnometry with air-automated tonometry predicts outcome in critically ill patients. Crit Care Med 2003;31:474–80
6. Vallet B, Teboul JL, Cain S, Curtis S. Venoarterial CO2 difference during regional ischemic or hypoxic hypoxia. J Appl Physiol 2000;89:1317–21
7. Mekontso-Dessap A, Castelain V, Anguel N, Bahloul M, Schauvliege F, Richard C, Teboul JL. Combination of venoarterial PCO2 difference with arteriovenous O2 content difference to detect anaerobic metabolism in patients. Intensive Care Med 2002;28:272–7
8. Vallée F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, Samii K, Fourcade O, Genestal M. Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive Care Med 2008;34:2218–25
9. Futier E, Robin E, Jabaudon M, Guerin R, Petit A, Bazin JE, Constantin JM, Vallet B. Central venous O2 saturation and venous-to-arterial CO2 difference as complementary tools for goal-directed therapy during high-risk surgery. Crit Care 2010;14:R193
10. Bakker J, Vincent JL, Gris P, Leon M, Coffernils M, Kahn RJ. Veno-arterial carbon dioxide gradient in human septic shock. Chest 1992;101:509–15
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