Tissue Oxygenation Parameters to Guide Fluid Therapy

Benoit Vallet, MD, PhD; Emmanuel Futier, MD; Emmanuel Robin, MD, PhD

Posted: 05/12/2011; Transfusion Alter Transfusion Med.2010;11(3):113-117.©2010Blackwell Publishing

Abstract and Introduction

Abstract

Because tissue hypoxia is a key trigger for organ dysfunction, adequacy of oxygen delivery (DO2) to tissue oxygen metabolic demand is essential during the perioperative period. Optimization of DO2, using either or both fluid loading and inotropic support, to prevent tissue hypoxia in relation to increased oxygen consumption (VO2), could improve outcome. In this context, the use of central venous oxygen saturation (ScvO2), which reflects important changes in the DO2/VO2relationship and of central venous-to-arterial carbon dioxide difference [P(cv-a)CO2], to address adequacy of oxygen utilization, has shown promising results. The threshold value for ScvO2at which the risk of impaired tissue oxygenation can be discarded might remain out of reach and the complementary use of P(cv-a)CO2would provide help to adjust the right DO2to both VO2and CO2production. When applying this dual view, and increasing cardiac output to lower P(cv-a)CO2below 6 mmHg, the adapted ScvO2is closer to 73% or 75%.

Introduction

Adequacy of tissue oxygenation is defined by an adapted oxygen supply [or oxygen delivery (DO2)] to oxygen demand.[1]Oxygen demand varies according to tissue type and time. Although oxygen demand cannot be measured nor calculated, oxygen uptake or consumption (VO2) and DO2can be both quantified since they are linked by a simple relationship: VO2= DO2·ERO2. ERO2represents oxygen extraction ratio. Increase in ERO2occurs via two fundamental adaptive mechanisms:[2](i) Redistribution of blood flow among organs via an increase in sympathetic adrenergic tone and central vascular contraction, responsible for a decreased perfusion in organs with low ERO2(such as the skin and splanchnic area) and a maintained perfusion in organs with high ERO2(heart and brain); (ii) Capillary recruitment within organs responsible for peripheral vasodilation (opposite to central vasoconstriction).

Sedation, anesthesia, inflammation and sepsis interfere with these two adaptive mechanisms and impair increased ERO2capabilities.

During circulatory failure and/or severe hypoxemia, as DO2declines secondary to a decrease in cardiac output and/or a decrease in arterial oxygen content (CaO2), VO2can be maintained by a compensatory increase in ERO2, authorizing VO2and DO2to remain independent. But as DO2falls further, a critical point (DO2crit) is reached, and ERO2can no longer compensate for this fall in DO2. At this critical level, VO2becomes dependent to DO2. Tissue dysoxia occurs which corresponds to a state of cellular energy crisis.

Improving DO2has been demonstrated in the perioperative period to reduce both morbidity and mortality.[3,4]But clearly, improvement of global perfusion to reach a fixed value of DO2is not sufficient by itself to improve outcome in the most severe high-risk patients. Inability of these patients to raise their DO2in response to the increase in their metabolic demand threatens tissue perfusion and leads to focal ischemia–reperfusion injury with subsequent oxidant stress which may lead to development of increased capillary permeability and organ failure. It is therefore much more important to consider the DO2-to-VO2balance than to indicate a certain value of DO2as a goal to direct therapy. With that perspective in mind, tissue perfusion can therefore be assessed by mixed venous oxygen saturation [SvO2or central venous oxygen saturation (ScvO2) for a more simple assessment of SvO2] as a surrogate of the balance between DO2and VO2.

Use of Central Venous Oxygen Saturation to Titrate Fluid Therapy and Oxygen Delivery

SvO2(or ScvO2) explores the relationship between DO2to tissues and oxygen use by tissues (VO2) as attested by the relationship linking the two: SvO2≈ SaO2– [VO2/(hemoglobin·1.39·Cardiac output)]. Therefore determinants of a decrease in SvO2(or ScvO2) are either alone or in combination: hypoxemia (decrease in SaO2), increase in VO2(sepsis, alert and awake distressed patient, work of breathing) without increase in DO2, any fall in cardiac output (decrease in mean arterial pressure or myocardial depression) and any decrease in hemoglobin (Hb) level.

The normal range for SvO2is 68–77% (+5% for ScvO2).[5,6]An increase in VO2without an increase in cardiac output or DO2, or a decrease in DO2with no change in oxygen requirements, will result in an increased ERO2and a fall in SvO2or ScvO2. ERO2and SvO2(or ScvO2) are linked by a simple equation: ERO2≈ 1 − SvO2, assuming SaO2= 1.[7]Tissue dysoxia is obligatory present when SvO2falls below 40–50%; however, this may also occur at higher levels of SvO2, when ERO2is impaired (sepsis, inflammation, sedation). Therefore, other markers of cellular oxygen inadequacy should be sought, such as hyperlactatemia or tissue hypercarbia (see below).

Usually, efforts to correct cardiac output (fluid or inotrope), Hb level, SaO2, VO2or a combination of the parameters must target a return of SvO2(ScvO2) from 50% to at least 65% (70% for ScvO2). A decision tree can be proposed according to ScvO2values and a stroke volume variation (SVV)-guided treatment protocol. SVV is an index of preload-dependency and fluid responsiveness. When larger than 12%, it indicates request for fluid loading if mean arterial pressure is lower than 70 mmHg, ScvO2is lower than 70% and/or lactate concentration is larger than 2 mmol/L (see Figure 1). When ScvO2remains lower than 70% with SVV being lower than 10%, decision must consider the use of an inotrope.

Hemoglobin is the oxygen transporter in blood. As such, it is the main determinant of CaO2and the main determinant of DO2aside from cardiac output. Thus, in goal-directed therapy, the decision to transfuse is based upon the hope of increasing DO2to tissues and subsequent cellular oxygenation. In clinical practice, decisions to transfuse are usually based on consensual thresholds derived from epidemiologic studies showing benefit or lack of benefit of transfusion in certain populations at various Hb values. Even though these arbitrary levels take into account underlying diseases such as ischemic heart disease and acute coronary syndromes, they are not so much applicable in dynamically changing situations such as sepsis, awakening, weaning from the ventilator, etc. In a prospective study in which recommendation-based transfusion in the postoperative period was compared to the resulting variation in ScvO2,[8]we found that: (i) 20 patients over 53 (37.7%) received blood transfusion in spite of recommendations; (ii) 65% of the patients (13/20) out of these recommendations with an ScvO2< 70% seem nevertheless to take benefit from blood transfusion (according to the VO2–DO2relationship): one may speculate that absence of recommendation for blood transfusion in those patients could have contributed to a 'lack of blood transfusion'; (iii) according to ScvO2(which remained largely below 70%) blood transfusion might even have been insufficient (an average of 2 blood units) in this subgroup; (iv) 54.5% of the patients (18/33) fulfilling the recommendations with an ScvO2≥ 70% received blood transfusion although VO2/DO2might have been adequate: one may speculate that transfusion of red cells in those patients could have contributed to an 'excess of blood transfusion'.

Figure 1.Goal-directed therapy with ScvO2-P(cv-a)CO2-SVV guided treatment protocol (SVV is stroke volume variation, an index of preload-dependency and fluid responsiveness when larger than 12%). Hb, hemoglobin; PEEP, positive end-expiratory pressure; RBCs, red blood cells.

Following the Riverset al.[9]study and our own observation[8]we can conclude that ScvO2appears as an interesting parameter to guide fluid therapy and help blood transfusion decision in hemodynamically unstable severe sepsis or in stable postoperative patients equipped with central venous catheter. The use of ScvO2was found to be a useful target during high-risk surgery and several studies have shown that low ScvO2is associated with increased postoperative complications.[10]The exact target value for ScvO2to consider remains a matter of controversy. It is possible that the sampling site can influence this value whether it is the superior vena cava or the right atrium. The target might be anyway much larger than 70%, and 75% would be a more appropriate threshold to consider.[11]By applying a target value of 73% (ERO2of 27%), early correction of altered tissue oxygenation with appropriate fluid loading in conjunction with low doses of inotropes was found to reduce postoperative organ failure in high-risk surgical patients for whom tissue oxygen utilization could have been inadapted.[10,12]

In a recent randomized study of patients treated with an individualized goal-directed fluid protocol, Futieret al.[13]found that optimization of preload alone with repeated fluid loading did not necessarily prevent postoperative morbidity. They also found that crystalloid restriction (6vs.12 mL/kg/hour) was associated with increased postoperative complications and reduced ScvO2values, although mean ScvO2values were 80% and 78% in the two groups studied.[13]The ScvO2threshold value in predicting complications (approximately 71%) was similar to those previously reported.[10,14]These results may therefore limit to some extent the clinical relevance of ScvO2for routine practice. Significant ScvO2fluctuations may occur during both surgery and sepsis, and high ScvO2values do not necessarily reflect well changes in DO2and do not always exclude macro and microcirculatory failure.[14,15]Persistent tissue hypoperfusion may coexist with increased ScvO2and oxygen extraction defects which can be related to microcirculatory and/or mitochondrial failures.[16,17]

Use of Central Venous-to-arterial Carbon Dioxide Difference to Address Adequacy of Oxygen Utilization

However, it may be possible to further explore tissue perfusion in order to detect abnormalities undetected by ScvO2. One approach is the bedside investigation of regional microcirculations, a field in itself.[17]Interference of sepsis-modified vasoactive drug properties by sepsis-induced microcirculatory disturbances has predominantly been investigated at the level of the splanchnic circulation, sublingual circulation and skin using techniques such as regional capnometry, laser Doppler flowmetry, indocyanine green dilution or orthogonal polarization spectroscopy.[17]Besides the pivotal measurement of lactate concentration,[18,19]determination of gastric tonometered-to-arterial carbon dioxide pressure (PCO2) remains the unique clinical monitoring tool that can aid in the assessment of the efficacy of fluid loading or catecholamine infusion on tissue perfusion in critically ill or high-risk surgery patients.[20,21]

The venous-to-arterial carbon dioxide difference [P(v-a)CO2] can be proposed as a surrogate for tissue perfusion assessment, as we suggested in several experimental approaches.[22,23]We also recently tested[16]the hypothesis that the central venous-to-arterial CO2difference [P(cv-a)CO2] may serve as a global index of tissue perfusion in a prospective observational study. Fifty consecutive septic shock patients with a ScvO2> 70% were included immediately after their admission into the intensive care unit following early resuscitation in the emergency room. We demonstrated that the presence of a P(cv-a) CO2> 6 mmHg was associated with the largest lactate value and might have been a useful tool to identify patients who remained inadequately resuscitated despite a 70% ScvO2goal being reached (with mean values close to 78%). These results are in agreement with those of Bakkeret al.[24]who showed that, in patients with septic shock, the PCO2gap was smaller in survivors than in non survivors, despite quite similar cardiac index (CI), DO2and VO2values. In septic shock patients, characterized by an increased PCO2gap and a low flow state, fluid challenge was found to lower the PCO2gap while increasing cardiac output.[25]In contrast, no significant changes in cardiac output and PCO2gap were found in patients with normal PCO2, thus confirming the relationship between an increased PCO2gap and insufficient flow.[25]

We tested the prognostic value of the P(cv-a)CO2in 70 adult patients, ASA I–III, undergoing major abdominal surgery in a secondary analysis of a published study[13]in which patients were managed according to the goal-directed therapy to maintain respiratory variation in peak aortic flow velocity below 13%.[26]In all, CI, DO2, ScvO2, P(cv-a)CO2and postoperative complications were recorded blindly. A total of 34% of patients developed postoperative complications. At baseline, there were no differences in demographic and hemodynamic variables, ScvO2(82 ± 10vs.81 ± 9%;P= 0.75) and P(cv-a)CO2(7 ± 4vs.6 ± 2 mmHg;P= 0.20). In complicated patients (n= 24), both meanScvO2(78 ± 4vs.81 ± 4%,P= 0.017) and minScvO2(67 ± 6vs.72 ± 6%;P= 0.0017) were lower than in uncomplicated patients (n= 46), despite similar volumes of fluids perfused and comparable CI and DO2values obtained. The optimal ScvO2cutoff value was 71%, and ScvO2< 70% was independently associated with the occurrence of postoperative complications (OR, 4.2; 95% CI, 1.1–14.4;P= 0.025). In patients with complications, P(cv-a)CO2was larger than in patients without complications (7.8 ± 2vs.5.6 ± 2 mmHg;P< 10−6). In patients with complications and ScvO2≥ 71%, P(cv-a)CO2was also significantly higher (7.7 ± 2vs.5.5 ± 2 mmHg;P< 10−6) than in patients without complications. The area under the receiver operating characteristic curve was 0.785 (95% CI, 0.74–0.83) for discrimination of patients with ScvO2≥ 71% who did and did not develop complications, with 5 mmHg as the best threshold value. We concluded that ScvO2reflects important changes in oxygen delivery in relation to oxygen needs during the perioperative period. P(cv-a)CO2appears a useful tool to identify persistent hypoperfusion when goal-directed therapy is associated with a ScvO2≥ 71% (see Figure 1).

Conclusion

Improving DO2has been demonstrated in the perioperative period to reduce both morbidity and mortality, but it is certainly promoting an adapted DO2to oxygen requirements which is to be encouraged. From that point of view, the use of ScvO2is an interesting integrative approach on the VO2-to-DO2balance. The threshold value for ScvO2at which the risk of impaired tissue oxygenation can be discarded might remain out of reach and the complementary use of P(cv-a)CO2would provide help to adjust the right DO2to both VO2and CO2production. When applying this dual view, and increasing cardiac output to lower P(cv-a)CO2below 6 mmHg, the adapted ScvO2is closer to 73% or 75%.

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