The index of availability of oxygen for the tissues/organs is DO₂ (oxygen delivery), that is, the product of cardiac output (CO) by the content of oxygen in arterial blood (CaO₂). This value can be obtained knowing the arterial hemoglobin saturation (SaO₂), since CaO₂ = SaO₂ × Hb × 1.34 (i.e., the oxygen-carrying capacity of Hb in mlO₂/g Hb) + O₂ dissolved in plasma. The amount of dissolved gas is negligible when Hb concentration is not very low and air is inhaled.

In a healthy resting adult, DO₂ ranges from 800 to 1,200 ml/min, while global oxygen consumption (VO₂) is 200–300 ml/min. The oxygen extraction ratio (O₂ER), representing the ratio VO₂/DO₂, is thus 20–30 % and a large reserve exists for metabolic demand. When DO₂ is reduced for any reason affecting the oxygen pathway, enclosed acute normovolemic anemia, VO₂ remains mostly stable (unless fever, anxiety, or other causes of increased oxygen consumption are present), resulting an increased O₂ER. Lowering further the DO₂, a certain point is reached (DO_{2 CRIT}), where VO₂ begins to decrease being O₂ER not increasable (value at peak 60–70 %). Then, oxygen is not sufficient anymore for the cell aerobic metabolism, hypoxia develops, and an anaerobic metabolism takes over, with a low production of ATP, unable to meet the tissue demand and lactate is released. Theoretically, DO_{2 CRIT} is one of the real, physiological trigger points. Therefore, we should be able to point at this key index, to guide any goal-directed therapy, including blood transfusion.

Nevertheless, it is to be considered that diverse DO_{2 CRIT} can coexist in an organism, because of reduced DO₂ and/or O₂ER at regional level, where an ischemic injury can develop in some organs, in the absence of global markers of hypoxia.

On the basis of what is described above, optimization of transfusion therapy would require reliable markers of hypoxia in tissues. Currently, because of the lack of validated, practicable markers of tissue hypoxia, we refer to surrogate ones. So, traveling back on the O₂ pathway (Fig. 7.1), the first element easy to derive (in quantitative terms) is hemoglobin concentration in blood. Therefore, it is obvious that, over last decades, a great effort has been put in research in the attempt to validate such an inexpensive and quickly obtainable indicator as a transfusion trigger. Nevertheless, the predictive value of determinate Hb levels as transfusion thresholds is high in patients who are young and without known comorbidities and become lower when other factors are present that can affect the oxygen pathway at any level.

A feasible index that can be integrated with Hb concentration is quantification of arterial hemoglobin saturation, (SaO₂), investigating the first part of the O₂ pathway, from inhaled air to diffusion toward pulmonary capillaries. SaO₂ measurement is effected by means of a pulse oximetry that gives a reliable esteem and is practicable in any ward.

Doing so, we still miss any information about the real amount of oxygen transferred to the tissues. As already mentioned, more refined indicators of tissue hypoxia, defined “physiological trigger points,” have been developed to address more closely questions related with the oxygen utilization by the tissues, in order to guide a goal-directed therapy. On the basis of what is described above, ideal investigation on the critical part of O₂ pathway would require measurement of the key factor O₂ER. This is indirectly obtainable through measurement of mixed venous O₂ saturation (SvO₂), being O₂ER = (SaO₂ − SvO₂)/SaO₂. Targeting O₂ER for goal-directed therapy has shown, when integrated in an algorithm of treatment, its capability to guide clinical decision and to increase the rate of favorable outcomes (Donati et al. 2007). SvO₂ measurement requires pulmonary artery catheterization (PAC), by means of a Swan-Ganz catheter, but because of low feasibility and risks associated with this maneuver, it has been almost abandoned. Through a more practical central venous catheter, it is possible to measure the ScvO₂ (central venous O₂ saturation). ScvO₂ has been advocated to be close to SvO₂, only slightly overestimating, according to some authors (Reinhart et al. 2004), but presenting a more variable relationship (Dueck et al. 2005) and not fully substitutable to SvO_2, according to other authors (Chawla et al. 2004). Therefore, extending its use has required an entirely new step of validation as a marker of global tissue hypoxia and tool for goal-directed therapy. Most, but not all, studies pointing at ScvO₂ as fundamental indicator for monitoring clinical conditions and therapy have shown its effectiveness in diverse critical illness (see van Beest et al. 2011). Moreover, its perioperative use for goal-directed therapy in high-risk surgery has been found to be effective in predicting complications (Pearse et al. 2005a; Boyle et al. 2014) and in improving clinical outcomes (Pearse et al. 2005b; recently reviewed by Arulkumaran et al. 2014). Therefore, ScvO₂ appears to be one of the best candidates to guide the goal-directed therapy in ICUs. Still, its intrinsic main limit is related to the requirement in invasive procedures, and currently it is not usable in most settings, such as in uncomplicated surgery.

Nevertheless, the value of ScvO₂ in monitoring goal-directed therapy in ICUs cannot overshadow other more “traditional” measures, such as blood pressure and heart rate monitoring, diuresis control, pulse oximetry, ECG, EEG, central venous pressure, serum lactate concentration, and other index obtained by hemo-gas analysis. However, it has to be considered that the rise in lactate is delayed in comparison to increased O₂ER (Donati et al. 2007). CO, assessed by thermodilution or by a less invasive ultrasound technique, is a central factor in evaluation of hemodynamics and therapy, since measures to support cardiac inotropy are critical for a favorable outcome.

In several studies performed in critical care settings such as fluid resuscitation and sepsis, focusing on the safety and effectiveness of goal-directed therapy, blood transfusion were administered according to an established protocol, usually Hb-based. It has been observed that monitoring and therapies based on global oxygenation indexes determine an improvement in clinical outcomes; we underline that this approach appears to entail an increase in blood transfusion rates (Rivers et al. 2001; Trzeciak et al. 2006). Thus, when transfusion therapy is guided by reliable indicators of tissue hypoxia, its beneficial effects appear to be maximized. On the other hand, in septic patients (Mazza et al. 2005; Fuller et al. 2012) as well as in unselected ICU population (Saugel et al. 2013), blood transfusion appears not to affect ScvO₂. What seems to emerge from these studies is that blood transfusion affects global indexes of hypoxia only in cases of severe dysfunction, while when RBC are administered on the base of Hb only, they may not exert any improvement and might be not beneficial at all.

Surprisingly enough, global oxygenation indexes have not been widely investigated as drivers for transfusion therapy; only a few published studies focus on transfusion “oxygenation” triggers. Targeting the potential utility of oxygen extraction ratio (O₂ER) as an adjunct to the hemoglobin (Hb) concentration for guiding RBC transfusion, it has been observed that, ultimately, ABT rate can be impressively affected, determining either a relevant reduction (by 40–43 %, according to Sehgal et al. 2001; Orlov et al. 2009) or an increase (de Oliveira et al. 2008) or no difference (Donati et al. 2007). An overlook at all the investigational work so far conducted on global oxygenation indexes as drivers for clinical decision about blood transfusion seems to suggest that the direction is correct, but the tools are limited, especially in the perspective of a wide clinical use. Limited results from controlled trials also suggest that application of more complex algorithms including multiple parameters, in the framework of specific clinical situations, may be more informative and useful for monitoring the balance between oxygen supply and tissue demand (Futier et al. 2010).