Clinical review: use of venous oxygen saturations as a goal - a yet unfinished puzzle

Shock is defined as global tissue hypoxia secondary to an imbalance between systemic oxygen delivery and oxygen demand. Venous oxygen saturations represent this relationship between oxygen delivery and oxygen demand and can therefore be used as an additional parameter to detect an impaired cardiorespiratory reserve. Before appropriate use of venous oxygen saturations, however, one should be aware of the physiology. Although venous oxygen saturation has been the subject of research for many years, increasing interest arose especially in the past decade for its use as a therapeutic goal in critically ill patients and during the perioperative period. Also, there has been debate on differnces between mixed and central venous oxygen saturation and their interchangeability. Both mixed and central venous oxygen saturation are clinically useful but both variables should be used with insightful knowledge and caution. In general, low values warn the clinician about cardiocirculatory or metabolic impairment and should urge further diagnostics and appropriate action, whereas normal or high values do not rule out persistent tissue hypoxia. The use of venous oxygen saturations seems especially useful in the early phase of disease or injury. Whether venous oxygen saturations should be measured continuously remains unclear. Especially, continuous measurement of central venous oxygen saturation as part of the treatment protocol has been shown a valuable strategy in the emergency department and in cardiac surgery. In clinical practice, venous oxygen saturations should always be used in combination with vital signs and other relevant endpoints.


Introduction
Shock is defi ned as global tissue hypoxia secondary to an imbalance between systemic oxygen delivery (DO 2 ) and systemic oxygen demand (VO 2 ). Unrecognised and untreated global tissue hypoxia increases morbidity and mortality. Accurate detection of global tissue hypoxia is therefore of vital importance. Physical fi ndings, vital signs, measuring central venous pressure and urinary output are important but insuffi cient for accurate detec tion of global tissue hypoxia [1][2][3]. Measurement of mixed venous oxygen saturation (SvO 2 ) from the pulmo nary artery has been advocated as an indirect index of tissue oxygenation [4]. As a result of an extensive debate in the literature [5][6][7], however, use of the pulmonary artery catheter has become somewhat unpopular. In contrast, insertion of a central venous catheter in the superior vena cava via the jugular of the subclavian vein is considered standard care in critically ill patients. Just like SvO 2 , the measurement of central venous oxygen saturation (ScvO 2 ) has been advocated in order to detect global tissue hypoxia.
Venous oxygen saturations have been the subject of research for over 50 years, but especially over the past decade the amount of literature describing changes in ScvO 2 and SvO 2 in critically ill patients, including high-risk surgical patients, increased substantially. Th is led to high expectations with respect to the use of venous oxygen saturation as a therapeutic goal. Th e aim of the present review is to summarise the evidence and to discuss the clinical utility of both SvO 2 and ScvO 2 in the treatment of critically ill patients, including high-risk surgical patients.
We performed a search of the PUBMED database from 1980 to 2010 using combinations of the following terms: SvO 2 , ScvO 2 , venous oxygen saturation, venous saturation, critically ill, shock, septic shock, high risk surgery, surgery, operation. Th e articles published in English were included when published in a peer-reviewed journal. Th e clinical investigations had to concern adults. Additionally, bibliographies of relevant articles were also screened.

Physiology
Understanding the physiology of venous saturations is essential for eff ective application in critically ill patients and during the perioperative period.

Abstract
Shock is defi ned as global tissue hypoxia secondary to an imbalance between systemic oxygen delivery and oxygen demand. Venous oxygen saturations represent this relationship between oxygen delivery and oxygen demand and can therefore be used as an additional parameter to detect an impaired cardiorespiratory reserve. Before appropriate use of venous oxygen saturations, however, one should be aware of the physiology. Although venous oxygen saturation has been the subject of research for many years, increasing interest arose especially in the past decade for its use as a therapeutic goal in critically ill patients and during the perioperative period. Also, there has been debate on diff erences between mixed and central venous oxygen saturation and their interchangeability. Both mixed and central venous oxygen saturation are clinically useful but both variables should be used with insightful knowledge and caution. In general, low values warn the clinician about cardiocirculatory or metabolic impairment and should urge further diagnostics and appropriate action, whereas normal or high values do not rule out persistent tissue hypoxia. The use of venous oxygen saturations seems especially useful in the early phase of disease or injury. Whether venous oxygen saturations should be measured continuously remains unclear. Especially, continuous measurement of central venous oxygen saturation as part of the treatment protocol has been shown a valuable strategy in the emergency department and in cardiac surgery. In clinical practice, venous oxygen saturations should always be used in combination with vital signs and other relevant endpoints. SvO 2 depends on arterial oxygen saturation (SaO 2 ), the balance between VO 2 and cardiac output (CO), and haemoglobin (Hb) levels. According to the Fick principle [8], SvO 2 can be described by the following formula: Increased VO 2 will be compensated by increased CO. If this is not adequate -that is, if oxygen demand is not met -elevated oxygen extraction occurs in the peripheral tissues and consequently SvO 2 will drop. SvO 2 thus refl ects the balance between oxygen delivery and oxygen demand [9]. Th e normal range for SvO 2 is 65 to 75% [4,10]. Low SvO 2 is predictive of bad outcome [4,11], whereas normal or supranormal SvO 2 (or ScvO 2 ) values do not guarantee adequate tissue oxygenation [12,13]. If tissue is not capable of extracting oxygen (for example, in the case of shunting and cell death), venous return may have a high oxygen content despite persistent cellular hypoxia.
A variety of physiological and pathological changes may infl uence venous saturation ( Figure 1) and thus require diff erent therapeutic interventions. Recognition of the aetiology of any derangement is obligatory for the safe use of venous saturation as a therapeutic goal.

Central versus mixed venous oxygen saturation
In general there has been considerable debate on equality or interchangeability of ScvO 2 and SvO 2 [14][15][16] (see Table 1). In critically ill patients, substituting SvO 2 by ScvO 2 results in large varia bility [16][17][18][19][20][21]. Th is could in part be explained by modifi cations of blood fl ow distribution and oxygen extrac tion by brain and splanchnic tissue. In this situa tion, ScvO 2 may provide the false impression of adequate body perfusion. Also, whether a positive ScvO 2 -SvO 2 gradient can be used as a marker of greater oxygen utilisation and a predictor of survival remains a subject of debate [20,22,23].
In contrast, other studies have stated that ScvO 2 could indeed be used as a substitute for SvO 2 [24][25][26]. For example, Reinhart and colleagues performed continuous measurements of venous oxygen saturations in anaes thetised dogs over a wide range of haemodynamic conditions, including hypoxia, haemorrhage and resuscitation, and described close tracking between ScvO 2 and SvO 2 [24]. However, correlation was lowest during hypoxia, one of the areas of greatest clinical interest. Nevertheless, precise determination of absolute values for SvO 2 from ScvO 2 was not possible, as was seen before [21,[27][28][29].
Additionally, the relationship between CO or the cardiac index and venous saturations has been evaluated in criti cally ill patients. So far, the results have been inconclusive for both SvO 2 and ScvO 2 . Larger trials are needed before clinical recommendations can be made regarding their clinical use [19,[30][31][32][33].

Cardiac failure
Venous oxygen saturations have been shown to have diagnostic, prognostic, and therapeutic qualities in critically ill patients with acute myocardial infarction (see   Table 2). SvO 2 was particularly reduced in patients with cardiogenic shock or left ventricular failure. Patients with cardiac failure are unable to increase CO during periods of increased oxygen need. Changes in oxygen demand will therefore only be compensated by changes in oxygen extraction in the same direction and indicated by inverse changes in venous oxygen saturations. Consequently, a drop in venous oxygen saturations will be a marker of  cardiac deterioration. Patients with low venous oxygen satura tions in the early disease stage may be considered in shock [34,35]. Also, patients with sepsis and known decreased left ventricular function seem to benefi t from early goal-directed therapy (EGDT) when treated for sepsis [36] according to the Surviving Sepsis Campaign guidelines [37]. Finally, in the setting of cardiopulmonary resusci tation, a ScvO 2 of 72% is highly predictive for return of spontaneous circulation [38].

Trauma
In the initial assessment of trauma patients, an adequate judgement of possible blood loss is essential. Compared with conventional parameters, venous oxygen saturations are superior in predicting blood loss [39,40]. Moreover, after major trauma with brain injury, ScvO 2 values below 65% in the fi rst 24 hours are associated with higher mortality (28-day mortality 31.3% vs. 13.5%) and prolonged hospitalisation (45 days vs. 33 days) [41].

High-risk surgery
In cardiac surgery patients, SvO 2 has been shown to be superior to the mean arterial pressure and heart rate as a qualitative warning sign of substantial haemodynamic deterioration. However, results on the predictive value of SvO 2 for CO in clinical settings are inconsistent [42][43][44]. Nevertheless, continuous SvO 2 monitoring enables the early diagnosis of occult bleeding or could show poor tolerance of a moderate anaemia due to the inability of the patient with chronic heart dysfunction or preoperative negative inotropic treatment (for example, βblockers) to increase CO in the face of anaemia. Furthermore, temporary decreases of SvO 2 values after cardiac surgery are of prognostic value and may predict the development of arrhythmias [45][46][47]. Also, probably due to an increased oxygen extraction ratio, decreased SvO 2 values during weaning from mechanical ventilation are predictive for extubation failure [48][49][50]. Finally, good predictive values of SvO 2 for mortality have been described [51,52]. Th is suggests benefi cial eff ects of SvO 2 monitoring, at least during and after cardiac surgery. Goal-directed therapy has been shown to improve outcome after major general surgery [53]. Originally, the goals in the protocol group were supranormal haemodynamic and oxygen transport values (cardiac index >4.5 l/minute/m 2 , DO 2 >600 ml/minute/m 2 , VO 2 >170 ml/minute/m 2 ). In this group a signifi cant reduction of complications, hospital stay, duration of mechanical ventilation and mortality was achieved when the pulmonary artery catheter was placed preoperatively [54]. Such a strict predefi ned concept holds certain risks, however, and should not be translated to all patients [55][56][57]. Metaanalyses of haemodynamic optimisation in high-risk patients revealed haemodynamic optimisation to be benefi cial only when interventions were commenced before development of organ failure [58,59]. Several of the studies described showed improved outcome, possibly including long-term survival, when goal-directed therapy was commenced before surgery [54,[60][61][62]. Perhaps owing to methodological short com ings, a multicentre trial that randomised surgical patients to pulmonary artery catheter guided or conventional management failed to show a diff erence in outcome [63,64]. More recently a reduction in postoperative complications and duration of hospital stay was described when goaldirected therapy was used postoperatively [65][66][67]. However, the above mentioned fi ndings do not provide defi nite answers on how to use venous saturations as a therapeutic goal. Only one interventional trial used ScvO 2 as a therapeutic goal in perioperative care [68]. In this study the intervention group received therapy to achieve an estimated oxygen extraction ratio <27% after predefi ned goals for arterial pressure, urine output, and central venous pressure had been achieved. Fewer patients developed organ failure in the ScvO 2 group [68].

Sepsis and septic shock
In a large multicentre study, three diff erent cohorts of a very heterogeneous population of critically ill patients were compared for survival after diff erent strategies for haemodynamic therapy had been applied: control versus supranormal values for the cardiac index (>4.5 l/minute/m 2 ) or normal values for mixed venous saturation. In total, the anticipated goal was only achieved in one-third of the patients. Th ere was no signifi cant reduction in morbidity or mortality in any group [69]. An important reason for this may be the late timing of the intervention (that is, after occurrence of organ failure), implying that all patients suff ered severe damage and received signifi cant treatment before inclusion.
Global tissue hypoxia as a result of systemic infl ammatory response or circulatory failure is an important indicator of shock preceding multiple organ dysfunction syndrome. Th e development of multiple organ dysfunction syndrome predicts the outcome of the septic patient [37]. Treatment strategies aimed at restoring the balance between DO 2 and VO 2 by maximising DO 2 have not been successful [57,69,70].
In line with studies over several decades [1,21,27,35,40,71] and based on recommendations [72], Rivers and colleagues randomised 263 patients with severe sepsis or septic shock to standard therapy or EGDT. Compared with the conventionally treated group, the ScvO 2 guided group received more fl uids, more frequently dobutamine, and more blood transfusion during the fi rst 6 hours. Th is resulted in an absolute reduction in 28-day mortality of 16% [73]. A large number of studies that implemented certain treatment protocols in the emergency departmentincluding antibiotic therapy and tight glucose control, for example [74][75][76][77][78][79] -showed a signifi cant decrease in mortality. EGDT endpoints (central venous pressure 8 to 12 mmHg, mean arterial pressure ≥65 mmHg, and ScvO 2 ≥70%) can well be achieved in an emergency department setting, suggest ing that a multifactor approach is a useful strategy in the treatment of sepsis [74][75][76][77][78][79][80]. Of note, three of these studies described similar populations with a high percen tage of end-stage renal disease in the control group being prone for higher mortality [76,77,79,81]. Although attainment of ScvO 2 >70% has been reported as a prominent factor for survival [82], several studies that used EGDT without this specifi c target were also able to achieve a survival benefi t [83][84][85]. In summary, as shown by Nguyen and colleagues [86], the use of (modifi ed) EGDT implies early recognition of the critically ill patient and enforces continuous reassessment of treatment. Th is observation seems to be the greatest gain in the treatment of patients with severe sepsis or septic shock over the past decade.
Earlier studies that enrolled patients admitted to the ICU were unable to show a decrease in mortality after aggressive haemodynamic optimisation [57,69]. In contrast, more recent studies that used modifi ed EGDT proto cols were able to show a signifi cant decrease in mortality [85,87,88], suggesting that compliance to dedicated sepsis bundles after the emergency department stage can still be useful.
Low incidences of low ScvO 2 values at ICU admission [89] or emergency department presentation [90] do occur together with baseline mortality, however, com pared with the original EGDT study [73,89,90]. For clinical appreciation of the above-mentioned results, a thorough look into the data is needed. Interestingly, fewer patients were intu bated before the fi rst ScvO 2 sampling in the EGDT study [73], and this could partially explain the diff erence of initial ScvO 2 values between both studies [73,89]: due to higher DO 2 (pre-oxygenation) and lower VO 2 (sedation, paralysis; lower work of breathing), ScvO 2 may very well improve in response to emergency intubation in the majority of patients [91]. Th is hypothesis partially explains the diff erences between populations [73,89,90] and provides another piece in the puzzle on the value of ScvO 2 [92]. Nevertheless, applicability of the results of the EGDT trial may be dependent on the geographical setting and the underlying healthcare system [92,93].
Additionally, no diff erence in outcome was found between a resuscitation protocol based on lactate clearance and a ScvO 2 -based protocol [94], and ScvO 2 optimisation does not always exclude a decrease in lactate levels [95]. Also, the pursuit of ScvO 2 >70% does not always seem to be the optimal solution. Recent data suggest that patients with initially high ScvO 2 values may also have adverse outcomes [12,13], probably due to impaired oxygen utilisation. High ScvO 2 values may thus represent an inability of the cells to extract oxygen or microcirculatory shunting in sepsis [96].
Finally, as a refl ection of an increased respiratory muscle oxygen extraction ratio, a reduced ScvO 2 or SvO 2 predicts extubation failure in diffi cult-to-wean patients [48,97]. However, a successful intervention to increase ScvO 2 in this context is not yet known. Nevertheless, it is conceivable that in the future ScvO 2 will be used as a parameter in weaning protocols for a subset of patients [97,98].

Continuous measurement
Should continuous measurement be considered when venous saturations are used as a therapeutic goal? It may be argued that changes in venous saturations may occur rapidly, particularly in haemodynamically instable patients, and that discontinuous spot measurements by drawing intermittent blood samples may miss these changes. Accordingly, continuous measurement of SvO 2 in septic shock patients revealed a higher frequency of short-term changes in SvO 2 in nonsurvivors. Variations in SvO 2 could thus be of prognostic importance [99]. However, the lack of therapeutic guidelines and cost-eff ectiveness issues question the clinical use of continuous measurement of SvO 2 in critically ill patients [5,7,58]. Continuous measurement in perioperative care allows detection of fl uctuations. Low SvO 2 values have been associated with increased complications and morbidity, especially in cardiac surgery [100]. Th e use of SvO 2 values >70% as a target seems promising in cardiac surgery and during cardiopulmonary resuscitation [38,43].
Th ere are currently two commercially available devices to measure ScvO 2 continuously. Continuous ScvO 2 measurement as part of treatment protocol has shown to be a valuable strategy in the emergency department [71,73] and in cardiac surgery [101]. Additionally, Reinhart and colleagues concluded that continuous ScvO 2 measurement in the ICU setting is potentially reliable [26]. However, continuous and intermittent measurements of SvO 2 or ScvO 2 have never been compared systematically.

Conclusions
Th e ongoing debate on diff erences between SvO 2 and ScvO 2 and their interchangeability should focus on welldefi ned populations. SvO 2 and ScvO 2 are clinically useful but both variables should be used with knowledge and caution. Evaluating the available evidence in a clinical setting, we conclude that low venous oxygen saturations are an important warning sign for the inadequacy of DO 2 to meet oxygen demands. Low values may warn the clinician about cardiocirculatory or metabolic impairment and should urge for further diagnostics and appropriate action, whereas normal or high values do not rule out persistent tissue hypoxia. Based on the numerous clues for its usefulness discussed in this article, the use of venous oxygen saturations seems especially useful in the early phase of disease or injury. In clinical practice, venous oxygen saturations should always be used in combination with vital signs and other relevant endpoints.