Infectious disease/original research
Multicenter Study of Central Venous Oxygen Saturation (ScvO2) as a Predictor of Mortality in Patients With Sepsis

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Study objective

Abnormal (both low and high) central venous saturation (ScvO2) is associated with increased mortality in emergency department (ED) patients with suspected sepsis.

Methods

This was a secondary analysis of 4 prospectively collected registries of ED patients treated with early goal-directed therapy–based sepsis resuscitation protocols from 4 urban tertiary care hospitals. Inclusion criteria were sepsis, hypoperfusion defined by systolic blood pressure less than 90 mm Hg or lactate level greater than or equal to 4 mmol/L, and early goal-directed therapy treatment. ScvO2 levels were stratified into 3 groups: hypoxia (ScvO2 <70%); normoxia (ScvO2 71% to 89%); and hyperoxia (ScvO2 90% to 100%). The primary exposures were initial ScvO2 and maximum ScvO2 achieved, with the primary outcome as inhospital mortality. Multivariate analysis was performed.

Results

There were 619 patients who met criteria and were included. For the maximum ScvO2, compared with the mortality rate in the normoxia group of 96 of 465 (21%; 95% confidence interval [CI] 17% to 25%), both the hypoxia mortality rate, 25 of 62 (40%; 95% CI 29% to 53%) and hyperoxia mortality rate, 31 of 92 (34%; 95% CI 25% to 44%) were significantly higher, which remained significant in a multivariate modeling. When the initial ScvO2 measurement was analyzed in a multivariate model, only hyperoxia was significantly higher.

Conclusion

The maximum ScvO2 value achieved in the ED (both abnormally low and high) was associated with increased mortality. In multivariate analysis for initial ScvO2, the hyperoxia group was associated with increased mortality, but not the hypoxia group. This study suggests that future research aimed at targeting methods to normalize high ScvO2 values by therapies that improve microcirculatory flow or mitochondrial dysfunction may be warranted.

Introduction

Sepsis, defined as the presence of infection with an associated systemic response, exists on a continuum of severity progressing from sepsis (infection with a proinflammatory response) to severe sepsis (sepsis plus acute organ dysfunction) to septic shock (sepsis plus tissue hypoperfusion). Sepsis is the 10th leading cause of death in the United States, with inhospital mortality rates of 30%.1, 2 Unfortunately, until recently, numerous therapies to treat sepsis failed to improve mortality. In 2001, Rivers et al3 demonstrated that early goal-directed therapy, consisting of fluid resuscitation, vasoactive interventions, and transfusions based on hemodynamics and other physiologic parameters, resulted in an absolute mortality reduction of 16%. The early goal-directed therapy protocol balances systemic oxygen delivery with oxygen demand by using targeted endpoints (or goals) as part of a standardized resuscitation protocol. The 3 main resuscitation targets are preload (measured by central venous pressure), perfusion (mean arterial pressure), and tissue hypoxia (central venous oxygen saturation [ScvO2]). To better understand early goal-directed therapy and the importance of improving global tissue hypoxia, one must understand the significance of the ScvO2 measurement.

ScvO2 values are obtained by measuring the oxygen saturation in venous blood returning to the heart. In simple form, it represents the balance between oxygen delivery and oxygen consumption. The story is more complex, however, as mechanisms of oxygen supply (macrocirculatory flow), distribution (microcirculatory flow), and processing (mitochondrial function) must all function at an adequate level to maintain normal physiology. Thus, a low ScvO2 may indicate a decrease in oxygen delivery, an increase in oxygen extraction, or a combination of the two. In the early goal-directed therapy protocol, a low ScvO2 is addressed through oxygen delivery optimization by improving arterial oxygen saturation, cardiac output, or oxygen carrying capacity to increase oxygen delivery. Accordingly, one may broadly categorize deficiencies in oxygen exchange into 3 types of failure: macrocirculatory failure, microcirculatory failure, and mitochondrial failure. Macrocirculatory failure is typically assessed through parameters such as central venous pressure, mean arterial pressure, cardiac index, and ScvO2.3 A deficiency in any of these parameters can result in an inadequacy in the net amount of oxygen delivered to the tissues. The cause of microcirculatory failure is multifactorial and includes physiologic shunting, maldistributed flow, increased microvascular permeability, and microvascular thrombosis. In some instances, there may be adequate macrocirculatory flow but microcirculatory failure prevents the oxygen from reaching tissues.4 Finally, in mitochondrial failure, oxygen is presented to the cell but the mitochondria are dysfunctional and unable to process the oxygen.5, 6 In the latter 2 cases, the ScvO2 may actually be increased, a condition referred to as tissue dysoxia. In these cases, increasing oxygen supply will not ameliorate the problem.

Although ScvO2 measurement is recommended by evidence-based practice guidelines and medical professional organizations, multiple challenges limit its adoption into standard practice. Although guidelines recommend normalizing ScvO2, it is based on the assumed association between ScvO2 and mixed SvO2 and studies compared patients receiving an entire protocol against those who did not.7 The clinical effects of abnormally low and high ScvO2 values in patients who receive the same protocol are not well characterized. The notion of abnormally increased ScvO2 levels representing hypoxia at the cellular level has been reported,5 but there is little evidence in support of its clinical significance. Furthermore, because the early goal-directed therapy–based protocol aims to correct a low ScvO2 level through a titrated resuscitation, it is not clear whether the initial ScvO2 level or the maximum ScvO2 achieved has an association with mortality.

In this article, we sought to test the hypothesis that an abnormal (both low and high) ScvO2 is associated with increased mortality in emergency department (ED) patients with septic shock. As a secondary objective, we sought to determine whether the initial ScvO2 or the maximum ScvO2 achieved was associated with mortality.

Section snippets

Study Design and Setting

This study was a secondary analysis of 4 prospectively collected registries of patients treated with early goal-directed therapy–based sepsis resuscitation protocols from 4 urban tertiary care hospitals. The registries were collected from ED patients, and the methodologies have been previously reported.8, 9, 10, 11, 12 Each of the studies was initially an independent single-institution prospective initiative; however, the patient selection characteristics (see below) were identical and the

Results

There were a total of 619 patients who met criteria and were included in the study. The mean age of patients was 61 years (SD 17 years), 46% were women, and there was a high prevalence of comorbidities such as diabetes mellitus (29%), hypertension (24%), and cancer (20%) (Table 1). The most common sources of infection were pneumonia (36%) and urinary tract infection/pyelonephritis (25%). The mean ScvO2 was initially 73% (SD 13%), and the overall mortality for all patients was 25% (95% CI 21% to

Limitations

Limitations of our study include the possibility of selection bias because our patient population was not consecutive, and we did not record, assess, or compare specific characteristic of enrolled patients versus missed patients. Our data were also subject to ascertainment bias if we missed an abnormal ScvO2 that was not recorded. In addition, institutional variation in patient population may have affected the data. We also did not take into account the effects of therapies such as antibiotics,

Discussion

Although the initial early goal-directed therapy study targeting an ScvO2 level greater than 70% suggested a mortality benefit for normalizing ScvO2 in septic patients,3 few studies have assessed the association of ScvO2 (or mixed SvO2) with mortality in sepsis. One study found that nonsurvivors in sepsis had more episodes of SvO2 desaturation (<65%) than survivors, suggesting a mismatch of oxygen supply and demand.13 Another study found SvO2 to be an independent predictor of mortality, but

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Supervising editor: Gregory J. Moran, MD

Author contributions: All authors participated in the conception of the study, study design, and data collection. JVP and NIS oversaw the final data compilation and statistical analysis. All authors participated in the drafting of the article into its final form. All authors take responsibility for the paper as a whole.

Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. This study was supported in part by National Institutes of Health grants HL091757 and GM076659 (Dr. Shapiro), the National Institutes of Health/National Institute of General Medical Sciences: K23GM83211 (Dr. Trzeciak), National Institutes of Health/National Institute of General Medical Sciences: K23GM076652 (Dr. Jones), and a research endowment from the Beatrice Wind Gift Foundation (Dr. Gaieski). Dr. Trzeciak has received research support from Novo Nordisk, Biosite, and Eli Lilly. Dr. Jones has received research support from Critical Biologics and Hutchinson Technology. Dr. Shapiro receives research grants from Hutchinson Technologies, Eli Lilly, and Inverness Medical and is on the Eli Lilly speaker's bureau.

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Publication date: Available online October 25, 2009.

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