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Tissue Oximetry and Clinical Outcomes

Bickler, Philip MD, PhD; Feiner, John MD; Rollins, Mark MD, PhD; Meng, Lingzhong MD

doi: 10.1213/ANE.0000000000001348
Technology, Computing, and Simulation: Narrative Review Article

A number of different technologies have been developed to measure tissue oxygenation, with the goal of identifying tissue hypoxia and guiding therapy to prevent patient harm. In specific cases, tissue oximetry may provide clear indications of decreases in tissue oxygenation such as that occurring during acute brain ischemia. However, the causation between tissue hemoglobin-oxygen desaturation in one organ (eg, brain or muscle) and global outcomes such as mortality, intensive care unit length of stay, and remote organ dysfunction remains more speculative. In this review, we describe the current state of evidence for predicting clinical outcomes from tissue oximetry and identify several issues that need to be addressed to clarify the link between tissue oxygenation and outcomes. We focus primarily on the expanding use of near-infrared spectroscopy to assess a venous-weighted mixture of venous and arterial hemoglobin-oxygen saturation deep in tissues such as brain and muscle. Our analysis finds that more work is needed in several areas: establishing threshold prediction values for tissue desaturation–related injury in specific organs, defining the types of interventions required to correct changes in tissue oxygenation, and defining the effect of interventions on outcomes. Furthermore, well-designed prospective studies that test the hypothesis that monitoring oxygenation status in one organ predicts outcomes related to other organs need to be done. Finally, we call for more work that defines regional variations in tissue oxygenation and improves technology for measuring and even imaging oxygenation status in critical organs. Such studies will contribute to establishing that monitoring and imaging of tissue oxygenation will become routine in the care of high-risk patients because the monitors will provide outputs that direct therapy to improve clinical outcomes.

Published ahead of print June 15, 2016.

From the Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California.

Published ahead of print June 15, 2016.

Accepted for publication March 1, 2016.

Funding: Funded by the University of California San Francisco (UCSF) Hypoxia Research Laboratory from funds derived from the validation and testing of pulse oximeters. No sponsor directly funded the study or participated in study design. None of the authors have financial interests in clinical monitoring companies. Casmed Inc has provided patient sensors for a tissue oximetry study at UCSF.

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

This article was presented as part of the international symposium “Innovations and Advances in Monitoring Perfusion, Oxygenation and Ventilation” (IAMPOV) held at St. Luke’s International University, Tokyo, Japan, October 3, 2015.

Reprints will not be available from the authors.

Address correspondence to Philip Bickler, MD, PhD, Department of Anesthesia and Perioperative Care, University of California San Francisco, 513 Parnassus Ave, Box 0542, San Francisco, CA 94143. Address e-mail to philip.bickler@ucsf.edu.

The oxygenation status of tissues can change deleteriously during hypotension, hypovolemia, hemorrhage, shock, or ischemia caused by embolism; compression; or other factors—situations during which arterial hemoglobin (Hb) oxygen saturation (SaO2) or even mixed venous saturation (SvO2) may remain normal. A number of different technologies have been developed to measure tissue oxygen or a surrogate of tissue oxygen. One example is tissue Hb-oxygen saturation. Recently, a number of observational and randomized controlled trials have tested the hypothesis that measurement of tissue Hb-oxygen saturation with near-infrared spectroscopy (NIRS) is associated with important clinical outcomes.1–4 The hypothesis that NIRS predicts outcomes has been tested in 2 paradigms: (1) in studies that test the hypothesis that desaturation events in the monitored organ predict outcomes specific to that organ (eg, cerebral oximetry used to predict stroke or cognitive changes); and (2) in studies that have tested whether desaturation in a specific tissue predicts remote or global outcomes such as failure of remote organs, length of intensive care unit (ICU) admission, or mortality. The main purpose of this article is to review the current state of knowledge about whether either of these hypotheses is supportable and to identify the gaps in knowledge and technology that would help to resolve the remaining unknowns.

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HOW COMMON IS TISSUE HYPOXIA OR TISSUE HbO2 DESATURATION DURING THE PERIOPERATIVE PERIOD?

Both tissue hypoxia and arterial desaturation events in the perioperative period may be more common than is recognized. The incidence of these events is a critical issue, but we have surprisingly little information concerning the frequency and depth of perioperative tissue desaturation events. Understanding the temporal patterns and amplitude of specific tissue vasculature desaturations events in hospitalized patients is essential for determining whether desaturations are linked to outcomes.

Consider a parallel situation regarding the incidence of arterial desaturation events detected by pulse oximetry. Although pulse oximetry has been used clinically for >30 years, it has not been until recently that we have learned that perioperative arterial desaturation events are common. Desaturations occur rarely in the operating room or postanesthesia care unit when patients are closely monitored, but frequently during the postoperative period when patients are less monitored and exposed to the respiratory-depressant effects of opioid pain medications. The Outcomes Research Group at the Cleveland Clinic recently reported that noncardiac surgery patients monitored with blinded, continuous pulse oximetry experienced a large number of desaturation events during the postoperative period. These events were both frequent and prolonged.5 We now know that interventions to correct pulse oximeter–measured desaturations can avert major undesirable outcomes. For example, in a study by Taenzer et al,6 institution of monitored pulse oximetry on a medical/surgical ward reduced serious adverse outcomes, such as ICU admissions for pulmonary complications. However, other studies of pulse oximetry and clinical outcomes have been unsuccessful in clearly proving clinical benefit.7–9

There is currently a limited amount of knowledge concerning the relative numbers of tissue desaturations associated with tissue hypoxia in the perioperative and postoperative periods. It is clear, and not surprising, that some of the events do occur in the postoperative period,10 and it is not known whether these postoperative events are more important to outcomes than are intraoperative events. With respect to the frequency of intraoperative desaturation events, several studies have shown that desaturation events are common in patients undergoing shoulder surgery in the beach chair or sitting positions.11,12 These observations were driven by the occurrence of severe neurologic complications in shoulder surgery patients. In major spine surgery, tissue desaturation events may be common. In 73 patients at the University of California San Francisco, there were 141 cerebral and 129 peripheral tissue desaturation events (defined as a decrease in saturation of ≥5% within 30 minutes), and only 43 of the total 270 events were simultaneous in both tissues (Lingzhong Meng, unpublished data, November 2015).

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REVIEW OF NON-NIRS TECHNOLOGY THAT MEASURES AND MONITORS LOCAL TISSUE OXYGEN LEVELS

Tissue oxygenation is the result of a complex interaction of blood perfusion, arterial oxygen tension, Hb level and dissociation conditions, and local oxygen consumption. Consequently, each oxygen-monitoring technology involves specific assumptions and limitations. Although the primary focus of this review is NIRS, we will also provide a brief overview of other tissue oxygen measurement technologies, so that the strengths and limitations of NIRS can be understood in a larger context.

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Direct Tissue PO2 Measurement

The polarographic or Clark-type oxygen electrode is still considered the “gold standard” of tissue oxygen measurement. It involves the placement of an electrode into tissue and provides a tissue oxygen partial pressure (PtiO2). It is invasive, has a limited tissue-sampling area, consumes oxygen in the surrounding tissue, is unable to reveal the heterogeneity of oxygen levels in the tissue, and requires temperature correction and periodic recalibration.13,14

Phosphorescence quenching fiber-optic probes involve a chemical sensor located at the tip of a probe that changes is fluorescence properties as a function of oxygen levels.15 Pulsed light is carried fiber optics to the sensor tip. The change in the wavelength and amplitude of the returning light is used to determine the oxygen partial pressure. Although these probes do not consume oxygen, they otherwise have similar limitations as the polarographic type of measurement.

Direct PtiO2 measurement has been used in clinical research applications, including wound healing,16 trauma and resuscitation,17 cancer tumor research and therapy optimization,18 and neurologic injury. The available evidence on the relationship of multimodality measurements to clinical neurologic outcomes has been reviewed.19 Of interest, the relationship of intracranial pressure monitoring to clinical outcomes remains uncertain, as revealed by a recent meta-analysis.20 However, the situation may be more positive for brain oxygenation and outcomes. Among the clinical settings in which PtiO2 monitoring tracks clinical events is treatment of arterial vasospasm in subarachnoid hemorrhage.21 For an excellent recent review of brain PtiO2 measurements and neurocritical care clinical outcomes, see the study reported by De Georgia.22

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Transcutaneous Tissue Monitoring

This noninvasive device uses both a polarographic oxygen electrode and carbon dioxide electrode affixed to the skin with a contact gel to promote gas diffusion. The skin is warmed to 42 to 44°C to promote diffusion of oxygen through the stratum corneum. Limitations of oxygen measurement are similar to the Clark electrode. Transcutaneous oxygen measurement is used clinically in wound healing and peripheral vascular disease requiring amputation16 and has also been used as a measure of resuscitation.23

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Electron Paramagnetic Resonance

This oxygen measurement method requires placement of a paramagnetic material, such as lithium phthalocyanine crystals or India ink, in the tissue of interest. Electron paramagnetic resonance oximetry is based on the paramagnetic characteristics of molecular oxygen, which in its ground state has 2 unpaired electrons and undergoes spin-exchange interaction with the paramagnetic material. The relaxation rate of the material (spin probe) increases proportionately with the surrounding partial pressure of oxygen, shortening both the spin-spin and spin-lattice relaxation times and broadening the electron paramagnetic resonance spectral line width, which becomes a linear function of PO2.24 This technique is limited by the need to implant a sensing material, potential foreign body reaction over time, limited sampling area, and lack of available spectroscopic instrumentation at most medical locations. Although human research protocols are currently being used in wound healing, cancer, and peripheral vascular disease, no large outcome data have been completed.24

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Microdialysis

This methodology tracks the levels of metabolites in various tissues of interest such as muscle or brain using microdialysis. A catheter composed of a fine double-lumen catheter is placed in the tissue of measurement and slowly perfused with an isotonic fluid collected in a chamber for analysis. The slow constant movement of fluid allows molecules of interest to diffuse along a concentration gradient across the semipermeable membrane.25 Compounds commonly measured include levels of lactate and pyruvate, glutamate, and glucose. The ratio of lactate/pyruvate correlates with tissue ischemia and anaerobic metabolism and has been used to aid in management of hemorrhagic shock.26 Cerebral microdialysis has noted an elevated lactate, and lactate-pyruvate ratio is associated with poor neurologic outcomes in subarachnoid hemorrhage and traumatic brain injury.27 Limitations are the indirect measure of tissue oxygen, that is invasive, technically demanding, and may be influenced by other pathologic processes separate from relative oxygen levels.

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Spectroscopy to Measure the Oxidation-Reduction State of Intracellular Cytochromes

The earliest efforts to use NIRS for clinical application involved attempts to assess the light absorption or fluorescence of cytochromes and of compounds such as reduced nicotinamide adenine dinucleotide (NADH) which are a function of PO2 in the cytosol and mitochondrion.28,29

Assessment of the redox state of cytochrome oxidase in complex tissues in vivo is challenging. Cytochrome oxidase contains 2 hemoproteins and 2 copper proteins with a wide absorption spectrum in the infrared region. This overlaps significantly with the near-infrared absorbance of Hb, which is also an order of magnitude greater in amplitude compared with the cytochrome spectrum in most tissue regions of interest. In addition, the absorption coefficient of cytochrome oxidase may not be constant.30 Validation of the signals can be based on measurements in experimental animals involving injection of cyanide to alter the cytochrome state independent of Hb-oxygen saturation.31,32

Even with these approaches, it is not surprising that NIRS of cytochromes is subject to errors because of interference from oxy- and reduced Hb in tissue and other factors.33,34 Promising efforts continue to measure the cytochrome redox state using new advanced multispectral approaches employing broadband light sources, spectrophotometer arrays capable of measuring the intensity of multiple to hundreds of wavelengths of light, and advanced computational algorithms.35,36 Currently, it is unknown whether the cytochrome oxidation state could predict clinical outcomes.

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Magnetic Resonance Imaging Techniques

19F Magnetic Resonance Imaging

This method uses direct tissue injection of microliters of perfluorinated compounds such as hexafluorobenzene at multiple locations. Tissue oxygen concentrations surrounding each droplet can be quantified with high specificity because of the linear relationship between PtiO2 and the spin-lattice relaxation (R1).37 This technique provides quantitative, specific, spatially resolved, temperature-independent PtiO2, with a linear relationship for PtiO2 between 0 and >500 mm Hg. The technique has shown value primarily in animal research studies evaluating oxygen levels in various organs but is limited in clinical studies by the need to administer a perfluorinated substance and periodic access to a magnetic resonance imaging (MRI) scanner capable of multinuclear imaging.38

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Blood Oxygen Level-Dependent–Based MRI and Dynamic Susceptibility Contrast

The paramagnetic nature of deoxygenated Hb provides an endogenous contrast agent for the blood oxygen level–dependent (BOLD) technique. Increased amounts of deoxygenated Hb accelerate the spin-spin relaxation time (T2) and weighted signal relaxation (T2*w). These parameters are used to determine the transverse relaxation rate of water in blood and surrounding tissue (R2). Tissues with increased perfusion have an increased R2 value. These changes in R2 are not a direct measure of tissue oxygen levels and can be influenced by other variables not related to tissue oxygenation. However, the changes in R2 are taken to imply changes in tissue oxygenation.39 Despite these limitations, a correlation between direct tissue oxygen measurement and BOLD imaging noted a significant correlation in a human study of prostate tumors.39

Dynamic susceptibility contrast MRI requires administration of a contrast agent and permits calculation of cerebral blood volume and mean transit time. This information combined with data from BOLD allows calculation of oxygen extraction rations and the potential to identify compromised tissue with mapping of cerebral metabolic oxygen consumption rates.40,41 Although these techniques have demonstrated promising results in patients with ischemic brain injury, they are still in the preclinical setting and need further validation.42,43

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NIRS-BASED OXYHEMOGLOBIN SATURATION MEASUREMENTS IN TISSUE

Overview of Technology

Figure 1

Figure 1

HbO2 tissue oximetry with near-infrared light is a noninvasive, optical technology that integrates blood Hb-oxygen saturation in a region of interest (Figure 1). By the nature of the technique, measurement is limited to the intravascular compartment and combines measures of arterial, venous, and capillary blood and depending on the wavelengths of light and tissue, oxy- and deoxymyoglobin. Unlike pulse oximetry, NIRS does not involve detection of a pulsatile tissue component but relies entirely on the Beer-Lambert law that relates the concentration of a substance to its light absorption. The ability to discriminate various types of chromophores varies with the number of wavelengths; for example, a 2-wavelength NIRS device cannot discriminate between the levels of reduced Hb, oxyhemoglobin, reduced myoglobin, and oxymyoglobin. This can be a significant issue when comparing the readings of an NIRS device on the forehead and thenar muscles, with obvious differences in the amount of myoglobin present in the 2 tissues. For cerebral NIRS devices, the assumption is that myoglobin is a trivial contributor to the signal and that the vascular Hb-oxygen component predominates. Cerebral oximeters are calibrated by the manufacturer assuming a constant 70% or 75% weighting toward venous blood saturation. A 2012 review of the development of this technology is by Ferrari and Quaresima.44 Oxygen consumption with insufficient oxygen delivery will lead to an increase in reduced Hb, and since Hb chromophores dominate the near-infrared absorption spectrum, the estimation of Hb-oxygen saturation is arguably less susceptible to errors and signal-to-noise problems than are NIRS-based assessment of cytochrome redox status. An in vivo calibration can be accomplished with direct measurement of cerebral venous and arterial saturation in blood samples.45 This calibration, incorporated into the calculation algorithm that determines the displayed value of ScO2, should theoretically reduce the interfering effects of different Hb concentrations and variations in tissue light transmission. However, this calibration approach assumes that all individuals have the same constant ratio of cerebral venous and arterial blood within the tissue of where saturation is measured. As discussed in the next section, this assumption is likely incorrect. Clinical interest in the devices is substantial, in part, because of the hope that brain oxygenation state assessed by cerebral oximeters might predict important long-term outcomes and complications.

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How Accurate Is NIRS for Measuring Brain Tissue Oxyhemoglobin Saturation?

Based on a study evaluating the accuracy of 5 cerebral oximeters by Bickler et al,45 currently manufactured cerebral oximeters do not provide an “absolute” measurement of oxyhemoglobin saturation in the tissue region of interest, despite the theory that spatially resolved spectroscopy can determine a scaled tissue Hb concentration and therefore the relative concentrations of oxy- and deoxyhemoglobin. The between-subject variability and dynamic error of readings revealed in the study by Bickler et al also make it difficult to determine the absolute threshold for predicting tissue injury. Furthermore, the measured ratio of venous and arterial blood in brain tissue is about 50:5046 and variable, whereas instrument manufacturers calibrate to fixed venous:arterial volume ratios of 70:30 or 75:25. Changes in cerebral venous and arterial blood volumes during changes in carbon dioxide or oxygen will violate assumptions about constancy of arterial to venous blood volumes.45

Contamination of signals from blood in extracranial tissue within the sampled volume of interest also complicates the clinical utility of this technology,47,48 as depicted in Figure 1. Administration of peripherally acting vasoconstrictors (eg, phenylephrine or norepinephrine) is one example of an influence that can change the contribution of extracranial blood and alter readings.49 In addition, sympathetically mediated vasoconstriction from pain, hypothermia, and hypovolemia significantly alters peripheral tissue oxygenation and may also influence the extracranial component of the reading. Therefore, the measurements are at best relative assessments of tissue oxygenation and are useful as trend monitors, not threshold of injury monitors.

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HOW WIDESPREAD IS THE USE OF TISSUE OXIMETRY?

Given the diversity of technologies available to assess tissue well-being, it is of interest to know something about current clinical practice patterns. For example, in a 2015 survey of all 31 neurocritical care units in the United Kingdom, Wijayatilake et al50 found that intracranial pressure monitoring was used in all the 31 institutions. Cerebral perfusion pressure was used in 30 of the 31 units, and a cerebral perfusion pressure target of 60 to 70 mm Hg was the most widely used target (25 of 31 units). Transcranial Doppler was used in 12 units (39%); brain tissue oxygen was used in 8 (26%); cerebral microdialysis was used in 4 (13%); jugular bulb oximetry in 1 unit; and NIRS was not used in any unit. The authors called for goal-directed therapy targeting readings of these instruments to improve outcomes, as has been the case for goal-driven therapy in sepsis.51 To our knowledge, a similar survey of clinical tissue-monitoring technology has not been done in the United States or other countries.

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ORGAN-SPECIFIC OUTCOMES AND NIRS

The brain is the organ most frequently directly assessed with NIRS. Although monitoring cerebral oxygenation to prevent the adverse consequences of acute cerebral hypoperfusion and hypoxia is supportable with current knowledge, the issue of predicting longer-term outcomes remains less clear. Focusing first on NIRS-based cerebral oximetry, we review a variety of central nervous system–specific outcomes that have been assessed in both cardiac and noncardiac surgery.

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Brain Ischemia Detection in Cardiopulmonary Bypass/Cardiac Surgery

Harilall et al52 examined the effects of interventions used to correct cerebral desaturation events during cardiac surgery on a biochemical marker of brain injury, S100B protein levels in blood. Harilall et al used a prioritized intraoperative management protocol to maintain cerebral oximetry values >75% of the baseline during cardiopulmonary bypass. The mean desaturation time for the control group was 64 and 25 minutes in the intervention group. A significant reduction in S100B levels was found in the intervention group, but it was not established if neurologic outcomes were affected by the interventions to reduce the brain exposure to lower cerebral saturations. Nonneurologic outcomes in cardiac surgery are reviewed below.

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Brain Ischemia Detection in Carotid Endarterectomy

The use of cerebral oximetry in carotid endarterectomy to diagnose cerebral hypoperfusion and determine which patients received selective shunting has been compared with electroencephalograph monitoring and transcranial Doppler. However, it remains unclear whether cerebral oximetry serves as a reliable clinical monitor in carotid endarterectomy.53 Studies have not been sufficiently powered to determine the relationship between cerebral NIRS and stroke, and the use of shunting is left to the surgeon’s discretion. Transcranial Doppler cannot always be measured because of the lack of an intracranial window, and it requires significant expertise. If cerebral saturation can be shown to have similar predictive value as other modalities, the simplicity and ease of measurement would be advantageous. Among the studies relating tissue oximetry to specific end points (if not outcomes such as stroke) are a series of studies using cerebral oximetry during carotid surgery by Pennekamp et al.53–56

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Cognitive Function and Postoperative Cognitive Decline

Postoperative cognitive function is of concern after cardiac surgery and after any surgery in the elderly. Studies have used a variety of cognitive tests and different measures of postoperative cognitive decline (POCD). Among the outcomes predicted by low cerebral oximeter readings include early postoperative neuropsychiatric impairment.

A number of studies have found an association between cerebral desaturation events and POCD in cardiac surgery patients. In an observational study of 101 cardiac surgery patients, Yao et al57 reported that a multivariate analysis revealed that time spent at saturations <40% predicted cognitive deficits. Similarly, de Tournay-Jetté et al58 found that cerebral desaturation correlated with both early and late POCD. Slater et al4 performed a prospective randomized trial in 240 cardiac surgery patients where interventions were initiated for a >20% decrease in cerebral saturation, compared with a control group blinded to the saturation. No difference was found between groups. The authors suggest that poor adherence to protocol may have contributed to the lack of a treatment effect because prolonged cerebral desaturation correlated to early POCD. In addition, 2 observational studies found no relationship between cerebral saturation and POCD in cardiac surgery patients.59,60 In conclusion, it is too early to tell whether cerebral desaturation events actually have significant predictive power for POCD, and a multicenter interventional trial may be needed to resolve the issue.

In elderly patients undergoing major abdominal surgery, Casati et al61 randomly assigned patients to an intervention group receiving treatment for low cerebral saturation or a control group where physicians were blinded to the cerebral saturation. In the study group, an intervention was initiated when cerebral saturation decreased <75% of baseline. The intervention group had significantly higher measures of saturation during surgery. Cognitive function, assessed with a mini mental status score (MMSE), did not differ between groups. However, in patients experiencing intraoperative cerebral desaturation, MMSE was lower at day 7 in the control group. In this study and an additional observation study in a similar patient population, Casati et al62 found that cerebral saturation correlated with MMSE and POCD. These findings are similar to those in a group of arthroplasty patients studied by Lin et al.63

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Adult Resuscitation and Care of the Premature Newborn

Cerebral oximetry has been proposed as a monitor of the adequacy of resuscitation during cardiac arrest.64,65 This interesting concept needs further study.

In neonates, cerebral NIRS monitoring with an intervention to correct cerebral tissue desaturations compared with blinded monitoring reduced the incidence of cerebral desaturation by 58% in a phase II clinical trial.66 Additional studies are needed to determine whether cerebral oximetry improves outcomes.

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Traumatic Brain Injury

The hypothesis that noninvasive assessment of brain tissue oxygenation predicts outcomes is based on studies that have used invasive methods to measure brain oxygenation. For example, in traumatic brain injury, an electrode-measured tissue PO2 of <28 mm Hg is associated with mortality.67

NIRS cerebral oximetry in traumatic brain injury has been explored as a prognostic index or to assess the impact of goal-directed treatment. An example is goal-directed treatment of cerebral perfusion pressure after head injury.68 In a study by Rosenthal et al,69 a correlation between cerebral oximetry measurements and jugular bulb venous measurements indicates that the NIRS technology may be able to provide an estimation of cerebral oxygenation status noninvasively. Whether trends in noninvasive oximetry predict clinical outcomes remains untested.

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PREDICTION OF GLOBAL OUTCOMES WITH NIRS

The possible association of tissue hypoxia or Hb desaturation and modifiable global outcomes is one of the most important factors driving both research and clinical application of NIRS. A number of studies have tested the hypothesis that oxygenation status measured in one tissue predicts dysfunction of remote tissues or determines global outcomes such as mortality. To date, 2 tissues have been associated with remote outcomes: (1) the frontal cortex of brain and (2) peripheral muscle (thenar muscle, leg muscle, and masseter muscle). A range of outcomes has been associated with desaturation events in these 2 tissue beds. Before we discuss the specifics of some of the key studies, it is important to note that muscle and brain are distinct physiologically with respect to blood flow autoregulation. During stresses impairing tissue oxygen delivery, such as hypotension, autoregulation of blood flow in the brain is substantially greater than in the skeletal muscle. Cerebral autoregulation was recently reviewed by Meng et al.70 Because of its relatively small autoregulatory capacity, muscle hypoxia/desaturation might be a “leading indicator” of impaired oxygen delivery. Muscle at rest has a low metabolic rate, and the degree to which this leading indicator’s role is true during different types of impaired oxygen delivery is not certain.

In contrast to muscle, hypoperfusion in the brain (absent a thrombus) is probably reflective of low cardiac output or shock, conditions with a poor prognosis. Because of autoregulation of blood flow in the cerebral cortex, decreased global brain oxygenation is likely reflective of a systemic problem with either low cardiac output or low vascular resistance, as in sepsis. The brain is therefore a “trailing indicator” of tissue hypoperfusion because of autoregulation. The opposite situation occurs in skeletal muscle because it experiences a relatively large reduction in blood flow during shock; muscle is therefore a leading indicator of global hypoperfusion compared with the brain. Figure 2 illustrates the complexity of understanding how desaturations in one tissue can relate to global outcomes and how interventions to correct desaturation in one tissue have global effects.

Figure 2

Figure 2

There are a number of different possibilities for a mechanistic link between stress in one tissue and remote effects on other tissues or the whole organism. The concept of tissue hypoxia as a biomarker for serious systemic illness has been proposed.33 Probably, the most compelling possibility is that tissue hypoxia or ischemia causes the release of proinflammatory cytokines and other inflammatory mediators. These mediators produce inflammatory reactions in remote parts of the body. Chemical mediators (eg, cytokines such as interleukins and tumor necrosis factor) or activated neutrophils released into the circulation from these leading indicator tissues could have global effects, including specific effects on different organs. Increases in circulating cytokines is a well-documented consequence of global hypoxia experienced during high-altitude exposure, after cerebral ischemia, myocardial infarction, sepsis, and a wide range of infectious and inflammatory conditions.71 There is a large body of literature on this topic, and we will not review it here except to direct the reader to a review by Thompson et al72 that describes how hypoxia modulates neutrophil function via the hypoxia-inducible factor signaling system. Activation of lymphocytes or monocytes in peripheral tissues and their subsequent migration into remote organs such as brain is a second possibility. In this later case, it has been proposed that activated monocytes and inflammation mediate cognitive changes after major surgery, via mechanisms involving nicotinic acetylcholine receptor signaling and other factors.73–77 Tissue damaged by surgery or subjected to ischemia or impaired oxygen delivery is the source of these proinflammatory cells.

We will next review what is currently known about the association between tissue oximetry and global outcomes.

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Cerebral Saturation Predicts Cardiopulmonary, Mortality, and Other Complications in Cardiac Surgery Patients

Most of the studies to date concerning the relationship of tissue oxygenation to remote outcomes have involved cardiac surgery patients, probably because this population of patients was among the first to be monitored with cerebral oximeters. In a prospective randomized study of 200 elective coronary artery bypass graft patients, Murkin et al3 compared a blinded control group and a group with interventions responding to a decrease in cerebral saturation. Cerebral desaturation was more prolonged in the control group, and treatment of saturations resulted in a lower incidence of major organ morbidity, mortality, and length of ICU length of stay. In aortic arch surgery, Fischer et al78 found significant associations between cerebral saturation and major complications.

In cardiac surgery, low baseline brain oxygenation in 1200 patients undergoing cardiopulmonary bypass was associated with mortality and other adverse outcomes such as cardiopulmonary dysfunction.79 Similarly, a study from Sun et al80 examined the association between mortality and cerebral saturation values <60% in approximately 2100 cardiac surgery patients. Sun et al found increased mortality in the approximately 600 patients in the study group with low cerebral saturation. Although in both studies, low cerebral oxygen saturation was associated with more significant comorbidities, a multivariate analysis still showed a link between low saturations and mortality.

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Outcomes in Noncardiac Surgery

The earliest group of studies concerning cerebral saturation and outcomes established only an association between tissue oxygenation and outcomes and were limited by the difficulty of establishing if other (possibly unmeasured and possibly not modifiable) factors were actually driving outcomes. In the cardiac surgery studies cited above, low cardiac output may be a nonmodifiable cause of low cerebral saturation.63 More recent studies have begun to explore whether tissue oxygenation is actually causing the outcomes examined and whether interventions to correct the desaturations/tissue hypoxia can avert the undesirable outcomes. In such an interventional study, Casati et al61 followed elderly surgical patients undergoing major abdominal surgery. In these patients, low cerebral saturation (“area under the curve” for saturations <75% of baseline) was associated with longer postanesthesia care unit stays and hospital admissions.61 The effect of interventions used to treat the desaturations observed in the study in 2005 by Casati et al (blood pressure support or propofol to decrease cerebral metabolic rate) had significant effects on outcomes. Hospital length of stay was reduced in the intervention group, with an average of 10 days (7–23 days) in a group in which cerebral saturation was treated with an intervention and 24 days (7–53 days) in the control (no intervention) group. A similar prospective observational study by Casati et al62 in 2007 confirmed that low cerebral saturation (in this case <50%) and a reduced mental status score predicted longer hospital stay in elderly abdominal surgery patients. Larger prospective randomized studies are necessary. Identifying patients at risk may be useful, given the simplicity of cerebral oximetry measurements.

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Muscle Oxygenation and Prediction of Outcomes in Sepsis or Trauma

This is an active area of current research, with >40 publications in the past 10 years reporting associations between muscle tissue NIRS and a range of outcomes, including volume responsiveness and prognosis in trauma, sepsis, and critical illness. These efforts have been based on the goal of identifying markers of tissue oxygen deficits during early management to guide therapy and establish prognosis for conditions that continue to have a high mortality rate.81,82 Before advances in measuring tissue oxygenation with NIRS, it was established that low values of central venous saturation and acid-base disturbances correlated with poor clinical outcomes.83,84 However, the changes in venous saturation and other variables were sometimes delayed and thus not useful for guiding early treatment or establishing early prognosis. Furthermore, overlap in the ranges of venous saturation in controls and sick patients makes these variables insensitive predictors of outcomes for individual patients.

Measuring tissue oxygenation in the thenar muscle of the hand as an indicator tissue for systemic stress is a relatively more recent methodology than measuring brain oxygenation. As is true with cerebral oxygenation, a large overlap of tissue oxygen saturation (StO2) values between healthy subjects and septic shock patients has limited the utility of this variable for clinical care. The combination of tissue oxygenation and a vascular occlusion test (VOT) has been proposed to increase the sensitivity and predictive power, with slower reoxygenation after VOT occurring in trauma patients compared with controls.85 The VOT involves inflating a cuff on the arm and measuring the changes in muscle tissue oxygenation; the rate of change in StO2 during this test is then used as an index compared with various outcomes. The rate of change in saturation in a VOT is greater in patients with septic shock than in healthy volunteers and can be a marker for death and organ system failure.86 The physiologic validity of measuring StO2 at the skeletal muscle of the thenar eminence as a marker for outcomes is partly based on the physiology of this tissue bed, as well as the convenience of being able to do VOTs on the arm. Also, signal contribution from skin and fat is typically small in the thenar area. With muscle oximetry involving NIRS, one has to be aware that myoglobin absorbs light at similar near-infrared wavelengths as Hb and although oxymyoglobin and deoxymyoglobin have overlapping spectra,87 the oxygen affinity (P50) of myoglobin is only approximately 2.4 mm Hg compared with approximately 26 mm Hg for Hb. Davis and Barstow88 estimated that the contribution of myoglobin to the absorbance of light at NIRS wavelengths may be as much as 50% to 70%.

In trauma patients, initial tissue desaturation in peripheral muscle correlates with central venous oxygen, acid-base disturbance, elevated lactic acid, and hemorrhagic shock.89,90 Studies involving thenar muscle NIRS in trauma patients have identified associations between low NIRS values and organ dysfunction.91–94 On the basis of the number of published studies, a meta-analysis on the value of NIRS readings in trauma to predict organ dysfunction could be performed.

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FUTURE DIRECTIONS AND SUGGESTIONS FOR THE DESIGN OF CLINICAL TRIALS

Wider use of tissue oximetry should be driven not by the uncritical attitude that “knowing something about tissue oxygenation is better than knowing nothing”; rather, evidence-based studies are needed to support the use of this moderately expensive but noninvasive technology. We have identified 4 areas where additional knowledge is needed:

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Technical Knowledge Concerning Exactly What NIRS Is Measuring

Evidence that NIRS tracks tissue oxygenation under all relevant conditions of patient and physiologic variables, including skin pigment, prevailing arterial PCO2, and other variables is often missing. Also, more information is needed about the sensitivity and specificity in detecting true alterations in the oxygenation state of a tissue. In the case of cerebral oximeters, this is essentially the accuracy of measurement of the cerebral oximeter compared with a gold standard reference. For cerebral oximeters, the gold standard reference is currently a prespecified mixture of cerebral mixed venous blood and arterial oxygen saturation. This reference standard probably needs to be adjusted to account for changes in the arterial:venous blood volume assumptions during hypoxia and alterations in carbon dioxide. This might be difficult in clinical situations because independent assessments of carbon dioxide and oxygenation would need to be incorporated into the calculation algorithm. Although we have proposed that something along these lines might reduce between-individual variation in cerebral oximeter readings,45 whether this would do so in practice remains to be determined.

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Physiologic Knowledge, Including Definition of Thresholds for Tissue Damage That Are Associated with Adverse Outcomes

This is a critical issue that remains unresolved. Previous studies have mostly used arbitrary cutoffs for analysis. One difficulty is that injury thresholds may vary among individuals because of differences in age, cerebral metabolism, anesthetic and sedative regimen, body temperature, and other factors. However, if the technology accounts for changes in oxygenation because of changes in flow and blood volume in the sensor field, then autoregulation of cerebral blood flow should not be a confounder in establishing threshold values. The other issue is the “area under the curve” problem: Is 3 hours at a 10% reduced cerebral saturation equivalent in injury to 1 hour at 30%? Greater knowledge in this area is critical for study design because interventions need to be assigned to an appropriate threshold and duration for potential tissue injury. Without appropriate thresholds, interventions will be initiated that are either unneeded or too late to alter outcomes. Furthermore, interventions have their own risks; for example, vasopressors may decrease blood flow in unintended ways and transfusions expose patients to a variety of risks.

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A Deeper Understanding of the Physiology of the Determinants of Tissue Oxygen Delivery

Knowing what interventions are most effective in resolving potentially clinically important desaturations is a key issue. The following types of questions are relevant: Is a vasoconstrictive medication (eg, phenylephrine) sufficient to restore cerebral oxygenation, or are increases in cardiac output (norepinephrine) and increases in oxygen delivery (eg, transfusion to increase oxygen-carrying capacity) to tissues more beneficial? Does banked blood (with reduced P50) cause problems? Are crystalloids or colloids equally effective?

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Improved Clinical Study Design

It is very important that clinical trials test whether goal-directed therapy based on tissue oxygenation measurements improves outcomes. For these types of studies, a powerful study design is to randomly assign patients to have continuously recorded but blinded or unblinded oximetry displayed and prespecified goal-directed therapy. An example of goal-directed therapy would be to increase arterial blood pressure if tissue saturation decreased by 10% from a baseline; if the tissue saturation did not respond, then another intervention would be specified. The control group would have standard clinical care, but the tissue oximetry reading would not be displayed to the clinician. Specified outcomes would then be compared in the 2 groups. The knowledge created by this type of study would be an important step in evaluating the clinical value of tissue oximetry. Finally, we need more studies concerning the frequency and depth of desaturation events across the perioperative period. This knowledge is essential because even if effective interventions are used during intraoperative tissue desaturation events, unobserved and untreated postoperative desaturations may be driving outcomes.

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CONCLUSIONS

We believe that tissue oximetry with NIRS has the potential to be a clinical monitor that can predict both tissue-specific and global outcomes and can guide therapy to avert poor outcomes. Because tissue oxygenation is coupled to organ function much more directly than is arterial oxygen saturation, it is not surprising that this could be true. However, establishing a linkage between NIRS oximetry and clinical outcomes has been challenging because it depends on being able to show that averting local tissue hypoxemia improves outcomes. The design of studies to do that must involve a nonintervention group in which the periods of tissue hypoxemia are blinded to the caregiver, and an intervention group in which a protocol is used to treat the event that is observed. Very few studies to date have met that standard. Other areas of improved understanding that are needed to move the field forward include the causes and frequency of decreased tissue oxygen levels in various organs and a better understanding of what interventions (eg, vasoactive medications, fluids, or blood) best treat each organ or regional hypoxemic event.

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DISCLOSURES

Name: Philip Bickler, MD, PhD.

Contribution: This author wrote all sections of the manuscript except for the specific contributions noted below for co-authors and read, edited, revised, and approved the entire manuscript.

Conflicts of Interest: Philip Bickler has received research funding from Masimo Inc, Nonin Medical Inc, Bluepoint Medical, CAS Medical, and numerous other pulse oximeter manufacturers. These sources have funded basic science research and human physiology experiments. No direct funding of this manuscript or research therein was derived from corporate sources.

Name: John Feiner, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript. He wrote the section of the manuscript concerning tissue-specific outcomes with tissue oximetry.

Conflicts of Interest: John Feiner received research funding from Masimo Inc, Nonin Medical Inc, Bluepoint Medical, Xhale, and CAS Medical. Various pulse oximeter manufacturers funded our laboratory to perform human accuracy studies. None of these sources funded anything to do with the conception or writing of this manuscript.

Name: Mark Rollins, MD, PhD.

Contribution: This author wrote the section of the manuscript concerning the technology for assessing tissue oxygenation and read, edited, and approved the entire manuscript.

Conflicts of Interest: The author declares no conflicts of interest.

Name: Lingzhong Meng, MD.

Contribution: This author wrote the section of the paper on the incidence of desaturation events. He was the principal investigator of a study in spine surgery patients. He read, edited, and approved the entire manuscript.

Conflicts of Interest: Lingzhong Meng received research funding from CAS medical for an on-going study on tissue oximetry and patient outcomes.

This manuscript was handled by: Maxime Cannesson, MD, PhD.

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