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Brain Tissue Oxygenation


Introduction

Primary brain injury results from traumatic or disease-related impact. Two major problems are associated with these injuries. First, damage after primary brain injury cannot be undone even with the best possible management. Second, secondary brain injury is inherent due to a variety of cellular processes. Hence, avoiding secondary brain injury due to hypoxia and/or ischemia is the mainstay and declared goal of neurocritical care.

Historically, monitoring of the brain's overall condition after injury began with intracranial pressure (ICP) and cerebral perfusion pressure (CPP) monitoring and was based on the Monro-Kellie doctrine, described more than two centuries ago. Further investigations originated from the assumption that ICP and CPP monitoring alone are not enough to avoid secondary brain injury, as these parameters do not sufficiently reflect cerebral blood flow (CBF) and oxygenation in the injured and the intact parts of the brain. Even when measuring a normal ICP and CPP, one cannot assume that there is uninterrupted oxygen and glucose delivery to the region of primary insult and particularly to at-risk regions in close proximity. In 1993, monitoring of partial pressure of brain tissue oxygen (PbtO 2 ) was introduced to further improve outcome in brain-injured patients by prevention of hypoxic events. Brain cortex PO 2 was measured after craniotomy, and low tissue PO 2 levels were found to be associated with ischemia. PbtO 2 measurements are used to quantify brain tissue oxygen delivery. PbtO 2 represents PO 2 in a small catchment area of tissue below the probe and is influenced by the O 2 content of the vessels in the investigated area. It is important to note that there is no perceived difference between capillary vessels and tissue PbtO 2 . PbtO 2 reflects oxygen availability for aerobic energy production and represents the balance of O 2 delivery and consumption, both of which are influenced by alterations in the microcirculation. Over time, various methods for assessment of brain tissue oxygenation have been developed and investigated not exclusively under pathological conditions. Table 9.1 gives an overview on the currently available and commonly used measurement methods for brain tissue oxygenation.

Table 9.1
Overview of measurements for monitoring of brain tissue oxygenation
Technique Device/measurement: variable Penetration depth
Reflectance spectrophotometry Hemoglobin oxygen saturation (e.g., jugular venous oxygen saturation: SjvO 2 ) 250 μm
Near-infrared reflectance spectrometry (NIRS) Various commercial devices based on discriminative NIRS methodology : cerebral blood volume, [Hb]/[O 2 Hb], cytochrome aa 3 Depends on NIRS methodology
Clark electrode Oxygen electrode: PO 2 Implantable electrodes: 15–20 μm
Surface devices: 20 μm
Luminescence: fluorescence Optode: PO 2 , PCO 2 , pH Unknown
HB , hemoglobin; NIRS , near-infrared spectroscopy; O 2 Hb , oxyhemoglobin; SjvO 2 , jugular venous oxygen saturation.

Basic Principles

Methods of brain tissue oxygenation measurement differ in spatial resolution ( Table 9.1 ). In this chapter, the methods will be discussed beginning with focal or regional monitoring followed by monitoring of global brain tissue oxygenation. They can be summarized as follows:

  • Clinically used methods:

    • Reflectance spectrophotometry (e.g., in jugular venous oxygen saturation (SjvO 2 ))

    • Near-infrared reflectance spectroscopy (NIRS)

    • Oxygen electrode (e.g., in PbtO 2 )

    • Optode (e.g., in PbtO 2 )

    • Other methods:

      • –

        Positron emission tomography (PET)

      • –

        Magnetic resonance spectroscopy (MRS)

      • –

        Magnetic resonance imaging (MRI)

Worth noting, the variables discussed in the literature and everyday practice are not always easily assigned to a particular method. Table 9.2 reviews the variables that are most frequently used.

Table 9.2
Arranging the variables
Variable attributed to this device General term
Reflectance spectrophotometry

  • Jugular venous oxygen saturation: SjvO 2

  • Mixed venous oxygen saturation: SvO 2

Global cerebro-venous Hb oxygen saturation
NIRS a , : SctO 2 equivalents

  • Modified Beer–Lambert law

  • Multidistance or spatially resolved spectroscopy

    • CerOx

    • Equanox

    • FORE-SIGHT: SctO 2

    • INVOS series: rSO 2

    • NIRO series: TOI (tissue oxygenation index)

    • Oxymon

  • Frequency-resolved (domain) spectroscopy: Oxiplex TS

  • Time-resolved spectroscopy: TRS-20

[Hb]/[O 2 Hb]
Oxygen electrode:

    • Licox ®

Optode:

    • Paratrend 7 ®

    • Neurotrend ®

    • Neurovent-PTO ®

PbtO 2 b
NIRS , near-infrared spectroscopy; O 2 Hb , oxyhemoglobin; SjvO 2 , jugular venous oxygen saturation; TOI , tissue oxygen index.

a Indicated by methodology.

b Brain tissue oxygen partial pressure; synonym: PbO 2 ; PtO 2 refers to tissue oxygenation in general (i.e., not specific for the brain).

All methods explained here are not exclusively valid for brain monitoring ( Table 9.3 ), and some general advantages or disadvantages should be considered when choosing one method over another ( Table 9.4 ). Invasiveness was suggested to be relevant for the development of a local or generalized infection. Current sparse data reveal that infections related to probe implantation rarely develop. Further, there are only very few reported cases of relevant bleeding post insertion of intraparenchymal probes.

Table 9.3
General indications grouped by method
Method Indications
Reflectance spectrophotometry

  • TBI

  • SAH

  • Neurosurgery (AV malformations)

  • Plastic surgery (tissue flaps)

  • Surface Hb oxygenation (vessel disease; fetal scalp)

NIRS

  • Carotid surgery

  • Cardiac surgery

  • Routine monitoring during general anesthesia

  • Brain injury

Oxygen electrode

  • PO 2 measurement of tissue and microcirculation in TBI or SAH

Optode

  • Continuous measurement of oxygenation

  • Local gas tensions in tissues

  • Study of brain tissue oxygenation in various pathological conditions

  • Neurosurgery (regional ischemia in cerebral bypass surgery)

  • TBI and SAH

  • Real-time measurement of organ PO 2 , PCO 2 , and pH

AV , arteriovenous; Hb , hemoglobin; NIRS , near-infrared spectroscopy; SAH , subarachnoid hemorrhage; TBI , traumatic brain injury.

Table 9.4
Overall characteristics of the different methods
Context of use Invasiveness Ease of use Reliability Safety
Reflectance spectrophotometry Clinical ± Yes Medium High
NIRS Clinical − Yes Medium High
Oxygen electrode Clinical + No High Good
Optode Clinical + Yes High Good
NIRS , near-infrared spectroscopy; ± , minimally invasive.

If a device is easy to use or a method easy to establish, there is lower risk for incorrect results. Such devices or methods can be more easily implemented in clinical studies and treatment algorithms. The reliability of various methods to monitor brain tissue oxygenation is reviewed in the Current Evidence section.

Reflectance Spectrophotometry

Spectrophotometry in this context quantifies reflection or transmission properties of tissue depending on the wavelength: light is emitted and then absorbed, reflected, or transmitted by molecules such as O 2 as it passes through tissue. As hemoglobin saturation status alters proportional to the amount of bound oxygen, it changes in color, hence light absorption. Light passes more easily in blood with high O 2 content.

A spectrometer produces, disperses, and measures light, whereas a photometer measures the intensity of light. In reflectance photometry, the reflected light (i.e., illumination) is measured after diffused light provokes a reaction in a medium.

Reflectance spectrophotometry measures the intensity of the reflected light compared to the light intensity of a reference. As O 2 concentration increases, light absorption increases linearly while light transmission decreases exponentially.

Near-Infrared Reflectance Spectroscopy

The basic principle of NIRS is based on the transmission and absorption of near-infrared (NIR) light in the tissues of interest. Light generated at specific wavelengths is then detected after passing through and reflected by tissues (e.g., brain, Fig. 9.1 ). The NIR spectrum of commercial devices for clinical use ranges from 700 to 950 nm and is suitable for cerebral tissue oxygen saturation (SctO 2 ) for two reasons. First, the relative transparency of tissue to light in this wavelength range allows transition of biological tissue permitting measurement of absorption peaks of biological molecules in this region of the NIR spectrum. Second, several biological molecules (chromophores; see explanation subsequently) happen to reveal distinct NIR spectra.

Figure 9.1, Basic components of near-infrared spectroscopy systems to measure [Hb] and [HbO 2 ] by light absorbance of either reflected or transilluminated light. Optical path length and intensity of the light detected by a photon-counter and the brain area monitored are influenced by the placement of the light source and the receiver.

There are several NIRS techniques, and all are attributed to the measurement of optical attenuation (i.e., the total loss of light due to absorption and scattering). The attenuation of light at a specific wavelength is described by the Beer–Lambert law. It states that attenuation is directly proportional to the following three variables:

  • chromophore concentration

  • distance between source and detector traveled by light

  • absorption coefficient of the chromophore (i.e., the tissue)

NIRS measures the concentration of three chromophores: oxyhemoglobin (O 2 Hb), deoxyhemoglobin (HHb), and cytochrome aa 3 . The first two allow measurement of Hb tot , HbO 2 , and cerebral blood volume.

Ideally, the only cause for attenuation between the light emitting source and the detector is light absorption by chromophores. However, biological tissue presents a more complex situation, beyond the scope of this overview. The different commercially available devices include special algorithms to compensate for the effect of the nonchromophore tissue.

In the end, output values from both reflectance spectrophotometry and NIRS can be derived in a similar way. They follow an algorithm based on measured changes of light transmission that are converted into a physiological signal (see the Readings and Interpretation section).

Oxygen Electrode

The oxygen electrode derives from the classic Clark electrode, and it measures the voltage change, which is proportional to the amount of O 2 molecules between the reference electrode (anode) and the measuring electrode (cathode) where they are reduced.

Oxygen electrodes can be implemented to various systems, involving the application of probes to the surface or their introduction into a liquid or gaseous medium of interest.

Optode

Optodes are optical sensors that can be used to measure the oxygen saturation. Changes in phosphorescence quenching (i.e., attenuation of fluorescence) being measured by the optode depend on the amount of O 2 . The dye responsible for the O 2 measurement changes its color depending on the amount of O 2 and is located within the electrode but not in the tissue itself (see the Understanding the Equipment section).

In addition to PO 2 , variations of PCO 2 and hydrogen ion concentrations lead to modification of fluorescence and absorbance of the indicators. Therefore, PO 2 , PCO 2 , and pH can be measured using this method.

Other Methods

Using imaging techniques bears the advantage that the metabolic parameters in a specific area of interest can be investigated and compared to other areas. However, imaging provides only a “snap shot” and cannot be classified as monitoring in the classical sense. Nevertheless, these methods are noninvasive, providing a safe method for the assessment of cerebral O 2 metabolism.

Positron Emission Tomography

PET can be used to calculate regional cerebral blood volume, O 2 metabolism, blood flow, and O 2 extraction fraction and has been found to be a highly reliable tool. However, due to the complexity of this method, it remains a research tool rather than a clinical monitor.

Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging

Magnetic resonance methods can also be used to assess oxygenation of a certain area of interest and have been used to measure tumor oxygenation. Under various oxygen conditions, these methods have been used as a marker of tissue pO 2 , as dissolved molecular oxygen serves as an endogenous contrast agent.

Understanding the Equipment

Reflectance Spectrophotometry

This method allows for a continuous estimation of oxygen saturation of arterial or venous hemoglobin. In the context of brain injury, probes are typically inserted into the jugular bulb to measure cerebro-venous oxygen saturation.

Jugular bulb saturation (SjO 2 ), or the arterio-jugular oxygen content difference (AJDO 2 ), is calculated as the difference between the arterial and jugular oxygen content in paired blood samples. It provides information about the adequacy of global CBF in relation to metabolic demands but is only correct if the cerebral metabolic rate for oxygen (CMRO 2 ) does not change independently of CBF. Therefore, coupling between flow and metabolism must be intact. The placement of catheters in the jugular bulb allows sampling of blood that drains almost exclusively from the intracranial circulation. Despite the fact that blood is usually sampled from only one jugular bulb, it is assumed that the values relate to global CBF rather than hemispherical CBF. However, typically only two-thirds of the sampled blood is drained from the ipsilateral hemisphere. In addition, interindividual variability of venous drainage of the brain is large, explaining why methods relying on blood sampling from just one of the jugular bulbs are prone to the influence of asymmetry of cerebral venous drainage. It is impossible to predict which side in a specific patient will provide more important data, and there is no consensus on which side should be cannulated. Generally, the right internal jugular vein is preferred because it is often the dominant vessel. Alternatively, the side with the larger jugular foramen can be used or the side on which a compression of the jugular vein causes a greater increase in ICP. The catheter tip should lie at the level of the first or second cervical vertebral body ( Fig. 9.2 ), which is above the point at which the jugular vein receives its first extracranial tributary, the facial vein. Extracranial contamination at this level is considered to be about 3%. Correct position of the catheter should be confirmed with a lateral cervical spine X-ray. Blood can be sampled intermittently, or a fiberoptic catheter can be used to continuously determine SjO 2 . If samples are withdrawn too quickly, falsely elevated values may be found because of retrograde aspiration of extracranial blood. A rate of blood withdrawal of less than 2 mL/min should be used. Fiberoptic catheters need to be recalibrated at regular intervals and are susceptible to artifacts as a result of the catheter position inside the vessel. It has been shown that when a fiberoptic catheter is used for continuous SjO 2 monitoring, “time of good quality data” can be as low as 43% of the monitoring time.

Figure 9.2, Jugular bulb oxymetry. A catheter is inserted into the internal jugular vein. The tip of the catheter must lie in the jugular bulb or at or above the level of the body of the second cervical vertebra (C2). Blood can be sampled intermittently or oxygen saturation can be measured continuously using a fiberoptic catheter. The facial vein is the first large extracranial vein draining into the internal jugular vein. Rapid aspiration of blood samples (>2 mL/min) will result in extracranial contamination of samples. Jugular bulb catheters should be flushed continuously with normal saline (∼2 mL/h). Thrombosis of the internal jugular vein is a possible complication that may result in raised ICP.

Near-Infrared Reflectance Spectroscopy

In this noninvasive method, NIRS devices are attached to the region of interest, usually the forehead.

NIRS values may be influenced by factors such as ambient light, skin pigmentation, temperature, or even variable location of the intracranial sinuses. Furthermore, vasopressors have been shown to have an influence. Devices typically display tissue oxygenation index (TOI) or regional tissue O 2 saturation (rSO 2 ). The precise volume and location of the monitored tissue remains unknown.

The display of the INVOS ® monitor ( Fig. 9.3 ), for example, is split into four panels. Two separate trend monitors can be found on the left side, one each for the left and right frontal sample volume. On the right side, the updated rSO 2 value is shown numerically and compared to the baseline value, which is indicated separately below the updated value. A fixed horizontal on the trend monitor (red line) indicates the threshold rSO 2 value below which the patient should not fall. Also below the updated rSO 2 value (red line), the variable (min%) of the area under the curve indicates both the magnitude of low rSO 2 values (%) and time spent below the threshold rSO 2 value (min).

Figure 9.3, Example of INVOS ® monitor display.

Oxygen Electrode

Oxygen electrodes for the measurement in tissue and microcirculation consist of silver-, gold-, or platinum-reducing oxygen due to a negative polarizing voltage. The change in voltage between the reference electrode (anode) and the measuring electrode (cathode) is proportional to the amount of oxygen molecules that are reduced at the cathode. In the Clark electrode, both anode and cathode are placed behind an oxygen-permeable and electrically insulating membrane ( Fig. 9.4 ). Transport of oxygen occurs due to diffusion from the surrounding tissue with a high PO 2 , to the area behind the membrane of the electrode where the oxygen pressure is close to zero. To obtain reliable measurement, the O 2 consumption of the electrode should be small compared to the local O 2 level within the tissue; otherwise the electrodes have the potential to alter their own environment. The sensitivity of the electrode is determined by the diffusion constant of the electrode membrane, while the surface of the electrode defines the amount of oxygen generating the current after combining the hydrogen. Calibration of these oxygen electrodes in a solution of known oxygen tension is needed prior to each measurement.

Figure 9.4, Illustration of a Clark oxygen electrode.

As needle tip oxygen electrodes measure PO 2 at a single point, the heterogenous oxygen distribution in the microcirculation is not represented. Clark-type electrodes for measurement of tissue oxygenation have made use of flexible catheter electrodes that are placed in tissue. Such PO 2 catheters are well-suited for long-term use and have been used for surgical implantation.

Optode

Optodes are used to measure concentrations of substances by photochemical reactions that create changes in the optical properties of indicator compounds. Changes in concentration of H + ions or CO 2 produces altered fluorescence or absorbance in indicators. pH-sensitive, photochemical dyes absorb light of a certain wavelength from a reference light source or alter the intensity of fluorescence proportional to the concentration of H + ions. CO 2 is measured using the altered optical properties of a pH indicator positioned behind an ion-permeable membrane. Oxygen-dependent quenching of fluorescence of indicator substances (e.g., ruthenium) has been used for optical sensing of PO 2 and has been incorporated into catheters. In summary, the optode is an optical sensor bearing a light source that is brought to the region of interest using a catheter ( Figs. 9.5 and 9.6 ).

Figure 9.5, (A) NEUROVENT-PTO optode, Raumedic AG, Helmbrechts, Germany; (B) catheter tip of NEUROVENT-PTO optode, Raumedics AG, Helmbrechts, Germany; (C) diagram of a catheter tip for the optical measurement of PO 2 , PCO 2 , pH, and temperature in either tissue or blood (PARATREND/NEUROTREND, Diametrics Medical, High Wycombe, UK). The membrane of the catheter consists of a permeable hydrophobic polyethylene matrix surrounding optical fibers with micropores of about 0.2 μm. These pores are filled with hydrophilic polyacrylamide gel. In the pH sensor, green light is transmitted along the optical fiber through a pH indicator dye immobilized in the gel and reflected back by a mirror. The intensity of back reflected light is a function of the pH. In the CO 2 sensor, the indicator is dissolved in a sodium bicarbonate solution and sealed behind a gas-permeable (but H + impermeable) polyethylene membrane. The change of light intensity due to this indicator dye is proportional to the PCO 2 . The oxygen cell consists of ruthenium dye bound to selectively gas-permeable silicone rubber. The measurement of PO 2 is based upon the quenching of fluorescence of the ruthenium dye. Temperature is measured by a thermocouple.

Figure 9.6, Schematic illustration of mode of action of NEUROVENT-PTO optode, Raumedic AG, Helmbrechts, Germany. NEUROVENT-PTO uses an optical method to measure PbtO 2 . The premise of measurement in a luminophore (L) enclosed in two separate compartments. These compartments are semipermeable to allow the diffusion of oxygen and thus enable its measurement while avoiding the direct contact between the luminophore and the brain tissue. The luminophore (L) contains ruthenium, which in the excited state emits a particular luminescence under oxygen-free conditions. In conditions with oxygen present, the collision of the luminophore (L) in an excited state and the extinguishing or reducing luminescence (oxygen) initiates a transfer of energy from the luminophore (L) to the oxygen in such a way that it removes luminescence from the former, differentiating the captured luminescence. The relationship between the concentration of oxygen and the intensity of the luminescence according to the Stern-Volmer equation provides the concentration of tissue oxygen. The area of sensitivity to oxygen in the NEUROVENT-PTO catheter is 22 mm 2 . The length of the area which detects PbtO 2 is 5.5 mm.

Attenuation of fluorescence (quenching) occurs in proportion to the O 2 concentration surrounding the sensor. The emitted, fluorescent light is transmitted through an optical fiber to a microprocessor to quantify changes compared to preinsertion calibration data.

Such optical sensors have been included in intravascular catheters for the on-line measurements of PCO 2 and pH. To provide continuous monitoring of oxygenation, an additional miniaturized Clark electrode for PO 2 measurement and a thermocouple for the determination of local temperature is included. Their use as alternatives to conventional ex vivo arterial blood gas has been shown in patients during long-term application.

These thin, multiparameter catheters with either a Clark-type electrode or an optical PO 2 sensor have been used to measure local gas tensions in tissues.

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