We hypothesize that in the presence of reduced oxygen delivery and extraction, blood flow will be redistributed in order
to protect the most vital organs (e.g., brain and heart) by increasing their regional blood flow, while O<sub>2</sub> delivery to the
less vital organs (e.g., GI tract or urethral wall) will diminish. Evaluation of mitochondrial function in vivo could be
done by monitoring the oxidation reduction state of the respiratory chain. Thus, the NADH redox state of less vital
organs could serve as an indicator of overall O<sub>2</sub> imbalance as well as an endpoint of resuscitation. We have therefore
tested, in a pig model, a new medical device providing real time data on NADH redox state and tissue blood flow- TBF
This device contains a modified three way Foley catheter with a fiber optic probe which connects the measurement unit
to the tested tissue. Female pigs underwent graded hemorrhage (GH) or Aortic clamping (AC). The main effects of GH
started when blood volume decreased by 30%. At 40% blood loss, minimal levels of TBF were correlated to the maximal
NADH levels. The values of the 2 parameters returned to baseline after retransfusion of the shed blood. Aortic clamping
led to significant decrease in TBF while NADH levels increased. After aortic declamping the parameters recovered to
normal values. Due to the short length of the urethra in female pigs and the instable contact between the probe and the
tissue, inconsistency of the responses was observed.
Our preliminary results show that the CritiView may be a useful tool for the detection of body O<sub>2</sub> imbalance.
In normal cell the mitochondria are the major source of energy for cellular functions. They serve as biosensors for
oxidative stress and involved also in termination of cell function by apoptosis. The involvement of mitochondria in
pathological states such as neurodegenerative diseases, sepsis, stroke and cancer are well documented. The involvement
of mitochondrial respiration and function in cancer development, proliferation and possible therapy were initiated 75
years ago by Otto Warburg.
Monitoring of NADH fluorescence in vivo as an intracellular oxygen indicator was established in the 1950-1970 by
Britton Chance and collaborators. In the last 20 years we developed and used a multiparametric monitoring system
enabling real time assessment of mitochondria NADH, microcirculatory blood flow and volume as well as HbO<sub>2</sub>
oxygenation. In order to use this technology in clinical practice the commercial developed device-the "CritiView" was
tested in animal models as well as in patients hospitalized in the critical care departments.
In patients we tested the viability of the urethral wall (a
less-vital tissue) by a 3 way Foley urinary catheter that contains
the optical probe. The catheter was introduced to patients underwent open heart by-pass surgery or abdominal aorta
aneurysm (AAA) operations. The monitoring started immediately after the insertion of the catheter to the patient and was
stopped when the patient was discharged from the operation room. The results show that monitoring of the vitality of the
Urethral wall provides information in correlation to the surgical procedure performed. In the AAA patients the occlusion
of the aorta led to severe ischemia developed in the urethral wall and recovery of signals were recorded after the
reopening of the aorta. In patients under went heart bypass surgery the urethra vitality was decreased dramatically during
the operation and recovery was noted in most patients after the discharge of the patient from the operation room.
Tissue viability represents the balance between O<sub>2</sub> supply and demand. In our previous paper (Mayevsky et al;
Proc.SPIE 6083 : z1-z10, 2006) the HbO<sub>2</sub> was added to the multiparametric tissue spectroscope (Mayevsky et al
J.Biomedical Optics 9:1028-1045,2004). This parameter provides relative values of microcirculatory blood oxygenation
(MC-HbO<sub>2</sub>) evaluated by the 2 wavelength reflectometry principle. The advantage of this approach as compared to pulse
oximetry is that the measurement is not dependent of the existence of the pulse of the heart. Also in the MC-HbO<sub>2</sub> the
information is collected from small vessels providing O<sub>2</sub> to the mitochondria as compared to the pulse oximeter
indicating blood oxygenation by the respiratory and cardiovascular systems.
In the present study we compared the level of blood oxygenation measured by the pulse oximeter to that measured by the
CritiView in the brain exposed to various systemic and localized perturbations of O<sub>2</sub> supply or demand. We exposed
gerbils to anoxia, hypoxia, ischemia and terminal anoxia. In addition we measured mitochondrial NADH (surface
fluorometry), tissue reflectance, tissue blood flow (laser Doppler flowmetry) from the same site of MC-HbO<sub>2</sub>
A clear connection was found between the two blood oxygenation parameters only when systemic perturbations were
used (anoxia, hypoxia and terminal anoxia). Under local events (ischemia) the MC-HbO<sub>2</sub> was responsive while the
systemic oxygenation was unchanged. We concluded that MC-HbO<sub>2</sub> has a significant value in interpretation of tissue
energy metabolism under pathophysiological conditions.
The most important parameter that reflects the balance between oxygen supply and demand in tissues is the
mitochondrial NADH redox state that could be monitored In vivo. Nevertheless single parameter monitoring is limited
in the interpretation capacity of the very complicated pathophysiological events, therefore three more parameters were
added to the NADH and the multiparametric monitoring system was used in experimental and clinical studies.
In our previous paper<sup>1</sup> we described the CritiView (CRV1) including a fiber optic probe that monitor four physiological
parameters in real time. In the new model (CRV3) several factors such as UV safety, size and price of the device were
The CRV3 enable to monitor the various parameters in three different locations in the tissue thus increasing the
reliability of the data due to the better statistics. The connection between the device and the monitored tissue could be
done by various types of probes. The main probe that was tested also in clinical studies was a special 3 points probe that
includes 9 optical fibers (3 in each point) that was embedded in a three way Foley catheter. This catheter enabled the
monitoring of urethral wall vitality as an indicator of the development of body metabolic emergency state.
The three point probe was tested in the brain exposed to the lack of oxygen (Anoxia, Hypoxia or Ischemia). A decrease
in blood oxygenation and a large increase in mitochondrial NADH fluorescence were recorded. The microcirculatory
blood flow increased during anoxia and hypoxia and decreased significantly under ischemia.
Real time Monitoring of mitochondrial function in vivo is a significant factor in the understanding of tissue vitality. Nevertheless a single parameter monitoring device is not appropriate and effective in clinical diagnosis of tissue vitality. Therefore we have developed a multi-parametric monitoring system that monitors, in addition to mitochondrial NADH redox state, tissue microcirculatory blood flow, tissue total back-scattered light as an indication of blood volume and blood oxygenation (Hb0<sub>2</sub>). In the present communication a new device named "CritiView" is described. This device was developed in order to enable real time monitoring of the four parameters from various organs in the body. The main medical application of the CritiView is in critical care medicine of patients hospitalized in the Intensive Care Units (ICUs) and intraoperatively in operating rooms. The physiological basis for our clinical monitoring approach is based on the well known response to the development of body emergency situation, such as shock or trauma. Under such conditions a process of blood flow redistribution will give preference to vital organs (Brain, Heart) neglecting less vital organs (Skin, G-I tract or the urinary system). Under such condition the brain will by hyperperfused and O<sub>2</sub> supply will increase to provide the need of the activated mitochondria. The non-vital organs will be hypoperfused and mitochondial function will be inhibited leading to energy failure. This differentiation between the two types of organs could be used for the early detection of body deterioration by monitoring of the non-vital organ vitality. A fiber optic sensor was embedded in a Foley catheter, enabling the monitoring of Urethral wall vitality, to serve as an early warning signal of body deterioration.
Optical monitoring of various tissue physiological and biochemical parameters in real-time represents a significant new approach and a tool for better clinical diagnosis. The Tissue Spectroscope (TiSpec), developed and applied in experimental and clinical situations, is the first medical device that enables the real-time monitoring of three parameters representing the vitality of the tissue. Tissue vitality, which is correlated to the oxygen balance in the tissue, is defined as the ratio between O2 supply and O2 demand. The TiSpec enables the monitoring of microcirculatory blood flow (O2 supply), mitochondrial NADH redox state (O2 balance), and tissue reflectance, which correlates to blood volume. We describe in detail the theoretical basis for the monitoring of the three parameters and the technological aspects of the TiSpec. The comparison between the TiSpec and the existing single parameter monitoring instruments shows a statistically significant correlation as evaluated in vitro as well as in various in vivo animal models. The results presented originated in a pilot study performed in vivo in experimental animals. Further research is needed to apply this technology clinically. The clinical applications of the TiSpec include two situations where the knowledge of tissue vitality can improve clinical practice. The major application is the monitoring of "nonvital" organs of the body [i.e., the skin, gastrointestinal (G-I) tract, urethra] in emergency situations, such as in the operating rooms and intensive care units. Also, the monitoring of specific (vital) organs, such as the brain or the heart, during surgical procedure is of practical importance.
In medical practice the monitoring of organ and tissue vitality is a critical need in operating rooms as well as in intensive care units (ICUs). The concept of multiparametric monitoring of tissue vitality was described in details in our previous publication. The device, called "Tissue Spectroscope" (TiSpec), contained a single light source (325nm) used as an excitation light. The emitted-reflected light from the tissue was analyzed to provide real-time information on the following three parameters: microcirculatory tissue blood flow, mitochondrial NADH redox state and tissue reflectance. Those 3 parameters represent the main components of tissue O2 balance under in vivo conditions. The 325nm He:Cd laser used was a large bulky and expensive to operate as a critical component in a modern medical device unit. The development of an ultraviolet laser diode by Nichia, Japan, enabled us to replace the light source of the TiSpec with a 390nm laser diode, stabilized by a system developed by Toptica Photonics AG. This change in light source permitted the construction of a second model of the TiSpec, having the following advantages: 1. Smaller in dimensions, 2. Safer in terms of UV radiation effects, 3. Better stabilized for long term monitoring. The new TiSpec was tested in various animal studies as well as in various clinical applications. In order to monitor the brain during neurosurgical procedures, two special fiber optic probes were developed and used. Preliminary studies have shown that the 390nm based TiSpec could be used in monitoring of various organs.
Evaluation of tissue O<SUB>2</SUB> balance (Supply/Demand) could be done by monitoring in real-time 2 out of the 3 components of the tissue O<SUB>2</SUB> balance equation. In our previous publication (Mayevsky et al, SPIE Vol. 4255:33-39, 2001) we had shown the use of the multiparametric monitoring approach in the neurosurgical operating room, using a device combined of laser Doppler flowmeter (LDF) and surface fluorometer reflectometer. The two instruments having two different light sources, were connected to the tissue via a combined bundle of optical fibers. In order to improve the correlation between tissue blood flow and mitochondrial NADH redox state, the new Tissue Spectroscope (TiSpec) that was designed has a single light source and a single bundle of optical fibers. Preliminary results show very clear correlation between TBF and NADH redox state. In addition, the reflected light at the excitation wavelength could be used as an indication for blood volume changes. The results obtained by the TiSpec enabled us to compare tissue O<SUB>2</SUB> delivery (TBF) with O<SUB>2</SUB> balance (NADH redox state) in the brain of gerbils and rats exposed to ischemia, anoxia and spreading depression. Real-time monitoring of the metabolic state of the tissue has immense potential during surgical procedures.