Radionuclide Probes for Tissue Damage" C-T. CHEN,b J. N. AARSVOLD; T. A. BLOCK:

K. L. MATTHEWS! R. A. MINTZER? J. MUKHERJEE? N. J. YASILL0,b L. P. RIVER: M. COOPER!

AND R. C. LEEC bFranklin McLean Memorial Research Institute

Department of Radiology CDepartment of Surgery University of Chicago

Chicago, Illinois 60637

INTRODUCTION

Nuclear medicine is a biomedical discipline that, in itself, is multidisciplinary: it integrates knowledge and technologies in physics, chemistry, engineering, computer science, biology, and medicine synergistically for the purpose of applying radioactive materials to the diagnosis and treatment of human disorders and for the study of fundamental physiologic and biochemical processes in health and disease. Its beginnings can be traced back to three major discoveries that took place nearly a century ago: that of X rays by the German physicist, Wilhelm Conrad Roentgen; that of radioactivity by the French physicist, Henri Becquerel; and that of the isolation of radioactive materials-polonium and radium-by the Polish/French physicist, Ma- rie Sklodowska-Curie, and her French physicist husband, Pierre Curie. It was soon suggested by many, including the American inventor, Alexander Graham Bell, that the penetrating gamma rays of radioactive materials could be used for the killing of cancer cells. Two decades or so later, the Hungarian chemist, Georg Hevesy, first suggested the use of radionuclides as physiologic tracers for the study of biological systems. Since then, a continuous stream of major breakthroughs in science and technology has become an integral part of the evolution of nuclear medicine.

In nuclear medicine imaging,' planar scintigraphy and emission computed tomog- raphy (ECT) are the two most important approaches for acquiring data regarding in vivo radioactivity distributions. In the former approach, two-dimensional (2-D) projection views are collected in the form of emitted photons from the three- dimensional (3-D) radionuclide distribution inside the body. In ECT, many such projection views at different angles are used in conjunction with mathematics and algorithms similar to those employed in X-ray computed tomography (CT) for reconstruction of a 3-D volume of radioactivity distribution.

Two general categories of radionuclides are commonly used in nuclear medicine imaging: single-photon emitters and positron emitters. A single-photon radionu- clide, in its nuclear decay scheme, emits gamma rays at one or more energy levels.

aThis work was supported in part by the United States Department of Energy through Grant Nos. DE-FG02-86ER60418 and DE-FG02-86ER60438 and by the Electrical Power Research Institute.

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Gamma cameras, with the use of scintillation crystals, detect those gamma rays that come out of the body and that impinge upon the detector face to form an image. A positron emitter decays with the release of a positively charged electron, called “positron,” which, in turn, is annihilated with a neighboring electron to produce a pair of photons, both with an energy of 511 keV and traveling along a straight line in opposite directions. By coincidence detection of the two annihilation photons with the use of a pair of opposing detectors, one can determine the line segment along which the annihilation event occurs, thus generating an image of the radioactivity distribution. In combination with the concept of tomography, these two types of radionuclides form the basis for single-photon ECT (SPECT) and positron emission tomography (PET), respectively.

Nuclear medicine imaging is the ideal choice as a technique for assessing cell viability in tissue injury because, in nuclear medicine procedures, a radionuclide- labeled tracer is introduced into the human body to reveal information regarding physiologic or biochemical processes in viva In principle, a selected radiotracer can localize the affected area and assess the extent of tissue injury, thus providing a powerful tool for diagnosis of tissue viability, for planning of surgery or other treatments, and for monitoring the progress of tissue repair after treatment. We will review the role of a number of radiopharmaceuticals in the assessment of tissue damage and their characteristics and we will discuss issues that need to be investi- gated further concerning ways in which these radiotracers can be employed more effectively. We will focus primarily on assessing tissue damage as a result of electrical injury and on evaluating the viability of muscle tissues.

MUSCLE INJURY IN ELECTRICAL TRAUMA

Muscle injury tends to be the dominant clinical feature observed in a typical electrical trauma victim.*“ Electrical injuries often take the form of a limited cutaneous burn and some extcnsive, deep muscle damage. In the first few days after electrical injury, multiple surgical procedures usually take place for removal of nonviable tissue. These surgical operations may include amputations for the removal of an extremity if the entire distal segment is considered necrotic, serial explorations, and debridements of nonviable tissue. These procedures are often repeated many times until all nonviable tissues are considered, upon the physician’s inspection, to have been removed. Residual nonviable tissue that is left in the injured area after surgery may lead to later complications that require additional treatments. There- fore, accurate discrimination of nonviable tissues from intact tissues before and during surgical procedures is essential to the successful management of electrical trauma patients. Nuclear medicine imaging can be used as a useful aid to physicians, beyond mere visual inspection, for making decisions about tissue viability.

For a long time, heating due to electrical current flow was commonly believed to be the only primary cause of tissue damage in electrical i n j ~ r y . ~ s ~ - ~ However, many clinical cases have shown that external signs of thermal injury are often minimal even when underlying muscle deep in the tissue is damaged extensively, indicating that other mechanisms may also play an important role in electrical injury. More recently, it has been postulated that electroporation may be a major factor contributing to

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tissue damage in electrical trauma patient^.^^^.^ It was also suggested that large cells, such as skeletal muscle and nerve cells, aligned in parallel with the electrical field, can experience transmembrane potentials that are sufficiently large to lead to rupture of cell membrane^.^,^,^ When muscle cell membranes break down after an electrical shock, large quantities of myoglobin are released from the intracellular space and the level of intracellular free calcium is increa~ed .~ These underlying mechanisms provide the basis for the design of suitable radionuclide probes for assessing tissue viability.

SINGLE-PHOTON IMAGING

Tc-99m-labeled Phosphate Compounds

In the early and mid-l970s, a series of developments took place in the search for new radiotracers as bone-seeking agents. At that time, Tc-99m emerged as the most important radionuclide for single-photon imaging because of its ideal physical characteristics and easy availability by use of a generator. Therefore, Tc-99m was employed to label a variety of phosphate compounds for bone imaging. Tc-99m- labeled stannous polyphosphate, pyrophosphate (PYP), and diphosphonate (DP) were examples of the phosphorus agents developed at that time.10-12 To date, Tc-99m-PYP is perhaps the most widely used radiotracer for bone imaging.

Although Tc-99m-PYP was originally designed primarily for skeletal imaging, it was soon recognized that it could also show abnormal accumulation at extra-osseous sites.13J4 The pathologic causes of an increased concentration at extraskeletal sites included breast carcinoma, lung carcinoma, liver metastases, soft tissue calcifica- tions, surgical incision, tissue damage caused by radiation, etc. It was also suggested that one of the possible mechanisms of localization of Tc-99m-PYP in these extraskeletal lesions was related to precipitation of calcium and phosphate in tumors.I3J4 In addition, it was demonstrated that Tc-99m-PYP accumulates in injured heart muscle cells after myocardial infarcti~n.l~- '~ It was postulated that PYP becomes associated with hydroxyapatite crystals that are formed in the mitochondria because free calcium accumulates in the damaged heart muscle cells.1s-20 Similar observations were made when Tc-99m-DP was used for assessing muscle tissue damage.21-24 Therefore, Tc-99m-PYP and Tc-99m-DP can be regarded as radiotrac- ers for calcium and their entry into muscle cells is associated with a rise in the ionized calcium concentration after injury.20,22

In the late 1970s, Hunt et al. employed Tc-99m-PYP in scintigraphy as a diagnostic tool to detect and localize both large and focal areas of skeletal muscle necrosis in acute electrical b ~ r n s . ~ , ~ ~ Muscle damage was identified on Tc-99m-PYP scans by increased cellular uptake of the radioactive agent. Gross and histologic evidence of muscle necrosis correlated well with the location and extent of the injured areas identified in the scans. It was also found that muscle appearing grossly to be normal might exhibit abnormalities on the Tc-99m-PYP scan. Histologic evaluation of muscle biopsies from these areas indicated that 20% to 60% of these affected regions contained nonviable tissue, as revealed by microscopic evidence. The Tc-99m-PYP scan proved to be a noninvasive technique that is reliable and sensitive for the early identification of damaged muscle and that is useful for

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identifying the approximate level of debridement and amputation. This radiotracer, used with a whole-body scanning procedure, was also found very useful for diagnosis of the location and extent of muscle damage after low-voltage electrical injury.26 In addition, Tc-99m-DP has been shown to be capable of playing a similar role in the management of electrical shock victims.27 To date, these two radiopharmaceuticals are perhaps the most commonly used radiotracers for early diagnosis and treatment planning of muscle damage in electrical injury.

Tc-99m-labeled Isonitrile Compounds

In the last decade, the development of Tc-99m-labeled isonitrile compounds as imaging agents for the assessment of myocardial perfusion and viability has received considerable a t t e n t i ~ n . * ~ - ~ ~ Among these isonitrile agents, Tc-99m-hexakis(2- methoxyisobutyl isonitrile) (Tc-99m-SESTAMIBI or T C - ~ ~ ~ - M I B I ) , ~ ~ . ~ ~ a lipophilic cationic Tc-99m complex, is noticeably the most promising radiotracer because it offers the best myocardial-to-background ratio for imaging.30 In general, myocardial uptake of Tc-99m-MIBI is proportional to myocardial blood flow, indicating that it has the characteristics of a perfusion agent?x-32

In a series of investigations on animal models, Piwnica-Worms et al. studied the fundamental biophysical mechanisms of the uptake and retention of Tc-99m-MIBI in heart cells and fibroblast^.^^-^' They found that both cellular uptake and retention of Tc-99m-MIBI have a strong dependency on mitochondria1 and plasma membrane potentials, indicating that this agent can be used as a probe for targeting the status of transmembrane potentials. Therefore, Tc-99m-MIBI also has the properties of a tracer for assessing tissue viability. It has been suggested that Tc-99m-MIBI can be employed as an agent for probing both perfusion and tissue viability of other tissues, including skeletal muscle, liver, kidney, and various tumors.37

Tc-99m-MIB1, originally developed for myocardial perfusion studies, has also been demonstrated to be valuable for assessing skeletal muscle perfusi0n.3~0 As in the case of myocardial application, this radiotracer enters skeletal muscle tissue by passive diffusion, binds to intracellular proteins, and stays inside the cell for a prolonged period of time.39 A relatively low uptake of Tc-99m-MIBI is an indication of the lack of perfusion or of a decrease in the blood supply. The use of Tc-99m-MIBI in electrical injury for the prediction of muscle viability has also been r ep~r t ed .~ ' In this case, a loss of perfusion on the affected extremity was postulated to be an indication of deep-tissue necrosis resulting from electrical burn.

POSITRON IMAGING

In recent years, positron imaging has become increasingly more important as a diagnostic tool that offers quantitative information on human physiology and biochem- i s t ~ . ~ ~ Many radiopharmaceuticals have been developed for assessment of in vivo metabolism, blood flow, receptor binding, etc. For example, F-18-labeled 2-deoxy-2- fluoro-D-glucose (FDG) has been used as a glucose analogue for the study of glucose me tab~ l i s rn .~~ In an assessment of glucose uptake in skeletal muscle of the rabbit

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hind limb, FDG was used in conjunction with a pair of collimated, coincidence photon detectors for following the time-activity curve after injection, thereby obtain- ing an estimate of the glucose phosphorylation rate.44 An increase in glucose metabolism was also observed when tolerable electrical stimulations were applied to the hind limb muscle to increase its contractile activity. Another example is the use of Rb-82 as a flow agent for assessment of skeletal muscle blood Again, it was demonstrated in rabbits that increased muscle contractile activity induced by electri- cal stimulations resulted in an elevated uptake of Rb-82. These two agents have the potential to be used as positron imaging probes for assessment of tissue damage in electrical trauma.

TISSUE DAMAGE DUE TO OTHER PHYSICOCHEMICAL INJURIES

In addition to probing of tissue damage in electrical trauma, Tc-99m-PYP and Tc-99m-DP have been found to be useful in the detection and evaluation of other physicochemical injuries. For example, the Tc-99m-PYP concentration in muscle was found to be elevated after extreme exercise and the pattern of increased uptake correlated well with regions of maximum pain.46 Tc-99m-labeled phosphate com- pounds have also been demonstrated to be very valuable for the assessment of sports injuries,4’ physical and various forms of r h a b d o m y o l y s i ~ ~ ~ ~ ~ ~ and osteomyeli- tis.51,s2 Studies of skeletal muscle necrosis in the extremities due to ischemia, infarction, or various injuries have shown that accurate localization and evaluation can be achieved with T c - ~ ~ ~ - P Y P . ~ ~ . ~ ~ In addition, Tc-99m-labeled phosphate compounds have been employed for assessment of damage to bone and muscle tissue as the result of radiation in j~ry- ’~ . - ’~ or frostbite i n j ~ r y . ~ ~ - ~ ~

OTHER RADIONUCLIDE PROBES USED IN ELECTRICAL TRAUMA

Xe-133, a single-photon emitter, was used in a washout study of muscle blood flow in detection of muscle ischemia after electrical injury.6n It was found, both in animal models and in patients, that muscle blood flow was reduced significantly in damaged areas. In-1 11, another single-photon radioisotope, was used for labeling of monoclonal antimyosin for assessing skeletal muscle In-1 1 I-labeled anti- myosin accumulates in the damaged muscle and delineates the extent of skeletal muscle injury. Unlike Tc-99m-PYP, this radiotracer does not accumulate in the adjacent bone, thus reducing the problem of obscuring structures. The usefulness of these two agents in assessing tissue damage in electrical trauma needs to be explored further.

Although muscle damage is the most prominent feature in electrical injury, other organs and tissues, including bone, the cardiopulmonary system, kidney, and brain, can also be affected.s For example, in assessing damage to bone, Tc-99m-labeled phosphate compounds are the natural choice.63 Both Tc-99m-PYP and Tc-99m- MIBI can be employed for localization and evaluation of cardiac i n j ~ r y . ~ ~ , ~ ~ ~ ~ ~ In studies of the effect of electrical trauma on brain function, PET with the use of FDG can be employed for assessment of changes in cerebral glucose metabolism. For

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evaluation of pulmonary and renal dysfunction after electrical shocks, established protocols for Tc-99m-labeled perfusion agents are readily available.

DISCUSSION

Although several radionuclide probes, notably Tc-99m-labeled PYP, DP, and MIBI, have been employed for assessing tissue damage in electrical trauma and have proven to be effective. the optimal utility of these agents in the management of electrical shock victims is yet to be fully explored before their applications can become widespread. Their current success is somewhat limited, in part due to the fact that the underlying biophysical mechanisms of the uptake and clearance of these radiotracers in vivo are not completely clear. In the last decade or so, some important findings in regard to phosphate c o m p o ~ n d s ~ ~ - ~ ~ ) and MIB13G37 have led to the beginning of a comprehensive understanding of the characteristics of these radiotrac- ers at the cellular and molecular levels.

Recently, it has been suggested that blood-compatible chemical surfactants be used for sealing, in vivo, electroporated muscle membranes injured by electrical, thermal, or other physicochemical In monitoring of the progress of recovery after this treatment, the radionuclide probes mentioned earlier can be useful tools for providing qualitative and quantitative information as indicators of membrane sealing and cell repair. However, the correlation between radionuclide scans and the degree of progress of cell repair is closely linked to the underlying biophysical mechanisms for the cellular transport of the radioactive agents. Therefore, a comprehensive understanding of these fundamental processes is essential to obtain a firm grasp of the design of treatment protocols with the use of surfactants and the subsequent procedures for monitoring of healing progress using radionuclide probes.

It is therefore of central importance that further detailed studies be carried out for investigation of the cellular and molecular mechanisms of the uptake, retention, and clearance of Tc-99m-labeled PYP, DP, MIBI, and other radionuclide probes that potentially can be applied to the diagnosis and monitoring of treatment of electrical injury. These investigations will have to include, especially for the present application in assessing tissue damage after electrical trauma and monitoring cell repair after treatment, the way in which these radiotracer uptake mechanisms are related to or interact with the biophysical mechanisms, also at the cellular and molecular levels, of electrical injury and of the sealing process provided by surfac- tants. The temporal characteristics of these underlying mechanisms are critically important for the design of experimental and clinical protocols regarding optimal injection time, injection dose, and imaging schedules.

In most cases of electrical injury, it is desirable that the victims be immobilized as much as possible once they have been admitted to the burn unit. However, typical nuclear medicine imaging devices are not easily transportable to the bedside in the burn unit. Therefore, there is a need to design and construct special imaging hardware for use in nuclear medicine imaging of electrical injury victims at the bedside in the burn unit. A miniature gamma camera that has relatively light weight and is easily portable has been developed in our laboratories for such a purpose.72 This portable imaging system is also ideally suited for use in laboratory investigation of experimental animal models.

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FIGURE 1 is an example of images from experimental animal studies, acquired by our prototype miniature gamma camera. The image on the right shows normal uptake of Tc-99m-PYP in the right hind limb of a laboratory rat. The left image demonstrates an increase in radiotracer uptake in the left hind limb of the same animal, which has been electrically injured. Quantitative analysis of Tc-99m-PYP uptake indicates that, in this particular experiment, there is a 6- to 7-fold increase in radiotracer concentration in the damaged tissues.

CONCLUSIONS

Radionuclide imaging techniques have been demonstrated to be very useful in the management of victims of electrical shock because images of the in vivo distribution of selected radiotracers can provide qualitative and quantitative informa- tion regarding the location and extent of tissue damage. Thus, radiotracer imaging is becoming a powerful tool for rendering an accurate diagnosis and for planning of an optimal treatment strategy. In addition, nuclear medicine imaging procedures can be employed in monitoring of the progress of tissue healing after surgery and of cell repair after treatment by the use of surfactants or other materials. Furthermore, radiotracer probes, used either as counting devices or as imaging scanners, are essential to the success of conducting laboratory experiments in which animal models are investigated for the understanding of underlying biophysical mechanisms of tissue damage in electrical injury, of uptake and retention characteristics of selected radioactive agents, and of the cell repair process after surfactant treatment. In this discussion, we have reviewed the use of several radiopharmaceuticals that potentially can be valuable in the assessment of tissue damage in electrical injury, most notably Tc-99m-PYP, Tc-99m-DP, and Tc-99m-MIBI. Although recent studies have led to some progress in our understanding of the characteristics of these radiotracers, there is a need for further comprehensive studies of the underlying uptake and retention mechanisms of these agents a t the cellular and molecular levels. The results from such studies will be essential to the optimal utilization of these radionuclide probes for assessment of tissue damage in electrical injury.

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