Continuing Education Activity

Fludeoxyglucose F18 is a radioactive tracer that acts as a glucose analog and is used for diagnostic purposes in conjunction with Positron Emitting Tomography (PET) to localize the tissues with altered glucose metabolism. It does not have therapeutic use. Altered glucose metabolism has implications in malignancies, epilepsy, myocardial ischemia, inflammatory conditions, and Alzheimer disease. This activity describes the indications, mechanism of action in various conditions, administration, precautions in the particular patient population, and relevant information to maximize patient and staff safety while obtaining optimal images and analysis.

Objectives:

• Identify the mechanism of action and administration of fludeoxyglucose (F18).
• Describe the importance of patient preparation before administering fludeoxyglucose (F18).
• Explain FDG use in various conditions for diagnostic or treatment monitoring.
• Discuss interprofessional team strategies for improving care coordination and communication to obtain suboptimal images while maintaining safety.

Indications

Fludeoxyglucose F18 (FDG) is a positron-emitting radiotracer used in conjunction with positron emission tomography (PET) for diagnosis and monitoring of various conditions. Standard imaging modalities such as X-ray, CT, and MRI allows the visualization of healthy and diseased tissue with great details. However, some diseases do not have any structural anatomic abnormalities, or they do not manifest until the late stage. Therefore, functional imaging techniques like PET scan can compliment structural modalities on overcoming some of the deficiencies. PET scan uses radiotracers that are injected into the patient before the scan to visualize the blood flow, metabolic, and biochemical activities in diseased and healthy tissues. FDG is a glucose analog, and it tends to accumulate in the tissue with high glucose demand like tumors and inflammatory cells.

Neurology: It can also help visualize the changes in glucose metabolism in various parts of the brain aiding in the diagnosis of various neurological conditions like Alzheimer's disease, epilepsy, and brain trauma.[1][2][3]

Oncology: In oncology, FDG can help diagnose, stage, and treatment monitoring for cancers such as non-small cell lung cancer, lymphomas, colorectal carcinoma, malignant melanoma, esophageal carcinoma, head and neck cancer, thyroid carcinoma and breast cancer.[4][5]

Cardiology: In cardiovascular diseases, FDG can help visualize atherosclerosis by accumulating in the macrophages and myocardial ischemia.[6]

Inflammatory Conditions: The clinical application of FDG in infectious and inflammatory diseases is in orthopedic infections, rheumatologic conditions, osteomyelitis, ileitis, and vasculitis.[6][7]

Mechanism of Action

Hexokinases catalyze the most essential and initial step of cellular metabolism of glucose. These enzymes have a high affinity for glucose and convert it to glucose-6-phosphate, creating a downhill gradient that results in increased facilitate diffusion of glucose through facilitative glucose transporters (GLUT1-13).[8] The rapid phosphorylation by hexokinases traps the glucose molecule inside the cell because glucose-6-phosphate is impermeable to facilitative diffusion. Healthy cells typically metabolize glucose-6-phosphate into different pathways depending on energy status and regulations. Fludeoxyglucose F18 is an analog of the glucose molecule. However, it does not have a hydroxyl group at the 2-C position. Instead, it contains a radioactive tracer 18-fluorine. Therefore, when it enters the cell using GLUT1 or GLUT3, it is phosphorylated and cannot be metabolized further. It accumulates inside the cell and must get dephosphorylated by glucose-6-phosphatase for it to leave the cell. However, tumor cells typically do not have a sufficient amount of glucose-6-phosphatase. Also, tumor cells express excessive glucose transporters and have a high glycolysis rate leading to increased transport and accumulation of FDG into those cells compared to healthy tissue.[9] PET scans detect this accumulation due to the radioactive decay of fluorine-18.

Positron Emission Tomography (PET), when used with radiolabeled drugs like [F18]FDG, can detect the rate of glucose consumption in the tissues using radioactive emission. The source of emission in FDG is fluorine-18 that has a half-life of about 110 minutes. When it decays, the nucleus of the 18F emits a positron, which collides with an electron within the tissue. Positron and electron collision results in annihilation leading to the conversion of the mass to energy in the form of two photons (E=mc^2). The scintillation crystals in the PET cameras absorb energy from the photons and emit light that gets converted into electrical signals.[10]

Neoplastic disease: Metabolic changes in the neoplastic cells generally occur before the tumor size increases, making FDG/PET an important diagnostic and treatment response monitoring tool in oncology.[11]

Cancer cells require a high amount of NADPH to produce phospholipids, triglycerides, cholesterol esters, and acylated proteins for rapid cell division. The increased demand for NADPH requires activation of aerobic glycolysis (Warburg effect). Aerobic glycolysis is the process of producing lactate in the presence of oxygen and functioning mitochondria. This process is enhanced by increased activity of glucose transporters, increased expression of hexokinases, and decreased expression of glucose-6-phosphatase.[12] As a result, there is an increased FDG uptake by malignant cells, and the PET scan can detect the accumulation of FDG. FDG-PET can also help distinguish the areas of radiation necrosis, edema, and tumor recurrence in patients previously undergone cerebral radiation therapy. FDG uptake is reduced in edematous areas, absent in necrosis, increased in tumors compared to the healthy tissue.[13]

Epilepsy: Brain uses glucose as the primary source of energy. Changes in glucose utilization from the normal metabolic pattern can help diagnose specific pathologic states. FDG can help identify the seizure foci. The seizure foci are hypermetabolic during the ictal state and hypometabolic during the interictal stage. In addition to localizing the seizure foci, FDG-PET can also provide information about the functional status of the rest of the brain.[14][2]

Alzheimer's Disease: FDG-PET can be used to distinguish Alzheimer's Disease from frontotemporal dementia and to help discriminate from non-neurodegenerative conditions like depression in patients with atypical presentations. Patients with Alzheimer's Disease have reduced glucose metabolism in the temporoparietal region of the brain. Drugs for Alzheimer disease are most efficacious when early in the disease course. During the late stage, there is cortical atrophy, and drugs are not as effective due to structural alteration. Therefore, detecting early metabolic changes with FDG-PET may be crucial when creating a treatment plan.[3][1] Also, 30% of Alzheimer disease has normal pressure hydrocephalus (NPH), and FDG-PET can improve recognition of NPH as well as a concomitant degenerative disease.[15]

Myocardial Viability: Free fatty acids are the primary source of energy for healthy myocardium. However, ischemic myocardium tissue shifts its metabolism from fatty acids to anaerobic glucose metabolism. FDG-PET is used in nuclear medicine to identify hibernating myocardium in patients with left ventricular dysfunction and coronary artery disease planning to undergo coronary revascularization. Its use is based on the principle that the reversible injured myocytes can use glucose, but irreversibly injured myocytes cannot use glucose. When FDG accumulates in the areas with reduced perfusion, it indicates that systolic function in that area is reversible if there is a restoration of blood flow. This pattern is quantified as a perfusion-metabolism mismatch because of the reduced blood flow and high glucose metabolism. Conversely, the areas with irreversible loss of systolic function or scarred areas have matched pattern, meaning there is a reduced accumulation of FDG and reduced perfusion in that area. This pattern is associated with a low likelihood of functional recovery after revascularization. Partially reduced myocardial perfusion with FDG uptake is a non-transmural match pattern. It represents a non-transmural scar that is not likely to recover unless it is associated with stress-induced reversibility. However, the decision for revascularization should not be based on FDG-PET alone because the reversibility of systolic function depends on successful coronary revascularization.[6][16]

Atherosclerosis: Atherosclerotic vessels uptake FDG. It is quite noticeable within the intima of large vessels like aorta and other major arteries. Increased metabolic activity by the macrophages in the atherosclerotic plaque is responsible for FDG uptake. Smooth muscles in the walls of arteries also uptake FDG and are visualized with PET.[17]

Infectious and Inflammatory Processes: FDG accumulates in inflammatory cells because of their high rates of glycolysis. FDG-PET is used to detect the sites of infection and inflammation, particularly orthopedic infections related to osteomyelitis and implanted prostheses. For complicated and challenging clinical cases, FDG-PET is the study of choice. FDG-PET is also helpful in detecting other inflammatory processes like sarcoidosis, vasculitis, rheumatologic diseases, and regional ileitis.[18][7]

Administration

The administration of FDG is via IV injection 30 to 60 minutes before imaging.

FDG is a radioactive tracer. The unit of radioactivity is the curie (Ci) (SI unit is becquerel – Bq). The radioactive decay factor is the fraction of the radioactive drug remaining after the end of synthesis (EOS). It is used to calculate the final dose of the medicine required for optimal PET imaging. The decay factor after 110 minutes of EOS is 0.5 because the half-life of fluorine-18 is 110 minutes. A 70 kg patient who is undergoing PET imaging needs between 5 to 10 mCi (185 to 370 MBq). The dose for pediatric patients is 2.6 mCi (96.2 MBq) for PET imaging. The optimal dose for pediatrics patients based on body size and weight is not determined.

Patient Preparation:

Patient preparation plays a vital role in obtaining good quality images. The patient needs to be fasting for 4 to 6 hours before administration. Using medical therapy and laboratory testing, ensure that glucose is well under control for at least two days before the injection. If blood glucose is not well controlled, it will result in suboptimal imaging. For cardiology use, 50 to 75 g of glucose-containing food or liquid 1 to 2 hours before FDG injection can facilitate the localization of myocardial ischemia. Insulin causes the heart to increase GLUT4 receptors and promotes the uptake of glucose. Insulin released by glucose load allows visualization of surrounding, healthy myocardium, resulting in superior quality images and less regional variation in FDG uptake.[16] Patients are required to remain inactive after receiving FDG injection because it tends to accumulate in skeletal muscles upon activity and results in suboptimal imaging. Hyperventilating can cause uptake in the diaphragm. Trapezius and paraspinal muscles can also uptake FDG if the patient is tense from stress.[7]

Special Population:

Diabetes: Diabetes mellitus patients should have normal blood glucose for at least two days before administration. Imaging for malignancies generally requires patients to reschedule imaging if their blood glucose is > 120 at the time of imaging. For tumor imaging, glucose competes with FDG for uptake and can result in false-negative results.[19] However, imaging for inflammation does not require strict control of diabetes or hyperglycemia before imaging because the false-negative rate is not significant in these scenarios.[20]

Pregnancy (suspected or confirmed): Using FDG-PET for diagnosis in a pregnant patient is a clinical decision based on benefits and possible harm.[7] Nongravid uterus absorbs 4.7 mSy after administering 7 mCi of FDG. FDG uptake in the fetus is even higher, and the recommendation is that for non-emergency situations, FDG-PET should be done 10-days after the onset of menses.[21][7]

Breastfeeding: Women who are breastfeeding do not have to stop the feedings because very little FDG is excreted in the milk. However, limiting contact between the mother and the child for 12 hours after receiving FDG injection is recommended to lower the infant risk of external exposure from the mother.[7]

Kidney Failure: Imaging with FDG in patients with renal failure is not contraindicated. These patients have decreased FDG accumulation in the brain, and they have increased FDG in the blood pool. However, the image quality might be suboptimal and prone to misinterpretation.[22]

Adverse Effects

There have been no reported adverse effects necessitating medical intervention. However, some reported cases had hyperglycemia or hypoglycemia, transient hypotension, and transient increase in alkaline phosphatase.[23]

Contraindications

No known contraindications exist, except for hypersensitivity to fludeoxyglucose or its formulation components.

Monitoring

FDG is used to monitor glucose accumulation in the cells with increased metabolism. FDG accumulates in the body in proportion to glucose metabolism. High glycolytic rates in organs like the brain generally have the highest accumulation. The liver, spleen, thyroid, gut, and bone marrow also show for moderate FDG uptake. Active skeletal muscles also accumulate FDG. It is cleared unchanged from the body within 24 hours in the urine.

Enhancing Healthcare Team Outcomes

PET imaging is used for detecting metabolic changes, and a CT scan is useful for detecting anatomical changes. Integrated PET/CT scanners allow the acquisition of both PET and CT in a single visit without having to move the patient and are more accurate for localizing lesions. Images from PET and CT can be viewed side by side or can be fused using the software. Fludeoxyglucose F18 is a radioactive drug and emits radiation. The goal of patient preparation, getting a good history, and using appropriate precautions when administering FDG is to minimize radiation exposure while obtaining optimal imaging.

Patient Preparation [24]:

Patient preparation is crucial when obtaining PET/CT imaging. [Level 1] When scheduling the patient for the morning study, they should be instructed to have a light meal the evening before with no alcohol and not eat anything after midnight. [Level 5] For afternoon schedules, patients can have light breakfast before 8 am without sugar-containing food and take their medications as prescribed. [Level 5] Pre-hydrating reduces artifacts and reduces radiation exposure. The patient should drink one liter of water in the 2 hours before FDG injection to minimize FDG concentration in the bladder. [Level 3] When assessing small pelvic tumors, radioactivity in bladder and ureters can impair interpretation of the lesion. Furosemide can be administered but usually not necessary because of proper pre-hydration.[24] [Level 5] 

After injecting FDG, the patient should remain still and silent to minimize muscle uptake of FDG. [Level 1] Injections in the darkened and quiet room will minimize brain activity and can prevent FDG uptake in the brain due to increased brain activation. [Level 3] Brown fat can accumulate FDG if the patient is not warm. [Level 4] Instruct the patient not to exercise at least 6 hours before injection, and they should not arrive at the hospital on a bicycle.[24] [Level 5] 

For patients with diabetes, schedule their PET study in the late afternoon. [Level 5] They also should follow the same fasting rules as mentioned above and continue to take their medications. [Level 1] The triage nurse can check the blood glucose levels when the patient arrives at the imaging center. That way, the patient would not have to wait if their sugar is too high or too low for imaging. [Level 5] Blood glucose level is obtained before administering FDG using a calibrated glucometer.[25] [Level 4] FDG PET can be performed if glucose is < 120 mg/dL and must be rescheduled if > 120 mg/dL depending on the patient circumstances. For tumor imaging, insulin must not be given to lower blood glucose within 4 hours of administering FDG because it causes FDG uptake in muscles.[24] [Level 1]  For cardiology imaging, oral glucose loading followed by supplemental insulin promotes maximum uptake of FDG by healthy myocardium allowing better image quality.[16][Level 5]

When ordering a PET/CT study for oncology, the following data will assist in coordination and image analysis [Level 5] [24]:

• Indications for ordering PET or PET/CT study
• Patient's height and weight for calculating standardized uptake values (SUV)
  • Weight can change rapidly during the disease course. Measure weight directly before each PET study when obtaining serial studies in the same patient.
• Tumor type and site (if known)
• Previous history of tumors, and relevant comorbidity (especially inflammation)
• Results of other imaging studies like CT and MRI
• Allergies
• Diabetes mellitus and medications
• If monitoring change from therapy, provide the date, and type of last treatment
• Kidney function

Required materials for properly administering FDG [Level 5] [24]:

• A triple-channel system which allows the administration of the tracer and flushing with normal saline. If using electronic bedside pumps, other lines may be needed to obtain the same results.
• Bedside glucose meter. It is needed to check serum glucose in patients who are susceptible to hyperglycemia. However, bedside glucose meters are not precise enough to be used for SUV correction. If rescheduling a hyperglycemic patient is not possible, SUV correction must take place by measuring blood glucose levels using calibrated and validated methods during all sequential PET examinations.[26] [Level 1] 
• Accredited weighing scales

 Clinical information for the scan and its interpretation [Level 5] [24]:

• Relevant clinical data includes history focused on the disease and location of the disease, diagnosis date, verification of diagnosis through biopsy, previous therapies, medications, and previous imaging results.
• Comorbidities that are relevant such as diabetes and concurrent inflammation disease
• Prior therapy, including steroids, surgeries, radiation, chemotherapy, and bone marrow stimulants.
  • The minimum interval between the PET imaging and chemotherapy should be about ten days and as close to the next chemotherapy as possible.
• The date at which the results must be available
• The ability of the patient to stay still for 20 to 45 minutes and ability to put their arms over the head
• History of claustrophobia

 Preparation and Administration [Level 5] [24]:

• Staff working at the facility should have gone through the competency-based training for handling radiopharmaceuticals. These include dose dispensing, calibration, labeling, quality control procedures, radiation safety, record keeping, and aseptic procedures.
• When handling the drug, use waterproof gloves and effective radiation shielding to avoid unnecessary radiation exposure to the clinical personnel, workers, and the patient.
• For manual administration, an indwelling intravenous line is placed after drawing the blood samples for the lab if needed. Using the three-way valve, flush and rinse the administration syringe with normal saline.
• For automated administration, make sure that the administered FDG activity is within 3% of the dose calibrator.
• Ask the patient to lie or sit comfortably and quietly. Ask them to use the void 30 minutes after administration and 5 minutes before imaging.