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RadiopharmaceuticalsFor Nuclear Cardiology
Studies
Mark Soffing, PharmD, MBA, MS, RPh, [email protected]
ObjectivesUnderstand basics and advantages of myocardial imagingDescribe isotopes and radiopharmaceuticals available in cardiac imagingDescribe methods of pharmacological stressReview some technical aspects of protocols
Kit PreparationAseptic technique ALWAYS
alcohol swabs, fresh syringes & saline vialsAssay the Tc99m activity
Do not exceed package insert recommendations
Add the Tc99m activitySufficient volume to dissolve contents of vial
Agitate gently and let standAdjust concentration by adding saline
Radiochemical Purity
Related to bonding of isotope to reagentFor Tc99m, it represents the reduction of
TcO4+7 to TcO4
+4and bonding of TcO4+4 to
carrier. Verification by means of chromatography
methods generally designed around the physical properties of both the radio-pharmaceutical and impurities that form.
For Tc99m, there may be bound Tc99m, or free and hydrolyzed/reduced impurities.
Sestamibi QC ProcedureEthanol:Top: Tagged radiopharmaceutical Bottom: Free Tc-99m, hydrolyzed reduced Tc-99m % tagged Tc-99m = (top counts)/(bottom counts + top counts) x 100
Heart Functions as a Pump Heart pumps blood around the vascular system in two circuits (right atrium pumps blood to the lung in the pulmonary circulation, and the left atrium pumps blood to the whole body in the systemic circulation)Main parameter for function is the Cardiac Output (Index) l/min (/m2)Each beat the ventricle pumps a volume of blood called the stroke volume (EDV-ESV)Ejection fraction: % of blood expelled by the ventricle in each beat EDV-ESV
EDV
Evaluation of Cardiac Function
Non-invasive tests:– Exercise physiology– Echocardiography (very beneficial for
measuring the ejection fraction)– GBPS, First pass studies, Gated
SPECTInvasive– Cardiac catheterization (angiopathy)
Radiopharmaceuticals In Nuclear Cardiac Imaging Procedures
Myocardial perfusionSPECT PETThallium-201 Rubidium-82Tc-99m Sestamibi N-13 ammoniaTc-99m Tetrofosmin
Cardiac function- Tc-99m Pertechnetate
Myocardial metabolism- F-18 Deoxyglucose
Regulatory “Food For Thought:
Pharmaceutical Outsourcing and JCAHO
RadioNuclide Cardiac Angiography (RNCA)
Multi-Gated Cardiac Blood Pool Imaging (MUGA)
Dynamic imaging of the cardiac blood pool (cavity) to evaluate ventricular size, wall motion and ejection fractionAccurate and reproducible measurement of LVEF (left ventricular ejection fraction) most suitable for follow up (after chemotherapy, MI) Can be done with exercise/stress in the study of patients with CAD (coronary artery disease)
Gated Blood Pool IndicationsPatients with coronary artery disease (rest and exercise):– EF response to exercise– Induced wall motion abnormalities– Prognosis post-MI (EF, ventricular
aneurysm)– Pre and post bypass surgery
Patients receiving anthracyclinechemotherapy (Adriamycin) to monitor cardiac toxicity because adriamycin is cardio-toxicPresurgical evaluation
Scintigraphic TechniqueRadiopharmaceuticals: Blood pool agents– 99mTc RBC: usually in vivo labeling, in vitro,
or modified in vivo/vitro give better labelingPertechnetate enters RBCs, reduced by intra-cellular stannous ion, and bound to hemoglobinInstrumentation:– Scintillation camera with on-line acquisition– ECG monitor (trigger)
The patient is given 99mTc and monitored with a gamma camera which is connected to ECG monitor.
Regulatory “Food For Thought:
Re-Infusion of Blood Products and DOH
MUGA Analysis
Qualitative:– Size and configuration of cardiac
chambers: dilatation, thick wall, etc– Regional wall motion: normal, hypokinetic
(decreased movement), akinetic (no movement),dyskinetic (movement in the opposite direction)
Quantitative:– LVEF, regional EF, stroke volume– Diastolic function: LV filling rate and time to
peak filling rate– RVEF: problem with reproducibility– Phase analysis
Infarct-Avid Imaging Pathophysiology
Necrotic tissue accumulates in phosphate compounds (bone imaging agents) due to presence of calcium deposits.
This finding is useful for the diagnosis of atypical cases of myocardial infarction in which clinical, biochemical and electrocardiographic data are inconclusive.
99mTc Pyrophosphate ScanNormal: no uptake in the heart (grade 0)Diagnostic value– Acute myocardial infarction with atypical
presentation and lab findings– Right (and left) ventricular infarction– Peri-operative infarction (CABG)
99mTc PYP, 25 mCi - given intravenouslyImage (planar & SPECT) at 3-4 hrRepeat after 3 hr if necessary
Myocardial Perfusion Study
Assess coronary blood flow
Demonstrate blood perfusing the LV myocardium
Performed at rest & stress
Software allows gating for EF
3D reconstruction of heart
Patient PreparationContinue taking cardiac meds when evaluating effectiveness of therapyAny stress procedure– NPO at least 4, preferably 12 hours – off beta-blocker medications
Chemical stress procedure– off caffeine and asthma medications for
adenosine/persantine chemical stressAny rest procedure– requires no patient prep
Hemodynamically & clinically stable at least 48 hours
Thallous Cloride
Thallium-201 is a potassium analog which can be detected by single photon emission computed tomography (SPECT)Uptake by myocardial cells depends on an active transport process requiring intact sarcolemmal membranes and adequate ATP storesImages are obtained at rest and 4 hours laterIn normal myocardium, intial uptake is high but decreases rapidly within hours
Technetium Tc-99m Sestamibi Technetium Tc-99m Tetrofosmin
Lipophilic cationic compounds– Methoxy isobutyl isonitrile – Ethoxyethyl phosphino ethane
Uptake across myocardial membranes is passive and requires presence of intact electrochemical membrane gradients– Binds to a low molecular weight protein
fraction in the cytosol complex There is limited redistribution after initial uptake which would appear to limit its usefulness in determining viability
Myocardial Resting DoseSelect agents for myocardium viability.Second reinjection may be needed. IV administrationTc-99m sestamibi adult doses 8-30 mCiTc-99m tetrofosmin adult doses 8-30 mCiTl-201 chloride adult doses 2-5 mCiTl-201 chloride redistributes 3-4 hours after injection.
Indications
Detection and evaluation of CAD (coronary artery disease)Coronary bypass surgery or angioplastyDetection of viable tissue (Tl-201) Evaluation of MI, chest pain, SOB, family history of heart disease.Evaluation of blood work indicators ie: elevated creatine phosphokinase, troponin etc.
Myocardial Stress Dose
Tc-99m sestamibi Tc99m tetrofosmin = 20-30 mciTl-201 chloride 3-5 mciIV administration. Must have patent line.Myocardial localization same as resting.
Indications
Same as resting protocals.Contraindications :– Chest pain– Discontinue chemical
stressors: CaffeinePersantineViagra
Contraindications
High blood pressureNot comfortable weaned from nitroglycerinAllergies to chemicals (stress pharmaceuticals)Lung conditions (asthmatic reaction to persantine or adenosine) dobutamineused in these cases.
Adenosine & DipyridamolePharmacologic Effect
Immediate with AdenosineDelayed with Dipyridamole (Converted to Adenosine; Peak reached after stopped)
Absolute Contraindications Asthmatics with persistent wheezing2nd or 3rd degree AV block, sick sinus node (Unless pt has functioning pacemaker)Systolic BP < 90 mm HgDipyridamole use < 24hrs; Xanthines <12hrs
Pharmacologic Stress - Adenosine
STARTINFUSION
END INFUSION
END INFUSION
START INFUSION
Adenosine Adenosine
1 2 3 4 5 6
Recommended Adult Dose: 140ug/kg/min x 6 mins
Hemodynamic EffectsModest increase in heart rateModest decrease in systolic & diastolic
Perfusion Radiopharmaceutical
Pharmacologic Stress- Dipyridamole
STARTINFUSION
END INFUSION
Dipyridamole Dipyridamole
1 2 3 4 5 6
Recommended Adult Dose: .142mg/kg/min x4 mins* No Added Benefit above 60 mg TOTAL Infusion
Hemodynamic EffectsModest increase in heart rateModest decrease in systolic & diastolic
7 111098 12
INJECTPERFUSION
AGENTOR OR
DobutaminePharmacologic Effect
Stimulates sympathetic nervous system β1 receptors and used when adenosine & dipyridamole contra-indicated
Contraindications Recent MI or unstable anginaCritical aortic stenosis, dissection or aneurysmAtrial tachyarrhythmiaPrior history of ventricular tachycardiaUncontrolled hypertension
Pharmacologic Stress- Dobutamine
END INFUSION
Dobutamine Dobutamine
3 4 5 6 5 6
Recommended Adult Dose: 5-10ug/kg/min x3 mins* Increase at 3 min intervals to 20, 30, 40
Hemodynamic EffectsModest increase in heart rate (Beta blockers limit effect)Modest decrease in systolic & diastolic
7 111098 12
to20
ug/kg/min
to40
ug/kg/min
to30
ug/kg/minINJECT
PerfusionAgt
STARTINFUSION
@ 5ug/kg/min
to10
ug/kg/min
1 2 13
Regulatory “Food For Thought:
Compounding Medications and JCAHO
Regadenoson
Lexiscan is simple, single unit dose injection standardized for all patients, regardless of weight8 out of 10 now use this agent
Cardiac PET Imaging
Perfusion studies– Rest-stress perfusion imaging– Detection of coronary artery disease
and assessing the progression of coronary artery disease
Viability studies– Perfusion-metabolism imaging– Identification of tissue that may recover
contractile function following revascularization techniques
Nitrogen-13 Ammonia
PET Perfusion Agent Cyclotron ProducedSynthesis < 30 minsHalf-life = 10 minsApproved by CMS
Shallow metal half-cyclinders, later called “dees” after their shape, serve as electrodesCharged particles injected into the gap near the center are pulled by the potential into the electrode AThe magnetic field, perpendicular to the plane of the cylinders, bends them in a semicircle back into the gapIn the meantime the electric field has reversed and can pull them into electrode B, emerging again in step with the electric field, eventually spiraling out to the edgeEach passage through the gap boosts the particles to higher energies.
Regulatory “Food For Thought:
PET Drugs and FDA
CardioGen-82® (Sr 82 / Rb 82 Generator)
PET Perfusion AgentNo cyclotron requiredHalf life = 75 secsLong-lived Sr85 contaminantDistinguish normal from abnormal myocardium in suspected MI
Infusion System Schema
Regulatory “Food For Thought:
Generator Breakthrough and FDA
F-18 FlurpiridazLonger half-life of F-18 vs N-13 Ammonia and Rb-82 would permit commercial distributionEliminates need for on-site medical cyclotron or costly generator infusion systemPhase III efforts demonstrated better target to background resolution vsAmmonia, over-reporting findingsTherefore, required increase in cohort
Representative Normal F18Flurpiridaz
J Am Coll Cardiol Img. 2012;5(12):1269-1284. doi:10.1016/j.jcmg.2012.10.006
A) Consecutive tomograms of paired stress (top row) and rest (bottom row) images show normal distribution of the radiotracer in all myocardial regions
Representative Abnormal F18Flurpiridaz
J Am Coll Cardiol Img. 2012;5(12):1269-1284. doi:10.1016/j.jcmg.2012.10.006
(B) Paired stress (top row) and rest (bottom row) images show extensive reversible regional perfusion defects in all 3 coronary artery vascular territories associated with transient ischemic cavity dilation.
Myocardial Viability ImagingMechanism of Uptake & Metabolism
Myocardial cells continuously utilize chemicals (K+ analogs & nitrates) and substrates (free fatty acids & glucose) to meet energy needs
Impact on Patient ManagementEarly referral to revascularization improves– Survival– Left Ventricular function– Heart failure symptoms & exercise capacity
Reduces readmissions for CHF
Cardiac Viability (Done only at rest)
Tl-201 SPECT studyFDG PET study
Ant
Inf
LatSep
Ant
Inf
Apex
Apex
Sep Lat
Preparation for FDG StudyNon-Diabetic Patients
NPO for six hoursOral ( Glucola ) or IV glucose loading
Diabetic PatientsOral glucose leads to sub-optimal imagesModified Protocol for IV glucose loading– Fasting BG < 125 mg/dL, give 25g 50% dextrose– Fasting BG 125-225, give 13g 50% dextrose– Fasting BG >225, give regular insulin
• # units = (BG – 50) / 25• Inject FDG if BG < 150mg/dL
Perfusion & Metabolism Patterns
Perfusion
GlucoseMetabolism
Normal Non-Viable Viable
Paradigm Shift in Markers?Stenosis-----------Ischemia---------Necrosis1980’s: Myocyte Necrosis1990’s: Cardiac Myocyte Necrosis2000’s: Ischemia and Vessel Inflammation
1. Dx prior to cell death2. Better outcomes3. Efficient resource use4. Risk stratification in the ED without need for
cardiologists/radiologists
New Biochemical MarkersHeart Type Fatty-Acid Binding Protein (H-FABP)CholineSerum Amyloid AMalondialdehyde-modified LDLGlutathione Peroxidase 1Monocyte Chemoattractant Protein 1 (MCP-1)Ischemia Modified Albumin (IMA) Myeloperoxidase (MPO) CD 40 Ligand C-Reactive Protein (CRP) Pregnancy-Associated Plasma Protein A (PAPP-A)Placenta-derived Growth Factor (PDGF)
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Dilsizian V, Taillefer R. Journey in Evolution of Nuclear Cardiology: Will There Be Another Quantum Leap With the F-18–Labeled Myocardial Perfusion Tracers?. J Am Coll CardiolImg. 2012;5(12):1269-1284.