Basic Physics Nuclear Physics

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Basic Physics of Nuclear Medicine/Dynamic Studies inNuclear Medicine

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IntroductionThis is a developing chapter of a Wikibook entitled Basic Physics of Nuclear Medicine.

The metabolism of a substance in the human body is the result of a number of inter-related dynamic processes which

include the absorption, distribution, utilization, degradation and excretion of the substance. The measurement of just one

of these parameters can give a result which is indicative of a disease, but may not identify the actual cause of the disease.

More detailed information about the cause may be determined when knowledge of the complete metabolic system is

obtained. One method of gaining such knowledge is through mathematical simulation of the physiological system. The

outcomes of this approach include generating a representation of the entire system as well as an understanding of

interactions between its component parts. The approach typically involves:

1. obtaining experimental data following stimulation of the system by addition of a suitable tracer,

2. comparing experimental data with data predicted by the mathematical simulation, and3. varying parameters of the simulation until the two sets of data agree as closely as possible using methods such as least

squares, maximum likelihood and Monte Carlo simulation.

The general assumptions for this approach are that:

the addition of the tracer does not perturb the system, the tracee (i.e. the substance under investigation) is conserved throughout the process, the tracer is conserved throughout the process - allowing for radioactive decay, and the system is in a steady state (i.e. the amount of tracee in each compartment of the system remains constant as

does the exchange of tracee between each compartment).

There are two major types of mathematical model in use:

Deterministic: where analytical expressions are used to describe the exact behaviour of the tracer in eachpart of the system with time. The mathematical expressions used are usually exponential or power functions,

Stochastic: where the behaviour of the system is determined by random processes which are described byprobability functions.

Deterministic models are considered in some detail below.

Compartmental Analysis

This form of deterministic analysis involves dividing the physiological system into a number of interconnectedcompartments - where a compartment is defined as any anatomical, physiological, chemical or physical subdivision of

a system. A basic assumption is that the tracer is uniformly distributed throughout a compartment. The simplest of such

systems to consider is the single compartment model. We will start our treatment with this simple model and then extend

it to more complex ones - the initial ones being considered simply to develop the framework with the later ones providing

direct relevance to nuclear medicine dynamic studies; their acquisition and analysis.

Note that a spreadsheet can be downloaded which will allow you to interact with and explore each of the models

described. Furthermore, there's an ImageJ plug-in available, named Compartments_TP, which provides simulations of a

number of additional models.

Single Compartment Model

The flow of a tracer through a blood vessel following an ideal bolus injection is shown in the following figure as an

illustration of a single compartment model. The compartment illustrated is closed except for the inflow and outflow of the

tracee, and the tracer is injected as indicated. In these theoretical conditions, the tracer will mix immediately and

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uniformly throughout the compartment following its injection. And its quantity will reduce with time depending on the

rate of outflow. The variables used in the figure are:

q: the quantity of tracer in the compartment at time, t, andF: the outflow.

We can define the fractional turnover, k, as the ratio of these two parameters, i.e.

which can be rewritten as:

Without going into the mathematical details (which are similar to the derivation of

the radioactive decay law!), the solution to this equation is:

where qo is the quantity of tracer present at time, t = 0.

This equation is plotted below to illustrate the influence of the value of the fractional turnover, k:

The graph indicates that the quantity of tracer in the compartment will decrease exponentially with time following

injection at a rate dependent on the outflow, as might be intuitively expected.

Two Compartment Model - Closed SystemA more complex, and yet still relatively simple, set of models are those based on two compartments. In a closed system

the tracer simply moves between the two compartments without any overall loss or gain - see the following figure:

The single compartment model

Graphical illustration of the quantity of tracer, q versus time forrelatively high and low values of the fractional turnover, k.




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Therefore,

Since there is no loss of tracer from the system,

Therefore,

,

indicating that as the quantity of tracer in Compartment #1 decreases, the quantity in Compartment #2 increases, and vice

versa. Now, consider the situation illustrated in the figure above, where the tracer is injected into Compartment #1 at

time, t = 0. At this time,

and, initially,

The solutions to these equations are:

and

Closed two compartment model

and

.

and

.




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and their behaviour in the special case when k12

= k21

, and the volume of the two compartments is the same, is illustratedbelow:

Note that this model predicts that a steady state will be reached as the quantity of tracer in Compartment #1 decreases

exponentially and the quantity in Compartment #2 increases exponentially, with the rate of each change controlled by the

sum of the turnover rates.

Two Compartment Model - Open Catenary System

This is an extension of the single compartment model considered earlier with two compartments connected in series, as

shown in the following figure:

In this model,

Graphical illustration of the change in the quantity of tracer inCompartments #1 and #2 versus time.

Open catenary two compartment model.




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and

,

and the behaviour ofq1 and q2 is shown in the figure below for the special case ofk20 being three times the value ofk12:

Note that the behaviour ofq2 in this figure is similar to arterial tracer flow following an intravenous injection, and to thecumulated activity parameter used in radiation dosimetry.

Two Compartment Model - Open Mamillary System

This model is equivalent to the closed two compartment system considered above with the addition of an outflow from

one compartment:

and

.

Graphical illustration of the quantity of tracer versus time in the open catenarytwo compartment model.




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In this case,

At t = 0:

and, initially


and

where

The behaviour ofq1 and q2 is illustrated in the figure below:

Open mamillary two compartment model.

and

.

and

.

and.




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This model has been widely adopted in the study of:

metabolism of plasma proteins, where Compartment #1 is the plasma and Compartment #2 is the extravascularspace,

trapping of pertechnetate ion in the thyroid gland, where: Compartment #1: the plasma, Compartment #2: the thyroid gland,

k12: clearance rate from plasma into the gland, and

k21

: leakage rate from the gland into the plasma.

Models with Three Compartments

The open mamillary model above has been extended to study iodine uptake using a third compartment which is fed by

an irreversible flow, k23, from Compartment #2:

where:

Compartment #1: the plasma, Compartment #2: the trapping of inorganic iodide in the thyroid gland, and Compartment #3: iodide within the gland which has become organically bound as part of hormone systhesis

processes.

The open mamillary type of model has also been applied to renal clearance with the system consisting of an intravascular

Graphical illustration of the quantity of tracer versus time in the openmamillary two compartment model.

Thyroid iodine uptake model.




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compartment, with an extravascular compartment exchanging with it and connected irreversibly with a urine

compartment:

The intravascular compartment (#1) in the figure above represents tracer which is exchangeable with the renal

parenchyma and the extravascular space. The urine compartment (#2) represents tracer which has been cleared by the

kidneys and is therefore associated with the renal pelvis and the bladder. The extravascular compartment (#3) represents

the tracer which has not been cleared, e.g. tracer which becomes bound to other molecules or tracer in extrarenal tissues.

When the tracer is injected into the intravascular compartment via a peripheral vein, the initial distribution will not be

uniform throughout the body - but this non-uniformity will even out as the blood circulates. For a highly vascular region,

a plot of the quantity of tracer versus time will show an initial sharp rise which will rapidly fall off. The magnitude of thisspike will vary with:

the anatomical region, the site of the injection, and the speed of the injection.

Compartmental analyis cannot therefore be applied to this phase of a renogram since the basic assumption of uniform

tracer distribution, implicit in compartmental analyis, cannot be applied.

Following this phase, the quantity of tracer in the intravascular compartment begins to fall because of:

uptake by the kidneys - represented by k12 in the figure above,

diffusion into the extravascular space - represented by k13.

As the quantity of tracer in the extravascular compartment builds up, exchange in the opposite direction begins to occur

(represented by k31

), and so a maximum is reached before its quantity of tracer falls off. This is illustrated in the figurebelow for a situation where:

Renal clearance model.

k12

= 0.05 per minute

k13

= 0.04 per minute

k31

= 0.06 per minute

l1

= 0.13 per minute

l2

= 0.024 per minute

A1 = 0.65

A2 = 0.35




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Ultimately, all the tracer will end up in the urine compartment.

The equations used for the figure above are:

where l1 and l2 are constants related to the fractional turnovers, and A1 thru A5 are also constants such that:

In practice, the renal clearance can be obtained by monitoring the quantity of tracer in the intravascular compartment, e.g.

the blood plasma concentration, P, where:

The time dependence of this plasma concentration will vary in the same way as q1, so that:

where C1 and C2 are related to A1 and A2, respectively. The renal clearance, which is related to k12, can therefore bedetermined by characterizing the biexponential fall off in the quantity of tracer in the intravascular compartment.

Predictions of the renal clearance model.




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Glomerular Filtration Rate

The Glomerular Filtration Rate (GFR) is generally regarded as one of the most important single indicator of renal

function. It is particularly important in assessing the presence and severity of kidney failure.

There are three major methods of determining a patient's GFR:

Inulin clearance, Creatinine clearance, Radiotracer clearance.

Inulin clearance has been used for many years and is often regarded as the most reliable and accurate of the three

methods. Its major disadvantages however include the need for continuous intravenous infusion, timed urine collections

via a bladder catheter and protracted chemical analysis. Creatinine clearance has been widely used for routine GFR

assessment as a result. However, while this method gives similar results as inulin clearance under normal conditions, the

validity of its results is questionable in patients who have moderate to advanced renal failure because of an increasing

significance of tubular secretion.

The third method, radiotracer clearance has been widely adopted using 51Cr-EDTA. This tracer is known to be

physiologically inert, not bound to plasma proteins and not metabolized by erythrocytes or organs other than the kidneys.It is normally excreted within 24 hours of injection, 98% via the kidneys. 51Cr has a half-life of about 28 days and decaysby 100% electron capture into stable vanadium, emitting monoenergetic (320 keV) gamma-rays in about 10% of the

transformations. In addition, 51Cr-EDTA determination of GFR can be used in conjunction with OIH renal plasma flowassessment for the differential diagnosis of various renal conditions.

The typical radioactivity administered for 51Cr-EDTA clearance is 1-10 MBq and the radiopharmaceutical is generallyadministered via intravenous injection. This Single Shottechnique assesses the GFR through venous blood sampling, in

the simplest case, or by continuous external monitoring of the gamma-rays from 51Cr in the more sophisticated approach.When the patient counts are plotted against time on a log/linear axis, a curve is generated which falls off rapidly at first

and thereafter decreases at a constant rate, representing the behaviors ofq1 is our last figure. This initial fall-off arises asa result of the establishment of an equilibrium between the radiotracer and the extravascular, extracellular fluids. The

slower second phase reflects renal excretion and contains the information necessary for GFR assessment.

A quick and simple technique is to obtain two blood samples from the patient, one at two hours and the other at four

hours post injection. The counts per unit volume in the plasma of each sample are determined using a scintillation counter

The plasma clearance of51Cr-EDTA predicted using the three compartment

model discussed above.

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and compared with the counts from a standardsolution. The standard solution is made by diluting an injection, identical

to the patient's, in a known volume of water, e.g. 1 liter.

The slope, m, of the second portion of the above curve can be determined from:

where:

t1: time from injection for the first blood sample, usually 120 minutes,

b1: counts per milliliter (mL) in the plasma from the first sample (corrected for background counts),

t2: time from injection for the second blood sample, usually 240 minutes,

b2: counts/mL in the plasma from the second sample (also corrected for background).

We can now extrapolate this straight line back to the time of injection, t0, to determine what the plasma counts would beupon instantaneous mixing of the tracer throughout the patient's plasma compartment, i.e.

as illustrated in the following figure:

Therefore, we can write:

Counts for the two plasma samples are fit to a straight line which is back-extrapolated tothe time of injection (dashed line) to determine the logarithm of b

0. The plasma

clearance, q1, predicted using the three compartment model is shown shaded.




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The Dilution Principle can now be used to determine the volume of this plasma compartment by comparing the plasma

counts with those from the standard solution, i.e.

which results in

when the standard injection is diluted in 1 liter. The clearance (in ml/min) is then given by the following equation:

Results for two patients are shown below to illustrate this technique.

Patient A

This patient's 51Cr-EDTA clearance was determined to be 38.8 mL/min. This result was assessed to be indicative ofchronic renal failure, which was later found to be due to lupus nephritis. The patient was then placed on steroid therapy.

Two months later the patient was re-tested and the clearance was found to have risen to 52.7 mL/min. For the patient's

age, this clearance was gauged as within the normal range indicating that the therapy was having a positive effect. The

therapy was then ceased. Two months further, the patient was again tested having been without steroid therapy for this

period. The result was 54.2 mL/min reflecting successful treatment.

Patient B

Sample Counts/mL

Background 477

b1 at 119 mins 11,438

b2 at 238 mins 6,235

Standard, S 150,020

Sample Counts/mL

Background 425




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This patient had a high blood pressure and a renal involvement required confirmation. The clearance however was 117.3

mL/min, which is well within the normal range. The kidneys were therefore excluded from the investigation of this

patient's condition.

Note that the number of blood samples is not limited to two, with some methods requiring three, four or more samples,

and other methods using external monitoring of the clearance. Each method is nevertheless based on the form of analysis

outlined above where the rate constant of the second phase of the clearance curve is determined along with the volume of

distribution of the radiotracer. The timing of blood sampling is therefore after the first phase has finished, i.e. more than

about two hours following injection, with the volume of distribution determined using a single-exponential fit to this later

phase.

It is important to appreciate that the clearance of51Cr-EDTA determined as described does not equate directly with the

Glomerular Filtration Rate (GFR) since the method assumes a single exponential dependence. 51Cr-EDTA clearanceresults are therefore typically corrected by a factor, either empirically- or theoretically-derived, to force them to express

the true GFR. Empirically-derived corrections include those of:

Chantler (1969), where the 51Cr-EDTA clearance is multiplied by a factor of 0.8; Brien (1969), where clearances above 50 mL/min are multiplied by 0.82 and added to 6; Brochner-Mortensen (1972), where a second-order polynomial is applied

to obtain the GFR. A correction based on a theoretical consideration of the relationship between true GFR and single-

exponential clearance values based on compartmental analysis has been introduced (Fleming, 2007) which gives

improved corrections, especially at high GFRs. This correction is of the form:

where f= 0.0017 min/mL.

As a final step, corrected clearance measurements are generally standardized to the body surface area (BSA) of the

Standard Man, i.e. 1.73 m2. This is typically done using estimates of the BSA based on the patient's height and weight -as derived from DuBois (1916) or Haycock (1978), for instance. A single-exponential correction technique, based on

BSA-scaled clearances has also been introduced (Jodal & Brochner-Mortensen, 2008) which is similar to that of Fleming

(2007) but provides improved correction in paediatric studies. The necessary calculations can be readily incorporated intospreadsheet software.

Renography

It should be apparent from the discussion above that the urine compartment (#2) consists of the quantity of the tracer in

the urine, without distinguishing whether the urine is in the renal pelvis, the ureters or the bladder. These anatomical

spaces can be incorporated by extending the three compartment mamillary model to five compartments:

b1 at 122 mins 3,103

b2

at 250 mins 1,390

Standard, S 104,600




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Note that the passage of the tracer through the renal parenchyma can be characterized by a transit time, t0, and that k56 is

related to the rate of urine production.

The solutions to the resultant differential equations for the quantity of tracer in the renal parenchyma, the renal pelvis and

the bladder incorporate consideration of the time delay, t0, so that:

When t < t0:

When t > t0:

Compartmental analysis applied to renography.




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where l3 is related to k56. The time course of the quantity of tracer in each compartment is shown below:

The quantity of tracer in the overall kidney can be obtained by summing the renal parenchyma and renal pelvis curves, so

that:

as shown below:

What is recorded in a renogram in practice is not just this kidney curve, but also the quantity of tracer in:

overlapping and underlying tissues, and in the intravascular space of the kidney itself.

These contributions add a background upon which the true renogram is superimposed. The quantity of tracer in this

background varies with time, but not in the same way as the true renal curve. The time course of this background is likely

The parenchymal (q4), renal pelvis (q5) and bladder (q6) curves,

generated using t0

= 2 minutes and k56

= 1 per minute.

The outcome of summing the renal pelvis and parenchyma curves.




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to behave in a manner similar to the sum of the intravascular (q1) and extravascular (q

3) curves dervied earlier using this

five compartment model.

The following equation can be derived on this basis:

where b1 and b3 represent the contributions to the detected renogram curve from the tracer in the intravascular andextravascular spaces, respectively. For example, the curves below were generated using b

1= 0.05 and b

3= 0.02 and

In practice, this background curve should be subtracted from the raw renogram data to obtain a curve which reflects the

true quantity of tracer in the kidney (see the previous figure). This process is sometimes referred to as blood background

subtraction - although you should now be able to appreciate that this is a bit of a misnomer!

The uncorrected and corrected curves are shown below to assist with direct comparison:

and an example from a patient's 99mTc-DTPA renogram is shown in the following figure, to assist you in comparing themwith the predictions from compartmental analysis:

Renogram and background curves typical of those acquired in practice.

Renogram curves pre- and post-background correction.




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A final figure illustrates a form of analysis that can be used in 99mTc-MAG3 renography in a patient with obstructiveuropathy:

Images from this study can be viewed at this webpage.

Background Subtraction in Renography

In practice, the background activity in a renogram must be taken into account when interpreting a renogram. This is

generally achieved by estimating the background activity and subtracting it from the raw renogram data. The question is:

how can this background activity be measured?

One method has been based on recording the activity at nephrectomy sites in patients whose remaining kidney is being

examined. However, it should be noted that removal of a kidney also removes an intravascular source of the background

activity. As a result nephrectomy sites commonly appear colder than the extra-renal tissues in renogram images.

A potentially better method is to record the activity in the region of a non-functioning kidney.

Analysis of a MAG3 renogram




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In most patients, however, a non-renal region must be used for background estimation. Ideally, the choice of region

should reflect the same intra- and extravascular background as the kidney itself. There appears to be no standardization in

this area, with practices including the use of a region between the kidneys, above the kidneys, over the heart and below

each kidney.

Once the background region is selected and the activity/time curves are generated, the background curve should be scaled

by a factor dependent on the relative areas of the background and renal regions, prior to subtraction from the raw

renogram curve. In addition, note that some practices also involve further scaling of the background curve depending on

the kidney location. Finally, more sophisticated methods of background correction have been developed and include:

the generation of interpolated background regions from samples of the background around the kidney, the estimation of background correction factors using extrapolation techniques, and deconvolution analysis.

Relative Renal Function

The relative function of a patient's kidney is generally defined as that kidney's renal clearance rate expressed as a

percentage of the patient's overall renal clearance rate, i.e.

where LK and RK refer to the left and right kidneys, respectively.

Suppose that:

NKidney(t): background corrected renal count rate, and

NBgd(t): count rate from an intravascular region of interest.

It should be apparent at this stage that:

We can therefore conclude that in the initial phase of the renogram, i.e. when t < t0:

where UC in the kidney uptake constant. This constant is related to that kidney's clearance rate, and we can thereforewrite:

and

However, we have already seen above that the background corrected renal count rate is directly related to the uptake

and

and




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constant and we can therefore conclude that:

Note that this analysis indicates that relative renal function can be determined from measurement of the relative counts in

each kidney following the initial vascular spike but prior to the commencement of the excretion phase.

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