Radiation Absorbed Dose Estimatesfor Oxygen-15 Radiopharmaceuticals(H215O,C15O,O15O)in Newborn Infants

William J. Powers, Michael Stabin, David Howse, John O. Eichung,and Peter Herscovitch

Mallinckrodt Institute of Radiology and the Department of Neurology and NeurologicalSurgery of the Washington University Medical School, St. Louis, MO; and theRadiopharmaceutical Internal Dose Information Center, Oak Ridge, Tennessee

In preparation for measurement of regional cerebral oxygen metabolism by positron emissiontomography, radiation absorbed dose estimates for 19 internal organs, blood, and total bodywere calculated for newborn infants following bolus intravenous administration of H215Oandbrief inhalation of C150 and 0150. Cumulated activity for each radiopharmaceutical was

calculated from a compartmental model based on the known biologic behavior of thecompound. Values for mean absorbed dose/unit cumulated activity (S) for internal organs andtotal body were based on a newborn phantom. S was separately calculated for blood. Totalradiopharmaceutical absorbed dose estimates necessary to measure cerebral oxygenmetabolism in a 3.51-kg infant based on 0.7 mCi/kg H215Oand 1 mCi/kg C15Oand O15O were

determined to be 1.6 rad to the lung (maximum organ dose), 0.28 rad to the marrow, 0.46 radto the gonads, and 0.22 rad to total body. These values are similar to those for current clinicalnuclear medicine procedures employing 99mTcin newborn infants.

J NucíMed 29:1961-1970,1988

. he value of positron emission tomography (PET)with oxygen-15 (I5O)radiopharmaceuticals for studying

regional cerebral blood flow (rCBF), blood volume(rCBV), and oxygen metabolism (rCMRO2) in adulthuman subjects is well established (1-3). Applicationof this technology to infants and children has receivedless attention, in part due to appropriate concerns aboutthe risks of radiation exposure and the benefit to beobtained from such studies. Measurements of rCBF innewborn infants performed with PET and H215Oat ourinstitution (4-7) have increased understanding ofpathophysiology and sequelae of intraventricular hemorrhage and hypoxic ischemie encephalopathy, two ofthe most common neurologic disorders in this agegroup. These two cerebrovascular diseases continue toproduce significant long-term neurologic disability inspite of advances in the care of critically ill newborn

Received Jan. 28, 1988; revision accepted Aug. 18, 1988For reprints contact: William J. Powers, MD, Div. of Radiation

Sciences, Mallinckrodt Institute of Radiology, 510 S. Kingshigh-way Blvd., St. Louis, MO 63110.

infants (4,5). Further insight into the pathogenesis andoptimal treatment of these diseases is greatly needed.

PET studies of adult cerebrovascular disease haveclearly demonstrated that measurements of rCBF aloneare inadequate to define pathophysiologic changes andresponses to therapeutic intervention. Further information such as that supplied by measurements of rCBVand metabolism is necessary to understand these complex processes (8-10). Although estimates of cerebralglucose consumption in newborn infants have beenobtained by several investigators using PET and fluo-rine-18 (18F)fluorodeoxyglucose(//,72), this technique

does not provide quantitatively accurate data in ischemie or infarcted tissue, and the results can be misleading under these circumstances (8,13). We have,therefore, chosen to extend our studies of rCBF innewborn infants to include measurements of rCBVfollowing brief inhalation of CI5O and measurementsof rCMRO2 following brief inhalation of O'5O (14,15).

These techniques have been extensively applied by usin studies of adult cerebrovascular disease to provide

Volume 29 •Number 12 •December 1988 1961

accurate, quantitative data (8). In order to apply themto newborn infants, accurate estimates of radiationabsorbed dose for these radiopharmaceuticals must beknown. The purpose of this communication is to reportradiation absorbed dose calculations for newborn infants for bolus i.v. injection of H2'5O and for briefinhalation of CI5O and O15O.

METHODS

Radiation absorbed dose calculations were performed according to the system set forth by the Medical Internal Radiation Dose (MIRD) Committee of the Society of NuclearMedicine (76). Due to the short half-life of 15O, cumulated

activity (A) for source organs could not be measured directlyand was calculated using compartmental models based on theknown biologic activity of these compounds. [A similar approach has been reported for adult subjects (17).] Values formean absorbed dose/unit cumulated activity (S) and totalbody to total-body 4>pfor 500 keV photons were based on thenewborn phantom of Cristy with mass 3.51 kg (18). These S-

factors are not available for blood. Separate calculations ofspecific absorbed fraction were performed for blood using themethod of Cloutier and Watson (79).

In order to allow calculation of a total study dose for allthree radiopharmaceuticals, some standardization of individual dosimetry calculation was necessary. H2'5O is a diffusible

substance distributed initially in the blood and then movingto high flow-low volume tissues (all internal organs) and lowflow-high volume tissues (bone, skin, fascia, and skeletal muscle) according to relative blood flow (20). CI5O may be

considered to be a purely intravascular tracer (21) that isdistributed homogeneously within the total blood volume(TBV). O'5O can be represented as a combination of a purelyintravascular tracer (15O-hemoglobin) and freely diffusibleH215O (14). For each radiopharmaceutical, therefore, cumu

lated activity was calculated for high flow tissues, low flowtissues, and blood. In addition, separate calculations for cumulated activity in lung were performed for C'5O and O'5O.

Abbreviations and source references for physical and biologicconstants are given in Tables 1 and 2.

Fractional Blood VolumeThe following assumptions were made about the distribu

tion of total blood volume (TBV): 0.265 is in the heart, largevessels, and arteries (fBVGv), 0.196 in the pulmonary circulation (fBVLN), and 0.539 in capillaries and veins (19). Bloodvolume in capillaries and veins was partitioned between highflow-low volume tissues and low flow-high volume tissues in

proportion to the fraction of total blood flow (TBF) receivedby each. The total organ mass of high flow tissue is 677.17 g(Table 3) and that of blood is TBV x PB = 321.18 g. The

remainder of the 3.51 kg mass, therefore, is low flow tissuewith mass of 2511.65 g. Blood flow to this low flow-high

volume tissue is 8 ml/100 g/min (22) or 200.9 ml/min (BF2)which represents 0.303 of TBF (662.4 ml/min). Since 0.539of TBV is in capillaries and veins, 0.303 x 0.539 = 0.163 of

capillary and venous volume is in low flow tissue (fBVLF) and(1 - 0.303) x 0.539 = 0.376 is in high flow tissue other than

lung (fBVHF). This fraction in high flow tissue is considered

TABLE 1Abbreviations

Symbol Quantity Units

AO Initial activity for administration mCiA Cumulated activity /iCi-hrA Mean energy emitted per unit g-rad/^Ci-hr

cumulated activity<t> Absorbed fraction* Specific absorbed fraction g~1

S Mean absorbed dose per unit rad//xCi-hrcumulated activity

D Mean absorbed dose radnp Nonpenetrating radiation (ß+)

p Penetrating radiation (511 keVphotons)

Compartmental modelsVx Distribution volume ml

of Compartment xq* Radioactivity mCi

in Compartment xkxy Transfer rate constant from min~1

Compartment yto Compartment x

kox Radioactive decay constant min"1

from Compartment x

to be evenly distributed among organs in proportion to massexcept that 0.032 is in the spleen (23).

Cumulated Activity 11:'"O Injection

Coleman et al. (20) have studied the kinetics of radiolabeledwater distribution following i.v. injection and determined thatit can be described best as a three-compartment model (Fig.

1) in which Compartment 1 is the initial volume of distribution (heart, lungs, vena cava, pulmonary vessels, aorta, andlarger arteries), Compartment 2 consists of low flow-high

volume tissues (bone, skin, fascia, and skeletal muscle plustheir capillaries and draining veins) and Compartment 3 consists of high flow-low volume tissues (all other internal organs

plus their capillaries and draining veins). From the time ofthe injection of radiolabeled water (t = 0) until the waterreaches the capillary bed (t = t'), radioactivity is restricted toCompartment 1. The mean duration of this interval t' was

measured in ten newborn infants as the time from i.v. injectionof H2'5O until activity was detected in the head by PET. Meant' = 0.218 min (range 0.13-0.37 min). For time intervals

subsequent to this, the three-compartment model of Coleman

et al. (20) was collapsed to two compartments under theassumption that Compartments 1and 3 will be in equilibrium.This simplified model (Fig. 1) consists of Compartment 1(heart, lung, great vessels, arteries, other internal organs, andthe capillaries and draining veins) and Compartment 2 (bone,fascia, skin and skeletal muscle, capillaries, and drainingveins).

Separate calculations for A due to H215O were performedfor two time intervals: t = 0 to t = t' using the original three-compartment model and for t = t' to t = <*>using the simplified

two-compartment model. Distribution volumes, initial con

ditions, and rate constants are given in the Appendix. Asummary of cumulated activity calculated for high flow tissue,low flow tissue and blood is shown in Table 4. One hundredpercent of the cumulated administered activity is absorbedinternally.

1962 Powers, Stabin, Howse et al The Journal of Nuclear Medicine

TABLE 2Physical and Biologic Constants"

Symbol15O

PhysicalconstantsaEOAnpApVGeneral

biologicconstantsfTBH2oHFMLFMOMR/BMRCardiovascular

constantsTBFBF2TBVTfBVGVLNSPHFLFpBtBH2oSao2Sv0zRespiratory

constantsPBP*H2OfFRCVTDLCOECOACOAo2'

All biologic constants are for anewbornf

5.5 kgchild.*Adult.QuantityRadioactive

decayconstantß

+ TransitionEnergy(See

TabletA)(See

TabletA)Absorption

coefficient for500keVphotons inwaterFractional

body watercontentHigh

flow tissuemassLow

flow tissuemassOrgan

metabolicrateBodymetabolicrateTotal

blood flow (systemic cardiacoutput)Blood

flow to low flowtissuesTotal

bloodvolumeMean

vascular transit time(TBV/TBF)Fractional

bloodvolumeHeart

and greatvesselsLungSpleenOther

high flowtissueOther

low flowtissueDensity

ofbloodWater

content ofbloodArterial

oxygensaturationMixed

venous oxygensaturationAtmospheric

barometric pressureAlveolar

partial pressureofwaterRespiratory

frequencyFunctional

residualcapacityTidal

volumeCO

diffusingcapacityElimination

of CO from bloodvialungsAlveolar

gas to bloodclearanceofCOAlveolar

gas to bloodclearanceofO2infant

of 3.51 kg mass or 0.23 m2surfaceValue0.335

min"11

.700MeV1.56g-rad/MCi-hr2.18g-rad/fíCi-hr0.0330

cm2/g0.74

g/g677.17g2511.

gO.W662.4

ml/min200.9

ml/min303ml0.457

min0.265*0.196*0.032*0.3440.16301

.06g/ml0.76

g/g0.950.70760

torr47

torr*40

min—1105.3ml24.6

ml1

.357ml/min/torr.0025min-1*6.9

min-1*2.6

min-1*area

unless otherwise notedReference323233333435Table

2Text3622Text3738212123TextText39394040414142424243214444

Volume 29 •Number 12 •December 1988 1963

TABLE 3Internal Organ Mass of the Newborn Infant'

RedMarrowAdrenalsBrainGall

BladderWallStomach

WallSmall

IntestineWallLarge

IntestineWallHeart

WallKidneysLiverLungsPancreasSpleenThymusThyroidBladder

WallUterusOvariesTotal46.948

g5.533340.3876.0925.1

(0.50 x mass ofwall andcontents)17.4824.121.711550.62.668.6410.71.222.743.960.311677.17g

' Data are derived from Ref. 18.

CI5O InhalationCalculation of cumulated activity for C'5O was performed

for two different conditions. The first calculation was performed for the period during which CI5O is breathed from an

external reservoir containing the radioactive gas. A0 is theactivity initially contained in the reservoir. Compartment 1 isthe reservoir. Compartment 2 is the lung, and Compartment3 is the blood (Fig. 2). The second calculation was performedfor the period following reservoir breathing when free respiratory exchange with the environment takes place (Fig. 2).Now, Compartment 1 represents the environment. Compartment 2 represents the lung, and Compartment 3 is the blood.Distribution volumes, initial conditions, and rate constantsare given in the Appendix. Results are summarized in Table4. Ninety-six percent of the cumulated activity initially present

in the reservoir is absorbed internally.

O"O InhalationCalculation of cumulated activity for O'5O was performed

with two compartmental models in sequence (Fig. 3). The firstmodel (Compartments 1, 2, and 3) describes the behavior ofmolecular O15O as free O2 in the gas reservoir and lungs andas "O-hemoglobin in the blood. The second model (Compartments 4 and 5) describes the kinetics of H2I5O water of

metabolism in tissue and its recirculation in the blood. Separate calculations for the period of reservoir breathing and freebreathing were performed for each 15O species. A0 is the

activity initially contained in the reservoir. Compartment 1 isthe gas reservoir or environment. Compartment 2 is the lung.Compartment 3 is the blood. Compartment 4 is high flow-low volume tissues, and Compartment 5 is low flow-high

volume tissues. Distribution volumes, initial conditions, and

rate constants are given in the Appendix. Results are summarized in Table 4. Ninety-three percent of the cumulated

activity initially present in the reservoir is absorbed internally.

Specific Absorbed Fraction for BloodCalculations to determine <l>„pfor blood irradiating blood

were performed according to the method outlined by Cloutier

'02

'01 21

V,

V,

12

31

13

;03

= oo

01 t.02

1v.2V2FIGURE 1Compartmental models for the distribution of intravenouslyadministered H215Obased on data from Coleman et al.(20) for two time intervals. Top: Original three-compartment model for the interval from time of injection untilH215Oreaches the capillary bed (t = t'). Compartment 1 is

the initial volume of distribution (heart, lungs, vena cava,pulmonary vessels, aorta, and larger arteries). Compartment 2 consists of low flow-high volume tissues (bone,skin, fascia and skeletal muscle plus capillaries and draining veins) and Compartment 3 consists of high flow-lowvolume tissues (all other internal organs plus capillariesand draining veins). Bottom: Simplified two-compartmentmodel for the interval from t = t' until t = oo.Compartment

1 consists of heart, lung, other internal organs, greatvessels, arteries, capillaries, and draining veins. Compartment 2 consists of bone, fascia, skin, skeletal muscle,capillaries, and draining veins.

1964 Powers, Stabin, Howse et al The Journal of Nuclear Medicine

TABLE 4Cumulated Activity (uCi-hr/mCi

C15O O15O

High flow tissues (includinglung)

Lung onlyLow flow tissuesBlood (Total)

Pulmonary (0.196)Splenic (0.032)Other high flow organs

(0.609) (includesheart and great vessels)

Low flow tissue (.163)Percent A«absorbed"

21.35 —

— 1.7017.98 —

10.442.050.336.11

46.199.051.48

27.02

1.95100%

8.6496%

11.56

4.079.7 ,

20.864.090.67

12.20

3.9093%

' Expressed as percent of total possible cumulated activity with

no loss to environment.

and Watson (19). The mean ratio of the diameters of arterialvessels in newborn infants compared to adults was calculatedfrom Altman et al. (24) as 0.335 and used to multiply thevascular diameters in Table 4 of Cloutier and Watson (19).The heart was treated as a right cylinder with diameter of2.0 cm [end diastolic diameter of the left ventricle (25)]. Theabsorbed fraction 0np for each newborn vessel diameter wasdetermined from the graph given by Cloutier and Watson(19) relating vd lo <t>.The value of v was calculated from theequation given by Loevinger et al. (26). A weighted mean

value for <p„p0.3721 was determined by weighting each vesselcategory according to the fraction of TBV contained (21). Thespecific absorbed fraction 4>np= 1.16 x 10~3g~' was calculated

by dividing 0np by the mass of blood = TBV x pB = 321 g.

In applying these calculations to radiation absorbed doseestimates for CI5O and "O-hemoglobin, the assumption of

equal hematocrit for all blood volume components was made.It is well established that vessels below 200 microns in diameter have a lower hematocrit (27). These vessels (small arteries,veins, and capillaries) comprise 0.128 of the blood volume ofnewborn infants with a mean diameter estimated at fivemicrons. No accurate data regarding hematocrit in vessels thissmall exist (27). However, even a 50% reduction in hematocritin these vessels would shift only 6.4% of the red blood cellmass to larger vessels. This would increase *„„for blood byonly 3% and reduce radiation absorbed dose from positronsto internal organs by a similar amount.

Mean Absorbed Dose CalculationsTarget organ: Blood.Source organ: Blood

* =npAnp =

1.16 x 10~3g-'

1.56 g-rad/fiCi-hr

*p = 4.75 x

500 keV photons)Ap = 2.18 g-rad/fiCi-hr

Source organ: High flow tissueS-factor for total body to total body

Source organ: LungS-factor for lung to total body

Source organ: Low flow tissueS-factor for total body to total body

10 5g ' (total body to total body for

RESERVOIR BREATHING

FREE BREATHING

FIGURE 2Compartmental model for the biologic behavior of inhaled C15Ofor two

time intervals. Compartment 1 is thegas reservoir, Compartment 2 is thelung, and compartment 3 is theblood. Top: Reservoir breathing. Bottom: Free breathing.

Volume 29 •Number 12 •December 1988 1965

RESERVOIR BREATHING

0150

FREE BREATHING

r

FIGURE 3Compartmental model for the biologic behavior of inhaled O15O. Com

partment 1 is the gas reservoir (reservoir breathing) or environment (freebreathing), Compartment 2 is thelung, Compartment 3 is the blood,Compartment 4 is great vessels, arteries, high flow-low volume tissuesplus capillaries and draining veins,and Compartment 5 is low flow-highvolume tissues plus capillaries anddraining veins. Top: Reservoirbreathing. Bottom: Free breathing.

Target Organ: Internal Organs, Total BodySource organ: high flow tissue. Àwas apportioned by frac

tional organ mass to each of the 18 internal organs in Table 3(including uterus and ovaries but excluding testes). Meanabsorbed doses for each target organ (Table 5) were calculatedusing individual organ-to-organ S-factors for 16 source organs

(except gallbladder and thymus) for which these data wereavailable. S-factors for total body were used for gallbladder

and thymus. Mean absorbed dose to total body was calculatedusing S-factors for each of 18 source organs to total body.

Source organ. Lung. S-factors for lung irradiating itself,

irradiating each of the target organs, and total body were used.Source organ. Low flow tissue. Àfrom low flow tissue was

treated as arising from total-body source. S-factors for total-

body irradiating itself and each of the target organs was used.Source organ. Blood. A from blood was apportioned into

four compartments according to the fractional blood volumecalculations described above (Table 4). A apportioned to highflow tissues was further divided among 16 source organs

(except lung and spleen) on the basis of fractional weight.Appropriate organ specific S-factors (total-body values for

gallbladder and thymus) were then used for all target organsand total body. Àfor low flow tissue was treated as arisingfrom total body source. Mean absorbed doses for each of thetarget organs as well as total body irradiating itself werecalculated. Since the S-factors for organs irradiating themselves assume 0np = 1, the dose from positron energy absorbed

into the blood for each organ (D9+) was subtracted from thetotal mean dose to that organ.

D0+ = ÄBX Anp(1.16X l(rV).

ÀBis the cumulated activity in blood ascribed to that organand 1.16 x 10~3g~' ¡s*„Pfor blood.

As Table 3 includes uterus and ovaries but not testes,radiation absorbed dose to testes was calculated as detailedabove after apportioning high flow tissue A and blood A

1966 Powers, Stabin, Howse et al The Journal of Nuclear Medicine

TABLE 5Radiation Absorbed Dose Estimates for Newborn Infants

TABLE 6Radiopharmaceutical Study Dose (Rad for 3.51-kg Infant)

VOrganAdrenalsBladder

wallBloodBrainStomachSmall

intestineUpper

largeintestineLower

largeintestineHeart

wallKidneysLiverLungsOvariesPancreasSkeletonRed

marrowSpleenTestesThyroidUterusTotal

bodySomatic

effectivedoseequivalentMaleFemaleDU/IIIWI

t\o)IntravenousH215O0.0520.0250.0430.0550.0460.0340.0500.0510.0590.0520.0540.0810.0500.0520.0210.0340.0820.0530.0510.0160.0230.0460.049InhaledC15O0.0500.0330.0880.0500.0450.0270.0450.0450.0400.0480.0500.220.0450.0480.0140.0280.180.0480.0480.00830.0230.0480.052Inhaled0'5O0.0460.0260.0540.0480.0420.0280.0430.0440.0390.0460.0480.190.0430.0460.0160.0280.100.0450.0450.0120.0220.0440.047H215OC'5O015O(0.7

mCi/kg) (1 mCi/kg) (1 mCi/kg)Totali

i in^i n OA r\ ~7~7 A c7 ^aLungu.¿u o.// u.o7 1.8

Spleen 0.20 0.63 0.351.2Totalbody 0.057 0.081 0.0770.22Lens

0.057 0.081 0.0770.22Redmarrow 0.084 0.098 0.0980.28Gonads

—Ovaries 0.12 0.16 0.150.43Testes

0.13 0.17 0.160.46Somaticeffectivedoseequivalent

Male 0.11 0.17 0.150.43Female0.12 0.18 0.170.47'

Due to low vascularity, absorbed dose to the lens is consid

eredto bethe sameasfor totalbody.as

total body, lens, red marrow, and gonads (Table6).Totalstudy mean absorbed dose from all three15Oradiopharmaceuticals

is estimated to be 1.6 rad tothelung(maximum organ dose), 1.2 rad to the spleen,0.22rad

to total body and lens, 0.28 rad to red marrow,and0.46rad to the gonads. Effective somatic dose equiva

lents are 0.43 rad for males and 0.47 rad forfemales.DISCUSSIONWe

have used available biologic data onnewborninfantsfor cumulated activity calculations. Theseare,of

course, mean values and biologic variability will

among the 16 somatic organs in Table 3 plus testes (0.80 g)in proportion to organ mass.

The somatic effective dose equivalent was calculated formales and females using age and sex specific organ weightingfactors for age group 0-9 yr (28).

RESULTS

All mean absorbed dose estimates (rad/mCi of administered activity) are summarized in Table 5. For allthree radiopharmaceuticals, the two organs receivingthe maximum absorbed dose are lung and spleen.

Our experience with rCBF measurements in newborninfant using i.v. H2'5O (4-7) has demonstrated that an

injected dose of 0.7 mCi/kg will produce images ofgood statistical quality on the PETT VI tomograph inthe low resolution mode (29) with collection times of40 sec. Based on our experience in adults, ~1.5 timesthe administered dose of H2'5O or 1 mCi/kg would be

necessary to achieve comparable quality images forC15O and O'5O. Using these estimates for a 3.51-kg

infant, we have calculated individual and total radio-

pharmaceutical study doses for lung and spleen as well

most notably fractional blood volume, specific data fornewborn infants were not available and adult data wereused. While these imperfect data are likely to producesome inaccuracies in our absorbed dose estimates, webelieve such inaccuracies will be small. Total bodyabsorbed dose estimates were conservatively based oninternal absorption of 93%-100% of cumulated admin

istered dose and could not be substantially greater. Theimpact of biologic variability was estimated by determining the effect of the observed threefold differencein vein to capillary circulation time (0.13-0.37 min) onabsorbed dose estimates for H2"O. Within this range

of time intervals, organ dose estimates vary by <5%from values computed using the mean value of 0.218min. Differences in fractional blood volume compartments between adults and infants are likely to havelittle effect. As discussed earlier above in relation to thecalculation of 4>npfor blood, even a shift of 50% of the

red cell mass in one compartment to another has littleeffect on absorbed dose calculations.

Kearfott (30) has reported radiation absorbed doseestimates for 70 kg adult human subjects following briefinhalation of CI5O and bolus injection of H2'5O. Our

values (rad/mCi A0) for mean absorbed dose to total

Volume 29 •Number 12 •December 1988 1967

body for the newborn infant are ~ 15 times greater. Thisis expected due to the twenty-fold difference in bodymass modified somewhat by a reduction in absorbedfraction of annihilation reduction due to smaller bodysize. These differences are reflected in the S-factors fortotal body irradiating total body, which is 16 timesgreater for newborn infants. Thus, the total-body absorbed doses for administered activity normalized tobody mass (A0/kg) are comparable. Our dose estimatesto specific organs for C15Oare also 10-20 times greaterthan Kearfott's, again reflecting differences in body andorgan sizes. For H2'5O, however, our organ dose esti

mates are up to 100 times greater. This greater difference is due to different assumptions about the distribution of radiolabeled water in the body. Kearfottassumed that cumulated radioactivity from H2'5O was

proportional to the water content of each organ. Whilethis may be true under equilibrium conditions, Cole-man et al. (20) have clearly demonstrated that the earlydistribution of radioactive water following i.v. injectionis primarily determined by organ blood flow not organwater content. With a short-lived radionuclide such as15O,this early distribution becomes of paramount im

portance, and we have incorporated this factor into ourcalculations. As a result, we have estimated a relativelyhigher dose to internal organs with high flow than theapproach used by Kearfott.

Based on our experience with PET measurements innewborn infants and adults, we have estimated theminimum necessary administered activity for eachradiopharmaceutical and calculated total mean absorbed dose for all three radiopharmaceuticals necessaryto measure rCMRO2 in newborn infants. Maximumorgan dose is 1.6 rad to the lung with 0.22 rad to totalbody (and lens), 0.28 rad to red marrow, and 0.46 radto gonads. These values are comparable to those forcurrent clinical nuclear medicine procedures using tech-netium-99m (99mTc)radiopharmaceuticals in newborn

infants (31). Total study effective somatic dose equivalents of 0.43 rad for males and 0.47 rad for femalescan be converted to estimated total lifetime excess fatalcancer risks of 0.005%-0.01% (28). Given the extentand severity of the clinical problems produced by cer-ebrovascular diseases in the newborn infant, this degreeof radiation risk seems reasonable for carefully designedand closely monitored research protocols that have thepotential to provide important information about thepathogenesis and treatment of these diseases.

APPENDIX

Distribution Volumes, Initial Conditions, and Rate Constantsfor Compartmental Models

I. H2150(Fig. 1)A. Interval from t = 0 to t = t' = 0.218 min

V, = Heart mass 24.1 g x fTBH2o = 17.8 ml

Lung mass 50.6 g x fTBH2o = 37.4 ml

fBVov x TBV x fBH2o = 61.1 ml

fBVLN x TBV x fBH2o = 45.1 ml

693.7mil0.930A,,1858.6

37.6

1896.2ml

161.4 mlq,(0) = Ao

ko. = a = 0.335 mirT1

k2i = k,2 = k,, = k,3 = 0

B. Interval from t = t ' to t = »

V, = HFM x fTBH2o = 501.0 ml

fBVHF x TBV x fBHjo = 192.7 ml

q,(t') = Aoe(-"5x2'8)

V2 = LFM x fTBH:o

fBVLF x TBV x fBH2o

«b(t')= 0koi = ko2 = «= 0.335 min"'

k2l = BF2/V, = 0.290 min"'

k,2 = BF2/V2= 0.106min-'

II. C'5O(Fig. 2)

V, = 50 ml

V2 = FRC = 105.3 ml

V3 = TBV = 303 mlA. Reservoir Breathing (t = 0 to t = t ' )

q.(0) = A«

q2(0) = qj(0) = 0

koi = ko2 = kos = «= 0.335 min"'

f. VT2, =-= 19.7 min"k2, =

k,, = 9.3 min-

DLCO•(Pa - PA„2o)~FRC

t' = l min

qi(t') = 0.001 Ao «0

B. Free breathing (t = t ' to t = «=)q2(t') = 0.002 Ao

q3(t') = 0.712 Ao

ko2 = kos = a = 0.335 min"'

k«= « 9.3 min-'

„- . ., ,„,. . .= 9.2 mm ' (Ref. 44)

k23 = ECO= 0.0025 min"'

DLCO . (P„- PAH;O)kî2= FRC = 9.2 min"'

1968 Powers, Stabin, Howse et al The Journal of Nuclear Medicine

III. 0150 (Fig. 3)

V, = 50 ml

V2 = FRC = 105.3 ml

V3 = TBV = 303 ml

V4 = 693.7 ml (Appendix IB)

V5 = 1896.2 ml (Appendix IB)A. Reservoir breathing (t = 0 to t = t ' )

1. Molecular O'5O

q2(0) = q3(0) = 0

= a = 0.335 min"'

k2, =-^= 19.7 min-'

f. VT-

Va= 9.3 min"

k32= Ao2/Aco.

k.3 + k53=

rKL.

T, = 0.568 min

k«= 0.568 min'1 •OMR/BMR = 0.528 min-'

k53 = 0.568 min"' - k«= 0.040 min"1t' = 1.5 min

2. Metabolized H2"O

q4(0) = q5(0) = 0le«= kos = «= 0.335 min"'

k43 = 0.528 min"'

k53 = 0.040 min'1

k45 = BF2/V5 = 0.106 min'1

k54 = BF2/V4 = 0.290 min'1

B. Free breathing (t = t ' to t = «>)

Initial values for q,, q2, q3, and q4 can be calculated fromtheir values at t' = 1.5 min using the equations above.

q,(f) = 0.0074 Aoq2(t') = 0.0143 Aoq3(t') = 0.321 Ao

q4(t') = 0.205 Ao

All values for k remain the same except that k2i = 0.

ACKNOWLEDGMENTS

This work was supported by NIH Grants NS06833,HL13851, Teacher Development Award NS00647 (Dr. Powers), Contract DE-AC05-75-OR00033 between the U.S. Department of Energy and Oak Ridge University, and Inter-agency Agreement FDA-224-75-3016.

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