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SUPPLE MES TUM CCL S VI (266) PAPERS ON MEDICINE THE HISTORY OF MEDICINE PROFESSOR OF IS TER SAL MEDICINE OXHIS SISTIETH A X NIV ERSARY AC COMP A SIES VOL.CSLll(142)
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WITH AND IVITHOUT CHRONIC COSGESTIVE HE.4R’r F.41LURE1) A knowledge of the time a t which a tracer quantity of radiochloride, CP. becomes equally distributed throughout the chloride compartments of the body of man is important for a better understanding of chloride and electrolyte metabolism in normal and abnormal physiologic states. For example, in order to measure t h e size of the chloride space of m a n by means of the tracer method. one must know when the tracer quantity has reached equilibrium of distribution throughout the body. The time at which equilibrium of distribution is obtained may y a r j with the physiologic state of the subject; certainly it cannot be assumed that data for a normal subject will apply for an abnormal one a-nd vice versa. Efforts have been m a d e to measure the time a t which equilibrium of distribution is reached with the use of CP(til9 = 38 min.)as the tracing substance (10). Similar efforts have been made to measure chloride space with this same tracer. a measurement Xvhich cannot be accurate unless equilibrium of distribution of the tracer h a s been obtained (10). O a k Ridge, and with permission t o use it in man, it became possible to study phases of chloride metabolism which were not approachable with the use of ordinary chloride of the short-life isotope C P . A s a result of experiments designed primarilv to measure certain aspects of biologic decay rates and other phases of chloride tracer or non tracer phenomenon in man with a n d without chronic congestive heart failure, data were obtained which 1) Aided by grants from the Public Health Service (H-1431,the L‘. S. Atomic Energy Commission. the Life Insurance Sledical Research Fund. a N’ar Department (;ontract SO. IVD-49-007-!dD-389 and t h e hlrs. E. J. Caire Fund f o r Research in Heart Disease. 2) From the Department of Medicine, T u l a n e University School of hledicinc and Charity Hospital of Louisiana at S e w Orleans. Submitted for publication August 31, 1951.
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assist in cstirnation of the lime rcquircd for radiochloride to rcach Cquilihriuin of distribution in the chloride compartrncnls of man. Because these eaperinicnts were not dcsigncd to nicasure this tinic prcciscly, details are lacking and only certnin gcncralizations can hc made. T h c r e are thrce methods available for determination of the time at whlch equilibrium of distribution of electrolyte tracers occurs \vithin the electrolyte compartments of the body: (1) by measurement of the time at which the rate of disappearance from the serum of a n intravenous1~-administered tracer becomes constant, (2) by measurement of the time at which the serum concentration of a n intravenously administered electrolyte tracer reaches a fairly constant value and values of space calculated by the dilution technic become constant (correction being made for the tracer lost by excretion), and (3) by measurement of the time a t which the specific activity of the tracer becomes equalized throughout the respective electrolyte compartments of t h e body. T h e last of these three methods is t h e most direct but it is difficult to employ because so many different compartments must be studied. Furthermore, it is almost, if not, impossible to measure satisfactorily all the compartments of the body of intact living man.This method may iend itself, however, to the study of selected compartments. The first two methods, though somewhat indirect, are applicable to intact living man and are sufficiently accurate for most biologic purposes. These two methods were employed in these experiments. .4 known quantity of CP, approximately 0.05 mc.. was rapidly injected intravenously into 2 control human adults without edema, 2 with moderately severe chronic congestive h e a r t failure and 2 with severe chrcbnic congestive h e a r t failure. Clinical details for each subject are presented in Table I. These subjects had received controlled constant dietary intake of CI35 for several days prior to and throughout t h e experimental period, a n essential requirement for this type of analysis.’) Samples of blood were collected at intervals of seconds t o a few minutes during the first 2 hours immediately after administration of t h e tracer then again several hours later on the first day and then a t approximately 24 hour intervals thereafter. Collections were made under oil, the serum and cells were separated by centrifugation within a few minutes a f t e r collection of the sample. and the serum was prepared for counting. All urine, feces and body fluids, such as pleural and peritoneal fluid and vomitus, were collected and assayed. Body weight was recorded daily to the nearest one hundred grams. 1) The cooperation in these studies of Sister Euphemia and Misses Gloria Kicklighter and Jeanne Reid of the Dietary Department of Charity Hospital is greatly appreciated.
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Ihe tracer in the serum. - A s discussed previously 1 , 2. 3). when a single dose of a tracer is administered int ravenously. the tracer disa1)1wars from the plasliia rapidly at first. This rate of disappcarancc later dcclinc5. and becomes essentially constant if the subject is in a stead). state. that is, i f the size of the compartment of the element being traced rcmains constant. Initially t h e concentration of the tracer declines a t se\.eral exponential rates, ultimately diminishing at essentially a single exponential rate. The initial rates of disappearance are due to transfer of' the element heing traced into erythrocytes, leukocytes. interstitial fluid, a n d other intra- and extracellular conipartments of the body. Ultimately the distribution of the tracer within these compartments reaches a state of' equilibrium in a n exponential f a s h i o n ; the specific activity of the tracer is then equal throughout. At that moment the decline in concentration in the plasma becomes a n expression of the rate of loss froni the body as a wholc. which is essentially a single exponential phenomenon. At the moment when this occurs, equilibrium of distribution has been reached. This may be detected from a plot on a semilogarithmic graph a s the inoinent when the curve of concentration-time course becomes a straight line, or w h e n the slope becomes constant ;ind the straight line portion iiiay be exprcssed by the \vhere t is a unit of time. CSzl is the concentration of' the tracer a t a n y given time tz, CSl is the concentration a t any previous time tl, and the exponent 1) is a n expression of t h e slope of the line. Therefore, the value of b becomes constant w h e n equilibrium of distribution is achieved. To determine when equilibrium of distribution is reached, one iiieasurcs t h e concentration of the tracer in serum at knoyn intervals of time and calculates 11 from the equation Thc time ol occu rrcncc of cquilil)rium of dist rih tion inay also be estiiiinted from a scrnilognrithmic plot of the curve of the conccntration-time coursc the curve hecoincs a straight line or the slope becomes constant. In order to apply this method. the subject iiiust he in halance with his dietary intakc of the traced elcnient and thc size of thc compartment of the clement must he constant. 'This method offers oiic principal difficult!. duc to the fact that thc curve of the concentration-time course rcgrcsses h y many exponential phenomena v i t h extreme variations in ratc and inyolving considcra1)lc variation in
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compartnlent sizc. Hecauw 0 1 thcse factors. t h c dcclinc in conccntration Occurs exponentially. t h e change to a single exponential rate being so gradual that i t is impossible t o dcterniinc I’rcciscly when equilibrium of T h e time at \vhich cquilihriuni of distribution occurred \vas estiinated t)y careful inspection of the curves of t h e concentration-time course o f C13G in the serum and from plots of the time course of the values of the exponent b shown in equation ( 1 ) . Although only approximations were obtainable. these results have biologic applications. quantity of an electrolyte tracer, such3s CI”. is injected intravenously into man as a single dose. the electrolyte a t first migrates rapidly into the intra- and extracellular chloride-containing spaces o f the body. A t first there is dilution by the blood, with mechanical m i s i n g in the circulating blood, and then continued transfer and dilution bythe body fluids and “spaces” as a whole. TheCP, of course, finds its way into spaces containing the C P of the body. If the size of the chloride compartment of the subject is not changing and if hii intake and output of chloride remain equal, then the chloride space of the body may b e calculated in “serum equivalents” of space by dividing the serum concentration of the tracer into the total quantity of tracer remaining inthe body. This may be determined from moment t o moment by adequate recording of the loss of tracer from the body and the serum concentration of t h e tracer. T h e equation may he tracer injected - tracer excreted serum concentration of tracer where St is the chloride space atany time t. Obviously. a s the injected CP permeates more and more into the chloride spaces of t h e body, the concentration will.decline and the values of St \vi11 progressively increase. Once permeation h a s become complete and equilib r i u m of distribution has become established. St will reach a maximum and constant value. The time when this constant value first appears represents the time a t which equiiibrium of distribution first becomes established. Unfortunately. this moment is not attained suddenly, and no sharp detection of this point is possible. The time can, therefore. only be approximated. From tables and plots of the values of space with C13G as the tracer it \-.-as possible to approsimate t h e time a t which equilibrium of distribution of theCP occurred. Although this time \vas not precise to the hour. it was sufficiently accurate to h a v e biologic applications. (3) Sludy of specific acf iv if y .- As stated previously. when cquilibriuni of distribution of an electrolyte t r a c e r is reached within that elemental conipartmcnt of the body, the specific activity of the tracer becomes equal i n all compartments. This phenomenon. o f course, could not be studied in these intact patients for all com part ni ents ancl W.IS studied only for
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accurate for any given compartments but off crs piing compartments and accuratcI_v incas u ring sonic difficullics of Samthe tracer and non tr x cr Results of t h e studies a r e summarized by Figures 1 through 4 and (1) Sludy of the rules o f decrease in serum concenIrafion of CpG. - Figures 1and2 show the time course of the values of b, expressions of RATE OF CHANCE IN SE RUY CONCENTRATION OF CL " Fig. 1. - Time course of the values of the erponcnt bfor sir human subjecfs following a single intrauenotis adrninistrafion of CW.TWO were control subjects (.\os. 501 and 50.i). two patients had niodrrately seuere chronic connesliuc hrar! fn i lure (Sos. 502 and 50.5). and two patients had seuere chronic congesfiue heart iaiiure (Sos. 503 and 506). Equilibrium of distribution of the tracer elenirnt i s essrnlicilly prrsvnt wh1.n !he b ualues beconic consfnnt. I t is evident i rom these plots fh nt this tim r is not n delinitioe one and Fig. 2. - Time course off he mean ualues of the exponent b shooin in Figure Ifor the six can only br. approriniatcd, as was donc l o obtain the oaiues recorded in Table 11. subjects studied with CW. t h e rates of regression in concentration of CPG in serum. for the 6 subjects studied. No sharp break in these curves can be seen; only approximations arc obtainable (Table 11). They vary widely from subject to subject, and within the same subject n o specific timc can be presented. The average values result in smoother curves (Figure2)hut offer the same difficult?. a s to selection of a specific time. Table I1 indicates that equilibrium of distribution, recorded by values of b, was not reached before approsimately 36 hours (Subject So. 504) and may have required as long as 120 h o u r s (Subject S o . 5 0 5 ) . The data available did not permit establishing t h e point more accurately than within
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a 13 to 2-4 hour intcr\.al. This mcthod of apliroach also indicates that e~~uilibriillllof distrihution is established ahout 24 hours sooner i n sii1)jccts without edema t h a n in those with edema. IVhen all subjccts Lverc considered collectively. equilibrium of distribution proinbly did not occur until sometime bctwcen 72 and 96 hours. ( 2 ) Study of the time course of chloride s p a c e . - Figures 3 and 4 are plots of t h e time course of chloridc space. Froni thc plots for t h c 6 subjects studied (Figure3), it can be seen that the value of space does not become ninsimnl and essentially constant until aftcr 24 hours and \vas apparently obtained by 48 hours. Since samples of blood \vert collectcd a t 21 hour in tenn ls. the time cannot be determined more accurately. Figure 3 also shows t h e curves of mcan values for the 2 control subjects. the2 patients with moderately sevcre chronic congcsti\,e hcart failure and the2 sulijects with se\.ere congestive heart failure. They obviously do not differ in the time at \vhich equilibrium of distribution of C P \vas estimated to hsv c occurred. All the curves differed essentially only in the magnitude of the chlorige spacc for the subjects concerned. Figure 4 shmvs the curves of space-tiMe course for the subjects with and without edema and for d l subjects collectively. Equilibrium of distribution appears to have becn reached slightly earlier in the subjects without edema. si:e of CW space app ronch csa cons la nf value so grad ti ally thnl i f is not possible to cleferniinr sharply f he lime at which if is reached.The time at which a constan ! ualur is renchistl ran,f hc re for c,only be approximated. as was done too bf a in f he ualucs recorded
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Table I1 summarizes the time at which equilibrium of distribution \vas found to be reached by the method of study of the time course of chloride space. Apparently in all subjects it was reached sometime after 21 hours and not later than approximately 18 …
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