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HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



hepatic escape of the dye during these procedures, 

 the agreement is remarkably good. Although these 

 comparisons have been limited to Bromsulfalein 

 there is no reason to suppose that rose bengal and 

 indocyanine green would not prove equally reliable. 



Of all the clearance materials at hand, BSP appears 

 at present to be clearly superior. Rose bengal as ob- 

 tained commercially is a mixture of several chro- 

 matographically separable components some of which 

 appear to be less readily cleared than others. Though 

 this defect is not important so long as hepatic extrac- 

 tion is determined, it may be troublesome. Composi- 

 tion varies from lot to lot with a resultant unpre- 

 dictable irregularity in extraction and removal rate. 

 The availability of I 13I -labeled rose bengal (91, 213) 

 simplifies analysis but does not compensate for the 

 other difficulties. Indocyanine green is most attrac- 

 tive for many reasons. It is easily and accurately 

 measured in the plasma; it is not conjugated, and it 

 does not enter the urine nor move perceptibly from 

 the plasma into any tissue other than the liver. Un- 

 fortunately, it is unstable on standing in aqueous 

 solutions, and may prove unsuitable, therefore, for 

 constant infusion. The chemical determination of 

 Bromsulfalein offers certain difficulties, since it is 

 difficult to remove the dye from the plasma proteins 

 and to eliminate interfering materials present in the 

 blank. It is possibly this factor that accounts for 

 Sherlock's (273) finding [which others (48, 77, 78) 

 have failed to confirm] that values for EHBF tended 

 to be excessively high when plasma BSP concentra- 

 tions were less than 1 mg per cent. Even a small 

 error in the determination of arterial and hepatic 

 venous concentrations may produce a large error in 

 the A-V difference. In any case, interference by 

 substances in the ""blank" can be avoided for all 

 practical purposes by appropriate dilution and use of 

 the Beckman DU spectrophotometer. 



A variety of other agents has been employed for 

 determining EHBF but none has won wide accept- 

 ance. Galactose has been found to be metabolized 

 by the liver alone with sufficient rapidity to permit 

 accurate measurement of extraction and computation 

 of hepatic removal at levels too low for significant 

 urinary loss (293). Metabolic changes may interfere 

 importantly, however. Alcohol has been suggested 

 for use in the same manner but more recent work 

 (191) has shown that it may be removed actively by 

 tissues other than the liver. Finally the role of the 

 liver as the major site of urea formation has been 

 exploited in the measurement of hepatic blood flow. 

 Urinary urea excretion has been taken as equal to the 



rate of hepatic synthesis and divided by the amount 

 of urea added to each milliliter of blood perfusing the 

 liver (the hepatic venous-arterial urea concentration 

 difference) to yield values for EHBF that agree with 

 those obtained by the BSP method (217). The diffi- 

 culties of analysis, correction for urinary delay, and 

 maintenance of a steady state, militate against its 

 routine use. Bromsulfalein appears to be relatively 

 innocuous. Anaphylactic reactions are exceedingly 

 rare (283) and occasional febrile responses appear 

 to be due to contamination during preparation. 

 Intense local inflammation follows extravasation of 

 BSP into the tissues. 



Single injection techniques. The hepatic ''clearance" 

 of any substance removed exclusively by the liver may 

 be computed from the change in plasma concentra- 

 tion with time, following intravenous administration 

 of a single dose. Here the word "'clearance" has been 

 used in a somewhat different sense than that out- 

 lined above. In renal physiology the term applies 

 to the amount of any material excreted in the urine 

 per minute relative to its concentration in each 

 milliliter of plasma. This ratio has the dimensions of 

 volume and is equivalent to the volume of plasma 

 that would have been " "cleared" completely of the 

 substance in question, if it had been completely ex- 

 tracted from each milliliter. But the clearance (195) 

 may also be computed from the falling plasma con- 

 centration following intravenous administration of a 

 single dose provided a) the disappearance follows a 

 simple exponential decay function : 



(when Co is the initial concentration, C\ the concen- 

 tration at time t, and k is the disappearance constant), 

 and b) the plasma volume of distribution (V) is 

 known. In this case clearance is equal to the product 

 of V and k, since /. is equal to the fraction of the 

 volume that is completely cleared. The constant k 

 is also often referred to, rather confusingly, as the 

 "fractional clearance." In the estimation of hepatic 

 blood flow by "single injection" it is necessary to 

 find substances that are removed by the liver alone 

 with almost 100 per cent efficiency, that are dis- 

 tributed within a determinable volume of distribu- 

 tion and that may be used for repeated determina- 

 tions. If a radioisotope could be employed as such, 

 or as a label for the ideal test material, changes in 

 plasma radioactivity might be followed by external 

 monitoring (over the thigh, for example), thus 

 eliminating the objectionable features of the "con- 



