28 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



size takes no longer than in man (170) and in the dog 

 (78) is most unexpected. It is unfortunate that data on 

 mixing are not given in other studies on the cow (57). 

 Tlie mixing time for radio-iodinated albumin in the 

 rat averages about 3 min (196). An arbitrary 6-min 

 mixing time for all species was used by Courtice 

 (45) in his studies of T-1824 plasma volume in rabbits, 

 goats, dogs, and horses. 



If plasma labels such as T-1824 srid I"' albumin are 

 observed over a period of several hours or days, it 

 becomes clear that they do not begin to disappear at a 

 truly exponential rate immediately at the termination 

 of the initial period of rapid disappearance (75, 151, 

 176). The disappearance rate of all the common 

 plasma labels decreases progressively with time for a 

 fairly long period, to become exponential at a time 

 which differs for the different labels. In man, for 

 example, T-1824 does not begin to disappear ex- 

 ponentially until about the 7th day, whereas only 3 

 days are required for I"' albumin (75). The disap- 

 pearance rate of T-1824 in man, which is 4 to 10 per 

 cent for the first hour, has decreased to about 2 per 

 cent at the i6th hour (77). 



It is not, obviously, a simple matter to determine 

 just when plasma labels are completely mixed within 

 their circulatory distribution. Both during and after 

 the circulatory mixing period they are progressively 

 expanding their distribution to include ultimately 

 the entire extracellular, exchangeable protein pool. 

 Probably something like 60 per cent of this is extra- 

 vascular (24, 40). The ideal operational criterion for 

 mixing, the achievement of a constant rate of disap- 

 pearance, indicates that mixing is complete in the 

 total pool rather than in the circulatory system alone. 

 In using this criterion for circulatory mixing, accord- 

 ingly, it is necessary to assume that mixing in the 

 circulation is complete when the initial period of rapid 

 disappearance is terminated. 



Sequestration nj Cells and Plasma 



If significant volumes of red cells were permanently 

 immobilized anywhere in the circulatory system, they 

 would, of course, fail to mix with injected tagged cells, 

 and would accordingly escape measurement by 

 present methods. Temporary sequestration, on the 

 other hand, which should be demonstrable, has not 

 been observed in normal animals or men, since the 

 distribution volume of Fe^' cells remains constant for 

 days following their injection, after completion of the 

 initial mixing phase (104). Gibson and his collabora- 



tors (82) used cells tagged with two radioisotopes of 

 iron to show the completeness of cell mixing in normal 

 dogs. Three to five hours after an initial injection of 

 Pp55 ceiis^ cells tagged with Fe^' were injected, and i 

 hour later the animals were killed and the ratio 

 Fe^':Fe^= was determined in samples of a variety of 

 tissues. Since the ratio of the two isotopes was the 

 same as in blood drawn from the central circulation, 

 it was concluded that the more recently injected cells 

 had mixed thoroughly with those injected earlier. 



When arterial pressure has been lowered by hemor- 

 rhage or by certain other types of shock-producing 

 procedures, microscopic examination of the living 

 circulation in accessible vascular areas reveals marked 

 slowing and complete stoppage of flow in many small 

 vessels (130, 145, 245, 246). Attempts to measure the 

 volume of sequestered cells by distribution space 

 techniques, however, have given conflicting results. 

 That many cells injected into dogs in shock fail to 

 enter small vessels has been shown by the use of the 

 two iron isotopes. If Fe^^ cells are injected during the 

 normal state, and the animal is in shock when Fe^' 

 cells are given, the ratio Fe^':Fe" in tissue samples is 

 considerably le.ss than in blood and nearly half the 

 cells remaining in the circulatory system appear to 

 have stopped circulating (83). This estimate of cell 

 sequestration is considerably larger than the values 

 found by most other investigators (193). Some of the 

 differences may be attributed to differences in type 

 or severity of shock. Some may be due simply to differ- 

 ences in methods of reporting. Huggins and his col- 

 laborators (119), for example, in studies on acute 

 hemorrhage, reported that after approximately one- 

 half the total cells had been withdrawn, only 4 to 6 

 per cent of the total were unaccounted for by a second 

 tagged cell injection. This is some 8 to 1 2 per cent of 

 the cells remaining in the circulatory system. In 

 nembutalized dogs subjected to acute blood loss, cell 

 sequestration is demonstrable only when arterial 

 pressure has been lowered to 50 mg Hg or less. At a 

 pressure of 35 mm Hg, about 16 per cent of the cells 

 remaining in the circulatory^ system appear to have 

 stopped circulating (52, 1 19). 



A report that no cell sequestration is demonstrable 

 in rats subjected to tourniquet shock or to acute blood 

 loss is difficult to evaluate, as no data were reported 

 on arterial pressure (180). For the same reason, it is 

 not possible to judge whether conditions conducive to 

 cell sequestration were present in studies on man in 

 which large quantities of blood were impounded in the 

 extremities. The estimate of cell volume with carbon 

 monoxide was unchanstcd, although a longer mixing 



