The manner in which edema develops in dogs maintained on a diet low in protein is described. Pre-edematous fullness of the tissues is observed for some weeks before palpable edema develops. The state of pre-edema does not merge gradually with that of true edema but rather the transition is relatively sudden. Among twenty dogs the time required for the production of edema varied from 35 to 100 days and averaged 61 days. With three animals in which the nitrogen metabolism was studied during the period before edema had developed, the observed loss of weight was consistently less than the theoretical loss of weight calculated from the negative nitrogen balance. Reasons are given for interpreting the discrepancy as evidence of increasing retention of fluid during the stage of pre-edema. In general the weight curve does not rise during the transition from pre-edema to edema. However, the weight does increase rapidly when fluid is accumulating in the peritoneal cavity. The level of serum albumin which is critical for the development of edema varied between 1.04 and 2.17 gm. per cent. The range is sufficiently wide to suggest the existence of other factors of importance in determining the exact time of appearance of edema. During the phase of recovery the level of albumin which is critical for the disappearance of edema may be appreciably higher than the level which was critical for the formation of edema. Among thirty samples of edema fluid the protein concentration was from 0.02 to 0.72 gm. per cent. The average protein level was 0.230 and the median level 0.165 gm. per cent. A positive correlation is not demonstrable between the duration of edema and the protein content of edema fluid. A difference in behavior toward fluid retention between subcutaneous tissue and peritoneal cavity is pointed out. Subcutaneous tissue is more resistant to acute stress and less resistant to prolonged or repeated stress than the peritoneal cavity. The rôle of tissue pressure in the etiology of edema is discussed. It is suggested that the critical level of protein in the serum is the concentration which permits the attainment in the tissue spaces of mechanical pressure great enough to break down the restraining action of the connective tissue boundaries of the spaces.
1. The concentration of protein in the serum and plasma of normal dogs is given. Analyses of serum from 38 animals yielded the following averages and standard deviations, ( a ) for albumin: 3.26 ± 0.48 gm. per cent, ( b ) for globulin: 2.72 ± 0.76 gm. per cent, and ( c ) for total protein: 5.98 ± 0.67 gm. per cent. Analyses of plasma from 19 animals showed, ( a ) for albumin: 3.38 ± 0.38 gm. per cent, ( b ) for globulin: 2.98 ± 0.55 gm. per cent, and ( c ) for total protein: 6.36 ± 0.71 gm. per cent. 2. A diet for dogs is described, the feeding of which results in a progressive decline in the concentration of protein in the serum. A composite curve constructed from the findings with 21 animals discloses a rapid initial fall and a slower subsequent decrease in albumin and total protein and an approximately constant level for globulin. The course of the globulin curve was subject to wide variation in separate experiments, both increases and decreases being recorded. 3. With five dogs the nitrogen balance was followed through a total of 42 metabolism periods of approximately 7 days each. The average daily loss of nitrogen was 1.15 gm. Approximate calculations disclose that only 3 or 4 per cent of the nitrogen eliminated is accounted for by the decline in circulating protein, the remainder being represented by loss from the tissues. 4. An episode is described with one dog when, during a period of self-imposed fasting, the serum albumin regenerated to a normal level, apparently at the expense of catabolized tissue protein. 5. The course of serum proteins is described during the recovery which follows interruption of the low protein diet and return to a regime of adequate feeding. 6. A discussion is given of the relationship between tissue proteins and plasma proteins. The data permit one to entertain the hope that a way will be found for stimulating an internal readjustment to provide temporary relief from hypoproteinemia, a way which will depend upon the potential ability of the tissues to provide sufficient protein for the needs of the plasma.
1. The experimental observations have been summarized at the end of an earlier section. The more important facts only will be recapitulated here. The capacity of the lymphatics for removing fluid from the tissues greatly exceeds the rate at which freshly formed tissue fluid can be made available for removal. Edematous regions can be rendered non-edematous by the application of measures, such as massage, passive motion, or normal exercise, which activate the lymphatics. During continuous activity the rate of lymph flow is first variable and later relatively constant. Constant rates of flow must correspond to the production of fresh lymph. A study of the constant rates indicates that lymph formation in the edematous animal is certainly only slightly greater, and possibly not greater at all, than under conditions of normality. When the protein of plasma decreases, the protein of lymph is also lowered. The loss of protein from lymph takes place at a faster rate than from plasma, so that the ratio of serum protein to lymph protein is greater in the edematous than in the normal animal. In edematous animals the concentration of protein in lymph is of the same order of magnitude as the concentration in edema fluids. The two fluids are not, however, identical in composition. Minor fluctuations in the protein content of lymph always occur during a period of continuous collection. 2. The factors involved in the circulation and accumulation of tissue fluid are discussed. Reasons are given for offering the following suggestions. Significant differences in tissue pressure or tension exist between the states resulting from quiescence and activation of the lymphatics. The differences give rise to variations in the relative areas of capillary wall, functioning for filtration and reabsorption. When the lymphatics are activated it is possible that capillary reabsorption may be completely in abeyance. A decline in the proteins of plasma may be associated with a diminished permeability of the capillaries. Such a lowering of capillary permeability would account for two features, both of which have been demonstrated: (1) failure to observe an appreciably increased rate of lymph formation in the edematous animal, and (2) the extremely low concentration of protein in lymph from edematous animals. Although the difference between the protein concentrations of edema fluid and lymph from the same region is small, the conclusion is not yet justified that a similarly small difference exists between normal tissue fluid and normal lymph.