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blood can be expected, even before the urine, to show evidence of failure of the organism to metabolize amino-acids with normal efficiency. The total non-protein nitrogen and urea nitrogen were also determined in most of the blood analyses.
As a measure of acidosis we have determined the volume percentage of carbon dioxide bound in the form of bicarbonate by the blood plasma7. Since all the reserve alkali of the blood, i.e. the alkali in excess of that combined with acids other than carbonic, take, the form of bicarbonates this figure indicates the alkaline reserve of the blood plasma, and of the body as a whole.
Urea was determined in both blood and urine by Marshall's urease method in the form developed by Van Slyke and Cullen.
Amino-acid nitrogen of the blood was determined after precipitation of proteins by alcohol, as described by Van Slyke and Meyer. The micro-amino apparatus was used, so that the determinations could be done on an amount of filtrate corresponding to 2 cc. of blood. As shown by Greenwald the proteins precipitated by alcohol absorb a portion of the amino-acid nitrogen, but the proportion is so constant that for comparative purposes the method is accurate.
Total non-protein nitrogen of the blood was determined by Folin10 micro-Kjeldahl determination on an aliquot portion of the alcoholic filtrate from the blood proteins.
Carbon dioxide capacity of the plasma was determined by Van Slyke's method 7.
The albumin of the urine was determined by a modification of Welker's method" as follows: Twenty-five cc. of urine were acidified with acetic acid and heated to coagulate the albumin. The volume of the solution then was brought to 50 cc. by the addition of an aluminum hydroxide suspension, prepared as described by Welker for absorption of proteins, and containing 0.5 per cent of AL2O2. The mixture was shaken and filtered through a folded filter. The nitrogen content was determined by Kjeldahl on 4 cc. of the filtrate, and on 2 cc. of the untreated urine. The difference indicated the albumin nitrogen.
The use of the aluminum hydroxide alone, without previous coagulation of the mass of the albumin, proved insufficient to remove all the albumin from some of the urines in which it was especially abundant.
The total amino-acid nitrogen of the urine was determined on 25 cc. of the albumin free filtrate by the gasometric method previously described, the urea being destroyed and conjugated amino-acids set free by heating with dilute sulfuric acid in an autoclave.
The ammonia was determined by Folin's aeration method, 5 cc. of saturated potassium carbonate solution being added to 5 cc. of urine, and the ammonia aerated into 0.02N hydrochloric acid.
DISCUSSION OF RESULTS.
Acidosis. Examination of between 20 and 30 normal plasmas by Van Slyke, Stillman, and Cullen, and of 30 by Gettler and Bailey12 have shown that 100 cc. of average normal plasma binds 65 cc. of CO2, no normal plasma showing a figure below 55 and very few above 75, the great majority ranging between 60-70. Our 14 cases of normal pregnancy all showed figures below the average normal of 65, and 10 of them were observed on at least one day to show figures below the minimum normal 55. Consequently we can agree with the conclusion reached as the result of their alveolar carbon dioxide determinations by Hasselbach and Gammeltoft, that a slight acidosis is usually present in even normal preg
Our cases of toxemia of both the eclamptic and vomiting type show little difference from noi mal pregnacy in their alkaline reserve. The same subnormal carbon dioxide is seen, but in no case does it approach. so low a value as 30 cc. of CO2 per 100 cc. of plasma, which experience with the acidoses of diabetes and nephritis indicates must be fallen below, before any but exceptional cases show serious distress or symptoms from acidosis per se.
The blood from the umbilical cord showed a bicarbonate content in only one case significantly different from that of the mother's blood. The results give no support to the presumption that the fetus elaborates amounts of acid sufficient to cause acidosis in the mother.
It is noteworthy that although the cases of pernicious vomiting show strikingly high ammonia figures, the plasma bicarbonate indicates no greater degree of acidosis than may be observed in non-toxic pregnancy A. W. Sellards mentions similarly a case of toxemia of pregnancy in which 40 per cent of the urinary nitrogen was ammonia but in which other evidence excluded acidosis13
Amino acids. In only 3 of the 23 cases of toxemia in which aminonitrogen of the urine was determined was the figure above the 3.6 per cent. the maximum noted in a previous series of normal men. In the 3 cases where a higher figure was observed the amino-nitrogen exceeded the usual limit by a margin smaller than the maximum observed either by K. W. Wilson or ourselves in normal pregnancy14. The results confirm those obtained by Murlin and Bailey with the formal method.
Not a single one of the 10 eclamptic women whose blood was examined for amino-nitrogen showed a figure outside the range 4-8 m.per. 100cc. noted by Ellis, Cullen and Van Slyke15, in a series of normal men. In brief, neither blood nor urine of eclamptic women shows as a rule an amino-acid content above normal limits.
Inspection of the other nitrogen figures of the urine shows that the urea in eclampsia is usually cases below the average normal, often strikingly so, even if calculated on the basis of total nitrogen of the urine
TABLE III. PLASMA BICARBONATE AND NITROGEN DISTRIBUTION OF URINE IN ECLAMPSIA.
Cc. CO2 bound by 100 cc. plasma
PLASMA BICARBONATE AND NITROGEN DISTRIBUTION OF URINE IN PERNICIOUS VOMITING.
Per cent of total N. as
Cc. CO2 bound by 100 cc. plasma
minus the albumin nitrogen. The only eclamptic urines which showed more than 70 per cent of urea nitrogen were those obtained one or more days post partum. The ammonia was often higher than the average in normal individuals, but the abnormality is less striking than that of the urea. The ammonia and urea ratios are suggestive of those which Nencki and Pavlov16, obtained from dogs from which the livers had been removed. All the cases of pernicious vomiting showed strikingly high ammonia percentages. It appears quite possible that this fact may be due, as pointed out by Underhill and Rand", merely to fasting, and that Williams' separation of pernicious vomiting cases into those of toxic and nervous origin18, according as the urinary ammonia is high or low, is not justified. Regardless of its etiological significance, however, the frequency of the appearance of high ammonia in pernicious vomiting (none of our six cases showed less than 16.9 per cent) must be admitted, to give to the ammonia ratio an undoubted diagnostic value.
The above findings concerning the ammonia and urea ratios in eclampsia and pernicious vomiting confirm the results of Ewing and Wolf.', In our five cases of non-toxic pregnancy the nitrogen ratios were normal.
The toxemias of pregnancy can be attributed neither to failure in diaminization of the amino-acids, nor to the moderate degree of acidosis observed. The nature of the toxin or toxins therefore remains unknown.
The nature of the functional disturbances which cause the abnormal nitrogen metabolism observed also still awaits a satisfactorily conclusive explanation. Nevertheless the constancy of the low urea ratios in the urine in eclampsia, and of high ammonia in pernicious vomiting, lends decided support to the opinion of Ewing and Wolf, that the nitrogen distribution of the urine, considered "in connection with all the data in the case", should assist in diagnosing the toxemias of pregnancy, and in differentiating them from conditions such as nephritis and transitory gastric disorders.
1. Ewing, J. and Wolf, C. G. L., Am. Jour. Obst., 1906, lv, 289. 2. Murlin, J. R. and Bailey, Jour. Am. Med. Assn. 1912, lix, 1522.
3. Hasselbach, K. A. and Gammeltoft, S. A., Biochem. Ztschr., 1915,
4. Zweifel, München. med. Wochenschr., 1906, liii, 297.
5. Levene, P. A. and Van Slyke, D. D., Jour. Biol. Chem., 1912, xii, 310.
6. Van Slyke, D. D. and Meyer, G. M., Jour. Biol. Chem., 1912, xii, 399.