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Chapter II

Contents

CHAPTER II

Liver Function in the Severely Wounded

Methods

The only specific laboratory test of liver function used in this study was that of bromsulfalein excretion, although the van den Bergh index and uric acid levels were also considered in conjunction with liver activity. The test was selected because of facilities available and on the basis of experience of the group studying infectious hepatitis in the Mediterranean Theater of Operations.

Procedures

The standard procedure for the determination of bromsulfalein dye retention, using the Hynson, Westcott and Dunning Comparator Block, was abandoned for the following reasons: Various degrees of hemolysis in the samples of plasma would result in readings that indicated as much as 5-percent retention when no bromsulfalein was present. Therefore low-retention figures could not be accurately determined, as results were often not reproducible to within ± 5-percent retention. Furthermore the method was time-consuming.

The test was set up on the Coleman Junior Spectrophotometer Model No. 6, using a 1:6 dilution of plasma, and reading the color of the alkalinized bromsulfalein at 575 millimicrons. Five milligrams of bromsulfalein dye per kilogram of body weight were injected intravenously and 45 minutes later a blood sample was drawn from a different vein. In brief, the procedure (fully described in Appendix C) was as follows:

    1. To 1 cc. of plasma in a cuvette were added 5 cc. of a 0.9-percent solution of sodium chloride. These ingredients were well mixed and the spectrophotometer was set to read 100-percent transmission at 575 millimicrons.

    2. Three drops of a 10-percent solution of sodium hydroxide were added to the same tube; the tube was inverted once and was read in the spectrophotometer.


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    3. The transmission percentage was observed and the percentage of dye retention recorded from the standard curve.

Standards of Normal and Abnormal Function (Controls)

In order to establish a standard of liver function that would be normal for our particular subjects who were all combat soldiers, 50 apparently healthy men on active duty in the combat zone were selected at random as a control group. The men selected were hospital personnel, ranging in age from 19 to 45 years, the average age being twenty-nine. Forty-five minutes after injection of bromsulfalein, 45, or 90 percent of the subjects, had less than 3-percent retention of the dye, with an average retention of 1.0±0.1 percent (standard error of the mean) for the group.

Five subjects, or 10 percent of the group, had more than 3-percent retention of the dye after 45 minutes, as shown in Table 38. It seems reasonable that the first three (Subjects A, B, and C) and possibly all five of these men may be considered to have had abnormal liver function of some degree, since the percentage of dye retention persisting after 45 minutes was "abnormally" high for this group. In any case, since 90 percent of men with apparently normal liver function had less than 3-percent bromsulfalein retention 45 min-

TABLE 38.-HIGH RETENTION OF BROMSULFALEIN IN 5 SUBJECTS* OF CONTROL GROUP


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utes after 5 mg. per Kg. of body weight were injected, we arbitrarily chose 3-percent dye retention as the upper limit of normal.

Liver Function in Severely Wounded Patients on Entry to the Most Forward Hospital

The average severely wounded battle casualty showed considerable impairment of liver function as measured by bromsulfalein retention on hospital entry. The average dye retention in 59 severely wounded patients was 12.4 percent ± 1.2 percent, which is well above the arbitrary normal limit of 3 percent. This finding was considered in connection with several factors. As in the entire study, the number of patients on whom various combinations of findings are shown represent the maximum number available for that particular comparison.

Relationship to Time from Wounding

Forty-eight patients were divided into two groups according to whether liver function was measured (a) within the first 6 hours following wounding or (b) more than 6 hours after wounding. The average percentage of dye retention was found to be: for (a), 14.4±1.8 percent (29 patients); for (b), 13.1±1.6 percent (19 patients). It was therefore concluded that there was no relationship between time from wounding and bromsulfalein retention.

Relationship to Location of Major Wound

Twenty-two patients with severe extremity wounds had an average retention of 13.3±2.3 percent; 18 patients with abdominal wounds 14.7±2.1 percent, and 11 patients with chest wounds 7.0±1.8 percent. If a conclusion may be drawn from this small number of patients, those with chest wounds appeared to have significantly less dye retention than those with wounds of the extremities or of the abdomen. Patients with direct injury to the liver had a somewhat higher average retention (18.4 percent) than those with abdominal wounds without direct liver injury (14.7 percent). However there was such a wide spread in the data, particularly in the patients with direct liver damage, that the difference between the two groups cannot be considered significant.


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CHART 9. COMPARISON OF DEGREE OF SHOCK, BLOOD LOSS, AND LIVER FUNCTION
 Relationship to Shock and Blood Loss

Whether liver malfunction increases with the presence and severity of shock was considered. Bromsulfalein retention was measured in 57 patients classified according to degree of initial shock, and the mean values are shown in Table 39. The test was made, on the average, from 6 to 8 hours after wounding. No significant increase in bromsulfalein retention was found with increased severity of shock; in fact dye retention was just as high in the patients without shock as it was in those with slight or moderate degrees of shock. Although a slight increase in retention is shown for patients in severe shock, there was considerable spread in the bromsulfalein data, as indicated by the large standard errors of the mean, and this increase is not significant. It is possible that a larger series might have shown some correlation with severe shock. As might be expected, there was also no correlation of bromsulfalein retention with blood volume loss or total hemoglobin loss (Table 40). Chart 9 compares this lack of correlation with the high correlation between degree of shock and blood loss (volume and hemoglobin) which was brought out in Chapter 1.

Liver function was clearly impaired in these severely wounded patients. It


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TABLE 39.-BROMSULFALEIN RETENTION AND SHOCK
was just as much affected in those without shock as it was in those with severe shock. Shock therefore was evidently not the key to this condition. The great deterioration of the circulation found with increasing degrees of shock did not appear to strain liver function measurably insofar as can be judged from these data. The main cause of the impaired function must be sought elsewhere.

Before it is assumed from these findings, however, that there was no more impairment of liver function in those patients who had severe shock than in patients without shock, the question should be raised as to whether the degree of liver impairment could be masked by the given dose of bromsulfalein in a patient who, for example, had lost 50 percent of his normal blood volume. In this instance the given dose of dye would be abnormally concentrated, since it would be less diluted in the abnormally small volume of blood present. Per-

TABLE 40.-BROMSULFALEIN RETENTION AND BLOOD LOSS


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haps an impaired liver would be able to excrete a greater absolute quantity of such unusually concentrated dye (unusually concentrated because of the abnormally small total volume of blood diluting it) than it would if the usual dilution of the dye had occurred. If so, this conceivably could mask liver impairment. Moreover, if normal circulation is preserved longer in the liver than it is in other organs, then good excretion of the dye might occur even in the presence of abundant blood loss and severe clinical shock. While it seems unlikely that these factors could account for the apparent masking of liver impairment as a consequence of severe shock, they must be considered.

Effect of Blood Plasma Therapy on Liver Function

There seemed to be a significant increase in bromsulfalein retention following administration of one or two units (250-500 cc. total volume) of plasma (Table 41). However, there was no further increase after administration of

TABLE 41.-EFFECT OF BLOOD PLASMA THERAPY ON BROMSULFALEIN RETENTION
three or more units. Whole blood, on the other hand, showed an opposite effect. At the time these bromsulfalein determinations were made, only negligible quantities of whole blood had been transfused. By the first day following operation, large quantities of blood, up to several liters in given cases, had been transfused, yet dye retention was less than it had been on the patients' hospital entry. The whole picture is puzzling and one would like to see more data. If the increase in dye retention following administration of plasma was a real effect, it was a transient one, and if real, might it have been due to the preservative used in the plasma, or to the foreign protein in pooled plasma?


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CHART 10. BROMSULFALEIN RETENTION AND PATIENTS' OUTCOME

Postoperative Course and Liver Function

In Table 42 liver function is considered in relation to the patient's outcome. Average bromsulfalein retention, measured during the preoperative period and the first 4 postoperative days, is shown for those who lived and those who, either in the period covered or subsequently, died, as well as those who at this time or later developed "high azotemia."1 The first group, showing bromsulfalein retention in those who lived, is the only one in which the data can be considered in any satisfactory quantitative sense (Chart 10). Not only are the cases relatively few in the other groups, but since death had not occurred nor had uremia or high azotemia appeared in many instances until considerably later than the time interval covered by this table, the high bromsulfalein retentions of those who died in the first four or five days are masked by patients whose values were normal at this time but later became abnormal. The data shown in Table 42 are given, however, because they do show qualitatively a typical trend.

    1In this study "high azotemia" was defined as a plasma nonprotein nitrogen level of 65 mg. per 100 cc. or higher at any time in the posttraumatic period.


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TABLE 42.-BROMSULFALEIN RETENTION AND PATIENTS' OUTCOME
So many factors influence the bilirubin and uric acid levels in the plasma that there is little point in discussing them in detail here; however, Tables 43

TABLE 43.-PLASMA URIC ACID LEVELS IN RELATION TO PATIENTS' COURSE
and 44, Charts 11 and 12 are presented to show the trend of these substances in the postoperative course of patients. One must assume that the transfused blood had a considerable influence.


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TABLE 44.-PLASMA BILIRUBIN LEVELS IN RELATION TO PATIENTS' COURSE


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CHART 11. PLASMA URIC ACID LEVELS IN RELATION TO PATIENTS' COURSE

CHART 12. PLASMA BILIRUBIN LEVELS IN RELATION TO PATIENTS' COURSE


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Effect of Ether Anesthesia on Liver Function

It has been repeatedly stated that liver function, as measured by bromsulfalein retention, is considerably impaired by ether anesthesia. Tentatively accepting this statement, it was necessary to determine just how important this factor might be in causing bromsulfalein retention in our patients, for many of the patients with oliguria2 or anuria3 were not seen until after operation at which time bromsulfalein retention was usually high. Accordingly data were obtained on 42 patients prior to operation and again on the first day after administration of ether anesthesia. In most of the cases the test was repeated on the second and even on the third postoperative day. The findings in the 42 individual cases are presented in Table 45 and the averages are shown in Table 46.

It was observed that in the patients who were in grave condition following operation, as proved by their early deaths, the average percentage of dye retention rose sharply. There were 8 of these moribund patients; they are grouped separately on Table 46. Presumably the failing liver function in these 8 cases was due to anoxia, but whatever its cause, the moribund patients reacted so differently from the others that the findings when these 8 are eliminated from the total of 42 are also shown. Surely this grouping gives a more accurate picture of the effect, or lack of it, of ether on liver function. Since there was a decrease in average bromsulfalein retention following ether anesthesia in both the entire group and the patients who survived, the point of whether or not the moribund patients should be included need not be labored.

The failure of ether to produce an increase in bromsulfalein retention was of considerable surprise to us, and we are at a loss to explain why our findings are the opposite of those reported by others. It must be taken into account, however, that our first postoperative examination of liver function was 24 hours after anesthesia. The intervening time should be studied, as healthy young soldiers may respond more quickly than average civilian patients. It may be stated, therefore, that so far as this study is concerned, evidence of poor liver function in patients seen for the first time postoperatively is not to be explained as an effect of ether anesthesia.

    2Oliguria was defined as a 24-hour urinary output of 100-600 cc. for at least 1 day in the posttraumatic period.
    3Anuria was defined as a urinary output of less than 100 cc. in 24 hours.


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TABLE 45.-ETHER ANESTHESIA IN RELATION TO BROMSULFALEIN RETENTION AND PLASMA NONPROTEIN NITROGEN LEVELS IN 42 PATIENTS


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TABLE 46.-EFFECT OF ETHER ANESTHESIA ON AVERAGE BROMSULFALEIN RETENTION AND NONPROTEIN NITROGEN LEVELS1
 SUMMARY

Liver function in the severely wounded was measured by bromsulfalein retention. In 90 percent of 50 apparently healthy soldiers, the average bromsulfalein retention was found to be 1.0±0.1 percent 45 minutes after intravenous injection of 5 mg. of the dye per Kg. of body weight. On the basis of the findings in this control group, the upper limit of normal retention was arbitrarily fixed at 3 percent.

Considerable impairment of liver function was observed in the newly wounded at the time of their arrival at a most forward hospital, the average impairment in 59 patients being 12.4±1.2 (standard error of the mean) percent as measured by bromsulfalein retention. This finding has been considered in connection with several factors:


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Time from Wounding.-No relationship could be found between time from wounding and bromsulfalein retention.

Location of Wound.-Patients with extremity wounds had the same average retention (13.3±2.3 percent) as those with abdominal wounds (14.7±2.1 percent). Curiously, those with chest wounds seemed to have less retention of the dye (7.0±1.8 percent) than those in the previous categories. Patients with direct injury to the liver showed 18.4-percent average retention. It is doubtful if this is significantly higher than that found in other abdominal wounds, since there was considerable spread in the data.

Shock.-No correlation between presence or degree of shock and liver function was shown, and, as might be expected, no correlation of bromsulfalein retention with blood-volume loss or hemoglobin loss. The great deterioration of the circulation found in patients in the more severe shock categories does not appear to strain liver function measurably insofar as can be judged from these data.

Plasma.-It was surprising that one of the great stresses placed upon the body, such as that due to shock, had little if any effect on liver function as measured by bromsulfalein retention, yet the administration of one or two units of blood plasma produced a considerable, although transient, increase in retention.

POSTOPERATIVE FINDINGS

Liver function during the postoperative course of the severely wounded, as determined by bromsulfalein retention and bilirubin and uric acid levels, is recorded.

The statement has been made repeatedly in the past that liver function as measured by bromsulfalein retention is considerably impaired by ether anesthesia. In order properly to assess patients seen for the first time postoperatively, liver function studies were carried out in 42 patients before and after prolonged ether anesthesia. Contrary to other reports, we found in these patients at least a decrease in bromsulfalein retention postoperatively, except in those who were moribund. There is generally a sharp increase in bromsulfalein retention in patients whose condition is deteriorating rapidly.

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