CHAPTER II
Liver Function in the Severely Wounded
Methods
The only specific laboratory test of liver function used in this studywas that of bromsulfalein excretion, although the van den Bergh index anduric acid levels were also considered in conjunction with liver activity.The test was selected because of facilities available and on the basisof experience of the group studying infectious hepatitis in the MediterraneanTheater of Operations.
Procedures
The standard procedure for the determination of bromsulfalein dye retention,using the Hynson, Westcott and Dunning Comparator Block, was abandonedfor the following reasons: Various degrees of hemolysis in the samplesof plasma would result in readings that indicated as much as 5-percentretention when no bromsulfalein was present. Therefore low-retention figurescould not be accurately determined, as results were often not reproducibleto 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 alkalinizedbromsulfalein at 575 millimicrons. Five milligrams of bromsulfalein dyeper kilogram of body weight were injected intravenously and 45 minuteslater 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 hydroxidewere added to the same tube; the tube was inverted once and was read inthe 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 normalfor our particular subjects who were all combat soldiers, 50 apparentlyhealthy men on active duty in the combat zone were selected at random asa control group. The men selected were hospital personnel, ranging in agefrom 19 to 45 years, the average age being twenty-nine. Forty-five minutesafter injection of bromsulfalein, 45, or 90 percent of the subjects, hadless than 3-percent retention of the dye, with an average retention of1.0±0.1 percent (standard error of the mean) for the group.
Five subjects, or 10 percent of the group, had more than 3-percent retentionof the dye after 45 minutes, as shown in Table 38. It seems reasonablethat the first three (Subjects A, B, and C) and possibly all five of thesemen 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 apparentlynormal liver function had less than 3-percent bromsulfalein retention 45min-
TABLE 38.-HIGH RETENTIONOF BROMSULFALEIN IN 5 SUBJECTS*OFCONTROL GROUP
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utes after 5 mg. per Kg. of body weight were injected, we arbitrarilychose 3-percent dye retention as the upper limit of normal.
Liver Function in Severely Wounded Patients on Entryto the Most Forward Hospital
The average severely wounded battle casualty showed considerable impairmentof 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 of3 percent. This finding was considered in connection with several factors.As in the entire study, the number of patients on whom various combinationsof findings are shown represent the maximum number available for that particularcomparison.
Relationship to Time from Wounding
Forty-eight patients were divided into two groups according to whetherliver function was measured (a) within the first 6 hours following woundingor (b) more than 6 hours after wounding. The average percentage of dyeretention 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 concludedthat there was no relationship between time from wounding and bromsulfaleinretention.
Relationship to Location of Major Wound
Twenty-two patients with severe extremity wounds had an average retentionof 13.3±2.3 percent; 18 patients with abdominal wounds 14.7±2.1percent, and 11 patients with chest wounds 7.0±1.8 percent. If aconclusion may be drawn from this small number of patients, those withchest wounds appeared to have significantly less dye retention than thosewith wounds of the extremities or of the abdomen. Patients with directinjury 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 patientswith direct liver damage, that the difference between the two groups cannotbe considered significant.
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CHART 9. COMPARISONOF DEGREE OF SHOCK, BLOODLOSS, AND LIVER FUNCTION
Relationship to Shock and Blood Loss
Whether liver malfunction increases with the presence and severity ofshock was considered. Bromsulfalein retention was measured in 57 patientsclassified according to degree of initial shock, and the mean values areshown in Table 39. The test was made, on the average, from 6 to 8 hoursafter wounding. No significant increase in bromsulfalein retention wasfound with increased severity of shock; in fact dye retention was justas high in the patients without shock as it was in those with slight ormoderate degrees of shock. Although a slight increase in retention is shownfor patients in severe shock, there was considerable spread in the bromsulfaleindata, as indicated by the large standard errors of the mean, and this increaseis not significant. It is possible that a larger series might have shownsome correlation with severe shock. As might be expected, there was alsono correlation of bromsulfalein retention with blood volume loss or totalhemoglobin loss (Table 40). Chart 9 compares this lack of correlation withthe high correlation between degree of shock and blood loss (volume andhemoglobin) 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 RETENTIONAND SHOCK
was just as much affected in those without shock as it was in thosewith severe shock. Shock therefore was evidently not the key to this condition.The great deterioration of the circulation found with increasing degreesof shock did not appear to strain liver function measurably insofar ascan be judged from these data. The main cause of the impaired functionmust be sought elsewhere.
Before it is assumed from these findings, however, that there was nomore impairment of liver function in those patients who had severe shockthan in patients without shock, the question should be raised as to whetherthe degree of liver impairment could be masked by the given dose of bromsulfaleinin a patient who, for example, had lost 50 percent of his normal bloodvolume. In this instance the given dose of dye would be abnormally concentrated,since it would be less diluted in the abnormally small volume of bloodpresent. Per-
TABLE 40.-BROMSULFALEIN RETENTIONAND BLOOD LOSS
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haps an impaired liver would be able to excrete a greater absolutequantity of such unusually concentrated dye (unusually concentrated becauseof the abnormally small total volume of blood diluting it) than it wouldif the usual dilution of the dye had occurred. If so, this conceivablycould mask liver impairment. Moreover, if normal circulation is preservedlonger in the liver than it is in other organs, then good excretion ofthe dye might occur even in the presence of abundant blood loss and severeclinical shock. While it seems unlikely that these factors could accountfor the apparent masking of liver impairment as a consequence of severeshock, they must be considered.
Effect of Blood Plasma Therapy on Liver Function
There seemed to be a significant increase in bromsulfalein retentionfollowing administration of one or two units (250-500 cc. total volume)of plasma (Table 41). However, there was no further increase after administrationof
TABLE 41.-EFFECT OF BLOODPLASMA THERAPY ON BROMSULFALEINRETENTION
three or more units. Whole blood, on the other hand, showed an oppositeeffect. At the time these bromsulfalein determinations were made, onlynegligible quantities of whole blood had been transfused. By the firstday following operation, large quantities of blood, up to several litersin given cases, had been transfused, yet dye retention was less than ithad been on the patients` hospital entry. The whole picture is puzzlingand one would like to see more data. If the increase in dye retention followingadministration of plasma was a real effect, it was a transient one, andif 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. BROMSULFALEINRETENTION AND PATIENTS` OUTCOME
Postoperative Course and Liver Function
In Table 42 liver function is considered in relation to the patient`soutcome. Average bromsulfalein retention, measured during the preoperativeperiod and the first 4 postoperative days, is shown for those who livedand those who, either in the period covered or subsequently, died, as wellas those who at this time or later developed "high azotemia."1The first group, showing bromsulfalein retention in those who lived, isthe only one in which the data can be considered in any satisfactory quantitativesense (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 appearedin many instances until considerably later than the time interval coveredby this table, the high bromsulfalein retentions of those who died in thefirst four or five days are masked by patients whose values were normalat this time but later became abnormal. The data shown in Table 42 aregiven, 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 RETENTIONAND PATIENTS` OUTCOME
So many factors influence the bilirubin and uric acid levels in theplasma that there is little point in discussing them in detail here; however,Tables 43
TABLE 43.-PLASMA URICACID LEVELS IN RELATIONTO PATIENTS` COURSE
and 44, Charts 11 and 12 are presented to show the trend of these substancesin the postoperative course of patients. One must assume that the transfusedblood had a considerable influence.
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TABLE 44.-PLASMA BILIRUBINLEVELS IN RELATION TO PATIENTS`COURSE
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CHART 11. PLASMAURIC ACID LEVELSIN RELATION TO PATIENTS`COURSE
CHART 12. PLASMABILIRUBIN LEVELS IN RELATIONTO PATIENTS` COURSE
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Effect of Ether Anesthesia on Liver Function
It has been repeatedly stated that liver function, as measured by bromsulfaleinretention, is considerably impaired by ether anesthesia. Tentatively acceptingthis statement, it was necessary to determine just how important this factormight be in causing bromsulfalein retention in our patients, for many ofthe patients with oliguria2 or anuria3 were not seenuntil after operation at which time bromsulfalein retention was usuallyhigh. Accordingly data were obtained on 42 patients prior to operationand again on the first day after administration of ether anesthesia. Inmost of the cases the test was repeated on the second and even on the thirdpostoperative day. The findings in the 42 individual cases are presentedin Table 45 and the averages are shown in Table 46.
It was observed that in the patients who were in grave condition followingoperation, as proved by their early deaths, the average percentage of dyeretention rose sharply. There were 8 of these moribund patients; they aregrouped separately on Table 46. Presumably the failing liver function inthese 8 cases was due to anoxia, but whatever its cause, the moribund patientsreacted so differently from the others that the findings when these 8 areeliminated from the total of 42 are also shown. Surely this grouping givesa more accurate picture of the effect, or lack of it, of ether on liverfunction. Since there was a decrease in average bromsulfalein retentionfollowing ether anesthesia in both the entire group and the patients whosurvived, the point of whether or not the moribund patients should be includedneed not be labored.
The failure of ether to produce an increase in bromsulfalein retentionwas of considerable surprise to us, and we are at a loss to explain whyour findings are the opposite of those reported by others. It must be takeninto account, however, that our first postoperative examination of liverfunction was 24 hours after anesthesia. The intervening time should bestudied, as healthy young soldiers may respond more quickly than averagecivilian patients. It may be stated, therefore, that so far as this studyis concerned, evidence of poor liver function in patients seen for thefirst time postoperatively is not to be explained as an effect of etheranesthesia.
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 46.-EFFECT OF ETHERANESTHESIA ON AVERAGE BROMSULFALEINRETENTION AND NONPROTEIN NITROGENLEVELS1
SUMMARY
Liver function in the severely wounded was measured by bromsulfaleinretention. In 90 percent of 50 apparently healthy soldiers, the averagebromsulfalein retention was found to be 1.0±0.1 percent 45 minutesafter 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 ofnormal retention was arbitrarily fixed at 3 percent.
Considerable impairment of liver function was observed in the newlywounded at the time of their arrival at a most forward hospital, the averageimpairment in 59 patients being 12.4±1.2 (standard error of themean) percent as measured by bromsulfalein retention. This finding hasbeen considered in connection with several factors:
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Time from Wounding.-No relationship could be found between timefrom wounding and bromsulfalein retention.
Location of Wound.-Patients with extremity wounds had the sameaverage retention (13.3±2.3 percent) as those with abdominal wounds(14.7±2.1 percent). Curiously, those with chest wounds seemed tohave less retention of the dye (7.0±1.8 percent) than those in theprevious categories. Patients with direct injury to the liver showed 18.4-percentaverage retention. It is doubtful if this is significantly higher thanthat found in other abdominal wounds, since there was considerable spreadin the data.
Shock.-No correlation between presence or degree of shock andliver function was shown, and, as might be expected, no correlation ofbromsulfalein retention with blood-volume loss or hemoglobin loss. Thegreat deterioration of the circulation found in patients in the more severeshock categories does not appear to strain liver function measurably insofaras can be judged from these data.
Plasma.-It was surprising that one of the great stresses placedupon the body, such as that due to shock, had little if any effect on liverfunction as measured by bromsulfalein retention, yet the administrationof 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 functionas measured by bromsulfalein retention is considerably impaired by etheranesthesia. In order properly to assess patients seen for the first timepostoperatively, liver function studies were carried out in 42 patientsbefore and after prolonged ether anesthesia. Contrary to other reports,we found in these patients at least a decrease in bromsulfalein retentionpostoperatively, except in those who were moribund. There is generallya sharp increase in bromsulfalein retention in patients whose conditionis deteriorating rapidly.
