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Chapter III



Renal Function in the Severely Wounded

The desirability of measuring renal function as accurately as possible in the severely wounded was clear at the outset of the study. In the majority of cases this was done by determination of phenolsulfonphthalein excretory capacity and by urine concentration tests, in conjunction with routine urine and blood chemistry analyses. Mannitol and sodium para-amino hippurate did not become available for clearance measurements until the last weeks of the Italian campaign. Results of the phenolsulfonphthalein, urine concentration, and the few renal clearance tests performed will be described.

Phenolsulfonphthalein Excretory Capacity

Because of practical considerations, the phenolsulfonphthalein excretion test was made postoperatively except on one patient who had no surgery, when it was done after transference from the shock ward, but in all cases it was some hours after the patient had been adequately resuscitated. Fifty-seven patients were tested, all of them within 72 hours after wounding, and some of them were tested again after the third day in order to follow their rate of improvement. The latter group comprised 12 patients available for retesting out of 37 in whom dye excretion had been found low in the first test and 3 patients on whom the first tests had been made later than the third day after wounding, but in whom the quantity of dye excreted was still low (Cases 125, 104, and 29 on Table 48).

Technique of Test.-The following technique of performing this test1 was commonly employed. Six milligrams of phenolsulfonphthalein were injected

    1See Appendix C for details of performing the test.


intravenously and urine was collected 15, 30, 60, and 120 minutes later. It was necessary to use an indwelling catheter in almost every instance to insure accurate collection. Oral intake of fluid was restricted in most patients at the time the test was performed; therefore, in order to promote urine flow, infusion of 1 liter of 5-percent dextrose in isotonic saline solution, or 10-percent dextrose in distilled water, was frequently started about 30 minutes before the dye was injected.

Excretory Capacity in the First 3 Days after Wounding.-The average results of the test made on 57 patients2 during this period, together with other pertinent data, are shown in Table 47 and Chart 13.

The most striking finding was the difference in the average percentage of dye excreted by the 20 patients who had not been in shock and that excreted by the 37 who had had slight, moderate, or severe shock. At all test periods the average excretion was normal for the group that had not been in shock. (See also section to follow on the effect of anesthesia on these patients.) During the first 30 minutes, the average excretion was low for the group that had been in shock, and decreased progressively with increasing severity of initial shock. Although standard errors of the mean are rather large, and although there are no significant differences between the three groups with slight, moderate, or severe initial shock, the qualitative variations are evident. After the first 30 minutes, average dye excretion became normal for all patients except the 14 who had been in severe shock at hospital admission. In them the average excretion was significantly less than normal even after 2 hours.

The table shows that as phenolsulfonphthalein excretory capacity diminished, not only did the severity of initial shock increase but also, as would be expected, there was a rise in the number of patients who had had hypotension on admission and the number who subsequently developed urinary suppression and/or high azotemia.

Effect of Anesthesia.-One might argue that the diminished ability to excrete phenolsulfonphthalein in these patients might have been largely or partially an effect of the anesthetics employed, especially ether. Our data indicate that this is not true. Nineteen of the 20 patients shown in Table 47 and Chart 13, who had neither initial shock nor hypotension, received ether anesthesia, either

    2Twenty-one of these are not included in the total series of 186 patients. They were added merely to enlarge the series of phenolsulfonphthalein tests without attempting to do complete studies. Seventeen of the 21 had no initial shock; 1 slight shock, and 3 moderate shock. Data on these additional cases were obtained from the 8th Evacuation Hospital.




INCREMENTS of the percentage of phenolsulfonphthalein excreted are represented. Findings are discussed in the text. (Minimum normal excretion from Stitt, E. R.; Clough, P. W., and Clough, M. C.: Practical Bacteriology, Haematology, and Animal Parasitology, 9th ed. Philadelphia, Blakiston, 1938, p. 733.)

alone or with sodium pentothal, and none showed any diminution of their excretory capacity. If ether per se had any marked effect on dye excretion, it should have been evident in this group. Moreover, the average interval between wounding and performance of the test (and thus between operation and performance of the test) in these 20 patients was much less than it was in those who had been in shock and there was less time in which to recover from the effects of anesthesia had there been any. Another observation in support of the conclusion that anesthesia did not affect the ability of the kidneys to excrete phenolsulfonphthalein was that excretion was greatly diminished in the crush case in which no anesthetic had been administered.

Rate of Improvement in Excretory Capacity.-The test was repeated one or more times on 15 patients who showed a low rate of excretion when first tested. Pertinent data on each of them are given in Table 48. Thirteen of these patients recovered (3 had the syndrome of recovery diuresis to be described in




Chapter V). One patient died with alkalosis and renal failure, and the other died of peritonitis.

Inspection of this table shows that of 15 patients tested on the fourth or fifth day after wounding, 7 had normal excretion; in all 7 excretion had been low during the first 3 days after wounding. Three had had moderate initial shock, 2 slight shock, and 2 none. Of the 8 patients in whom excretion was low on the fourth or fifth day after wounding, 3 had been tested for the first time during this period, and 5 are known to have had diminished excretion during the first 3 days. The degree of shock on hospital admission in the 8 patients had been severe in 3, moderate in 3, and slight in two.

Four patients were retested between the seventh and fourteenth days. One had normal excretion by the eleventh day; another had slightly diminished excretion only during the first 15 minutes of the test on the eighth day, and two who had recovery diuresis (Cases 60 and 125) still had abnormal excretion on the twelfth and fourteenth days after wounding, respectively.

With the exception of one patient (Case 107) who died with alkalosis and renal failure, all patients in whom excretion was low on initial tests showed improvement in excretory capacity, reflected chiefly in ability to excrete increased quantities of dye during the first 30 minutes, although the total quantities excreted also increased with passage of time.

The time required for phenolsulfonphthalein excretory capacity to return to normal was well correlated with urinary output, nonprotein nitrogen retention, and degree of initial shock and hypotension (Table 48). In general, those patients with a normal output of urine or only slight suppression, with minimal nitrogen retention, and only slight initial shock regained renal function, as measured by phenolsulfonphthalein excretion, most rapidly.

Summary, P.S.P. Test

Phenolsulfonphthalein excretory capacity was determined during the first 3 days after wounding in 57 patients. The test was made after resuscitation had been effected and, with the exception of 1 patient who was not operated upon, after surgery had been completed. In 20 of these patients who had had neither initial shock nor hypotension, the average dye excretion was normal. In the remaining 37, all of whom had been in various degrees of shock, with hypotension occurring in 27, the average dye excretion was low, especially during the first 30 minutes. The amount of dye cleared decreased as severity of


previous shock increased. In patients who had had slight and moderate shock, average excretion was abnormal only in the first 30 minutes; in those who had had severe shock it was low throughout the 2-hour period.

The test was repeated one or more times between the fourth and fourteenth postoperative days on 15 of 37 patients in whom initial excretion had been found low. In 14 of them dye excretion returned to normal during this time. In those patients in whom impairment was only mild, kidney function was apparently normal by the fourth or fifth day. In patients in whom it was more severe (e.g., in recovery diuresis) renal insufficiency, as gaged by phenolsulfonphthalein excretory capacity, persisted much longer.

Renal Clearance Studies

The majority of the severely wounded patients who died exhibited evidence of renal insufficiency (see Chapter V). Histologic examination of the kidneys of these patients showed damage predominantly in the lower nephron and relatively little evidence of glomerular damage (see Chapter IX). The anatomic findings immediately raised the question of how closely functional impairment corresponded with anatomic alterations. One obvious approach to solution of this problem was utilization of clearance methods of measuring renal function. This was done in 11 patients--a small series but the largest we could obtain after the materials necessary for performance of the tests became available.

Mannitol was used for measurement of glomerular filtration rate (CM), sodium para-amino hippurate for effective renal plasma flow (CPAH) and maximum tubular excretory capacity (TmPAH). Analysis of these substances is discussed in Appendix C. Quantities given and rates of administration were essentially those suggested by Goldring and Chasis.3 Indwelling, multiple-eyed catheters were routinely employed. The bladder was washed with 10 to 30 cc. of isotonic salt solution at the end of each collection period, followed by 10 to 20 cc. of air to insure complete emptying.

Renal clearance findings together with other pertinent data on the 11 individual patients are shown in Table 49. Five patients were studied within the first 31 hours after wounding, but not until resuscitation had been effected and operation completed. One of them had had no shock, 1 slight, 2 moderate, and

    3GOLDRING, W., and CHASIS, H.: Hypertension and Hypertensive Disease. New York, The Commonwealth Fund, 1944.


1 severe initial shock. None of them had high azotemia (a plasma nonprotein nitrogen level of 65 mg. per 100 cc. or higher) while we observed them. Output of urine was normal in 4 patients; one was listed as having had oliguria for 1 day (Case 142), but it was slight and can be disregarded.

The remaining six patients were first studied between 3 and 30 days after wounding. All of them had high azotemia at some time during their course. One had no initial shock, two moderate, and three severe shock. In three patients clearances were first measured while renal failure was severe and repeated after recovery diuresis had taken place. A fourth had had severe renal failure, but clearance tests were not made until 30 days after wounding, by which time he had recovery diuresis and his plasma nonprotein nitrogen was normal. The remaining two patients died 16 hours and 5 days, respectively, after clearance studies were done; in both uremia was present at the time of death but in neither was it an immediate or contributory cause of death.


Charts 14 through 16, in each of which all 11 cases are included, were constructed from mean normals4 5 6and average values listed in Table 49. The 5 patients who did not have high azotemia are represented by open symbols; the 6 who had renal failure by solid or semi-solid symbols. For Cases 138, 150, and 133--those with the lowest renal clearance values--only the initial observation is shown. Chart 17 shows these initial values in addition to results when the tests were repeated on 1 of these 3 patients.

Glomerular Filtration Rate and Effective Plasma Flow (CM/CPAH)-Table

49 and Chart 14.--These were definitely below normal in one patient (Case 139) 20 hours after wounding; he was the only one of the five studied during the early postoperative period who had had severe initial shock. In two of these five glomerular filtration rate and effective plasma flow were in the low normal ranges. Marked diminution of both components in the three patients (Cases 133, 138, 150) with severe renal failure is evident. There were lesser degrees of impairment in the two in whom renal failure was only coincident in death

    4 Ibid.
    5BERGER, E. Y.; FARBER, S. J., and EARLE, D. P., JR.: Renal excretion of mannitol. Proc. Soc. Exper. Biol. & Med. 66: 62-66, Oct. 1947.
    6CHASIS, H.; REDISH, J.; GOLDRING, W.; RANGES, H. A., and SMITH, H. W.: Use of sodium p-amino hippurate for functional evaluation of human kidney. J. Clin. Investigation 24: 583-588, July 1945.


THE VALUES represented in this and in the succeeding two charts were obtained from average values shown in Table 49. The diagonal line shows normal filtration fraction (CM/CPAH. The solid and semisolid symbols represent patients with high azotemia and various degrees of renal failure; the open figures patients who at no time had azotemia.

(Cases 143 and 147), and in the one (Case 125) who had fairly well recovered from renal failure. The tendency of glomerular filtration rate and effective




plasma flow each to diminish proportionately was demonstrated by the relatively normal filtration fractions (CM/CPAH) in most cases.

Maximum Tubular Excretory Capacity (TmPAH)-Table 49 and Chart 15.-There is wide variation in this measurement which may represent the actual amount of actively functioning tubular tissue, and is hence related to the functional size of the kidneys. It was significantly low in only the three patients with severe renal failure (Cases 133, 138, 150). It is of interest that the one patient with severe initial shock, who was studied 20 hours after wounding, had a low filtration rate and effective plasma flow but normal Tm (Case 139). Relating plasma flow to maximum excretory capacity (CPAH/TmPAH) provides substantially an expression of the quantity of plasma cleared per unit of functionally active tubular tissue. The diagonal line in the chart is the normal ratio. Ratios significantly

THE SYMBOLS for the individual cases represented are explained on Chart 14. The diagonal line represents CPAH/TmPAH.

Variation is wide, but noteworthy perhaps is the fact that all but two patients had normal ratios or ratios less than normal.


THERE IS an unexpected tendency for the ratio of CM/TmPAH to be below normal. The symbols used for individual

cases are the same as those of Charts 14 and 15.

below normal presumably indicate relative renal ischemia. It may be significant that this ratio was normal or below normal in nine patients, and that it was lowest in the patient tested shortly after he had recovered from severe shock (Case 139).

Relating filtration rate to maximal tubular excretory capacity (CM/TmPAH)

(normal ratio: the diagonal line in Chart 16) gives an expression of glomerular function per unit of functioning tubular tissue. Ratios below normal presumably indicate greater relative impairment of glomerular function than tubular, and high ratios the reverse. Nine of the 11 patients had either a normal or low ratio, a fact which, if significant, is difficult to explain in view of the anatomic lesion in this type of case.

Rate of Recovery as Gaged by CM,CPAH, and TmPAH-Table 49 and Chart 17.-Findings in three patients (Cases 133, 138, and 150) who had severe renal failure but recovered (see discussion of recovery diuresis in Chapter V) are


NOTE (1) the relatively proportionate reduction in glomerular filtration rate, effective plasma flow, and maximum tubular

excretory capacity, and (2) similar recovery rates for all three.

shown in Table 49 and Chart 17 (Case 133). Initial observations were made during periods of maximum failure, subsequent ones after recovery had largely taken place. In general, on the basis of clearance measurements, all portions of the nephron were about equally affected; recovery likewise occurred at about an even rate in all portions. Function was apparently completely restored in one patient (Case 133) 49 days after wounding and partially so in another patient 26 days after wounding.

Summary, Renal Clearance

Renal clearance was measured in 11 patients in this study. Of 5 tested within 31 hours after wounding, findings were essentially normal in four. The fifth patient showed significantly low rates of glomerular filtration and effective


plasma flow, but normal maximum tubular excretory capacity. He was the only one studied in the early postoperative period who had had severe initial shock.

Six patients in whom high azotemia (a plasma nonprotein nitrogen level of 65 mg. per 100 cc. or higher) developed were studied in various stages of renal failure. The results suggest that in this type of renal insufficiency all portions of the nephron suffer functional impairment, and that all portions regenerate at about an equal rate if recovery ensues. Evidence has been presented that a relative renal ischemia may exist, but the number of cases is too small for this to be of significance.

Urine Concentration Test

Although the value of the urine concentration test was self-evident, practical difficulties prevented our using it as a measure of renal function in many cases. Restriction of fluids during the first few postoperative days was almost always inadvisable for the patients' welfare. Pituitrin was therefore employed, using the accepted method of administering 0.5 cc. of posterior pituitary extract (10 units) subcutaneously and collecting urine specimens 1 and 2 hours afterward. However, many of the patients in whom we should like to have known concentrating ability were daily receiving considerable quantities of sodium chloride intravenously. Since the antidiuretic hormone may be ineffective during saline administration, there was concern that in a large number of cases the pituitrin test would be complicated by recent administration of isotonic saline solution, but in most instances we did not feel justified in requesting that the saline solution be withheld.

A compromise regimen was therefore established in which all parenteral fluids were withheld for 7 or 8 hours before the pituitrin was administered whenever such restriction clearly would not be harmful in any way to the patient. Under these conditions a value for normal concentrating ability is difficult to state; we have assumed that a specific gravity of 1.025 or higher represents normal integrity of tubular reabsorptive capacity for water. Data on the 32 patients in whom concentrating ability of the kidneys was tested in this manner during the postoperative days indicated are shown in Table 50.

Of the 17 patients in whom we assumed there was no impairment of concentrating ability (that is, the specific gravity of one hourly specimen was 1.025 or higher) during the first week after wounding, 8 had had moderate or severe




shock and hypotension on admission. In 2 of these 17, high azotemia subsequently developed. Of the 9 patients with slightly decreased ability to reabsorb water from the kidney tubules (specific gravity of urine 1.018 to 1.025), 8 had been in moderate shock, 5 had hypotension on admission, in 5 oliguria or anuria developed, and in 1 high azotemia. In the 6 patients with marked impairment of concentrating ability, 4 had had moderate or severe shock, and 4 hypotension. Severe and prolonged azotemia developed in 5 of these 6; they are discussed in the section on recovery diuresis in Chapter V.

The urine concentration test was made more than once in eight patients. In two of them the specific gravity, which was 1.018 at the time of the first test, rose to l.020 two and seven days later, respectively. In one it increased from 1.017 to 1.022 in three days. One of these three patients also had high azotemia and oliguria, and two had normal output of urine and a plasma nonprotein nitrogen level under 65 mg. per 100 cubic centimeters. The remaining five patients had recovery diuresis, and after periods of from 14 to 40 days still were unable to produce a concentrated urine.

Although the series was small, it suggests that the concentrating ability of the kidneys may follow somewhat the same pattern as ability to excrete phenolsulfonphthalein, mannitol, and sodium para-amino hippurate. Ability to make a concentrated urine appeared to diminish within 2 days following shock, and improve over a period of from 3 to 7 days, unless renal failure was severe (recovery diuresis) in which case maximum tubular reabsorption of water remained diminished for many days or even weeks. In two patients (Cases 125 and 133) specific gravity remained fixed even after clearance of mannitol and sodium para-amino hippurate had returned to normal.


It has been demonstrated by Lauson, Bradley, and Cournand7 that during shock glomerular filtration rate and effective plasma flow are reduced. These workers have also advanced evidence that reduction in renal blood flow is partially explained by active vasoconstriction of the renal blood vessels as well as by reduction of arterial pressure.

    7LAUSON, H. D.; BRADLEY, S. E., and COURNAND, A.: Renal circulation in shock. J. Clin. Investigation 23: 381-402, May 1944.


None of our studies were carried out while the patients were in shock. Those performed in the first few days after trauma suggest that the impairment in kidney function may persist for some days after shock is relieved, even though the usually accepted signs of renal failure (suppression of urinary output, nitrogen retention) may be meager. These patients probably rapidly regain normal kidney function.

If the initial insult, whatever it might have been, was great, the resulting renal insufficiency was much more severe and prolonged, and in a significant proportion of cases resulted in death in uremia. A few patients, however, did recover, with gradually increasing function over a period of days to weeks, as indicated by their progress in restoration of ability to excrete phenolsulfonphthalein, improvement in the glomerular filtration rate, and by increased effective plasma flow, maximum tubular excretory capacity, and concentrating capacity of the urine.

Although the histologic picture in fatal cases might suggest a selective functional impairment of the lower nephron, our studies indicated that all functional components of the kidneys were about equally impaired. Glomerular filtration rate and effective plasma flow were reduced in essentially proportionate degrees in most of the patients we studied. That there may have been some relative renal ischemia in these cases is suggested by the fact that in the few patients on whom clearance tests were done, the ratio of CPAH/TmPAH tended to be low. One bit of evidence in favor of greater relative insult in the lower nephron may be cited from the two patients in whom ability to concentrate urine was still much impaired after clearances had returned to normal. Mannitol measures glomerular filtration; sodium para-amino hippurate is believed to be excreted by the proximal tubules. Urine concentration takes place primarily in the distal tubule: The question arises whether this lag in recovery of concentrating capacity is a manifestation of greater relative damage to the lower nephron. The discrepancies between the physiologic and anatomic findings could perhaps be explained by the production in these patients of renal vascular shunts, such as Trueta8 and his associates have recently demonstrated in animals. It is impossible to state from our data whether such a mechanism was operative.

    8TRUETA, J.; BARCLAY, A. E.; DANIEL, P. M.; FRANKLIN, K. J., and PRICHARD, M. M. L.: Studies in the Renal Circulation. Springfield, Ill., Charles C Thomas, 1948.



Renal function in the wounded man was studied by measuring phenolsulfonphthalein excretory capacity in 57 patients; glomerular filtration rate, effective plasma flow, and maximal tubular excretory capacity of para-amino hippuric acid in 11 patients, and urine concentration, employing pituitrin, in 32 patients. All studies were made after resuscitation had been effected, and in all surgical cases after operation had been completed. The results were qualitatively similar and indicated that functionally all portions of the nephron were about equally impaired for a period of a few to many days, depending on the severity of the initial insult which in most patients paralleled the degree of shock on admission. Similarly, diminished renal function, as indicated by these tests, was associated with corresponding increases in the level of plasma nonprotein nitrogen and with decreases in urinary output. When recovery occurred, improvement of most of these functions proceeded at about an equal rate.

These physiologic findings do not correspond with the histologic findings in fatal cases, where the lesion was observed predominantly in the lower nephron. The fact that ability to produce a concentrated urine was impaired in a few patients long after phenolsulfonphthalein excretion, glomerular filtration rate, effective plasma flow, and maximum tubular excretion of PAH had returned to normal might suggest greater relative damage to the lower nephron.


P.S.P. Re-test

1 29 60 81 102 106 111

15 53 63 83 104 107 125 128

Renal Clearance Test

125 134 139 142 147

133 138 141 143 148 150