CHAPTER III
Renal Function in the Severely Wounded
The desirability of measuring renal function as accurately as possiblein the severely wounded was clear at the outset of the study. In the majorityof cases this was done by determination of phenolsulfonphthalein excretorycapacity and by urine concentration tests, in conjunction with routineurine and blood chemistry analyses. Mannitol and sodium para-amino hippuratedid not become available for clearance measurements until the last weeksof 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 excretiontest was made postoperatively except on one patient who had no surgery,when it was done after transference from the shock ward, but in all casesit was some hours after the patient had been adequately resuscitated. Fifty-sevenpatients were tested, all of them within 72 hours after wounding, and someof them were tested again after the third day in order to follow theirrate of improvement. The latter group comprised 12 patients available forretesting out of 37 in whom dye excretion had been found low in the firsttest and 3 patients on whom the first tests had been made later than thethird day after wounding, but in whom the quantity of dye excreted wasstill low (Cases 125, 104, and 29 on Table 48).
Technique of Test.-The following technique of performing thistest1 was commonly employed. Six milligrams of phenolsulfonphthaleinwere injected
1See Appendix C for details of performing the test.
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intravenously and urine was collected 15, 30, 60, and 120 minutes later.It was necessary to use an indwelling catheter in almost every instanceto insure accurate collection. Oral intake of fluid was restricted in mostpatients at the time the test was performed; therefore, in order to promoteurine flow, infusion of 1 liter of 5-percent dextrose in isotonic salinesolution, or 10-percent dextrose in distilled water, was frequently startedabout 30 minutes before the dye was injected.
Excretory Capacity in the First 3 Days after Wounding.-The averageresults 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 percentageof dye excreted by the 20 patients who had not been in shock and that excretedby the 37 who had had slight, moderate, or severe shock. At all test periodsthe average excretion was normal for the group that had not beenin shock. (See also section to follow on the effect of anesthesia on thesepatients.) During the first 30 minutes, the average excretion was low forthe group that had been in shock, and decreased progressively with increasingseverity of initial shock. Although standard errors of the mean are ratherlarge, and although there are no significant differences between the threegroups with slight, moderate, or severe initial shock, the qualitativevariations are evident. After the first 30 minutes, average dye excretionbecame normal for all patients except the 14 who had been in severe shockat hospital admission. In them the average excretion was significantlyless 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 wouldbe expected, there was a rise in the number of patients who had had hypotensionon admission and the number who subsequently developed urinary suppressionand/or high azotemia.
Effect of Anesthesia.-One might argue that the diminished abilityto excrete phenolsulfonphthalein in these patients might have been largelyor partially an effect of the anesthetics employed, especially ether. Ourdata indicate that this is not true. Nineteen of the 20 patients shownin 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.
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CHART 13. PHENOLSULFONPHTHALEINEXCRETORYCAPACITY IN RELATION TO INITIALSHOCK
INCREMENTS of the percentage ofphenolsulfonphthalein excreted are represented. Findings are discussedin 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 theirexcretory capacity. If ether per se had any marked effect on dye excretion,it should have been evident in this group. Moreover, the average intervalbetween wounding and performance of the test (and thus between operationand performance of the test) in these 20 patients was much less than itwas in those who had been in shock and there was less time in which torecover from the effects of anesthesia had there been any. Another observationin support of the conclusion that anesthesia did not affect the abilityof the kidneys to excrete phenolsulfonphthalein was that excretion wasgreatly diminished in the crush case in which no anesthetic had been administered.
Rate of Improvement in Excretory Capacity.-The test was repeatedone or more times on 15 patients who showed a low rate of excretion whenfirst tested. Pertinent data on each of them are given in Table 48. Thirteenof these patients recovered (3 had the syndrome of recovery diuresis tobe described in
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TABLE 48.-PHENOLSULFONPHTHALEINEXCRETION AND RELATED DATAIN 15 PATIENTS ON WHOM THE TESTWAS REPEATED
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Chapter V). One patient died with alkalosis and renal failure, and theother died of peritonitis.
Inspection of this table shows that of 15 patients tested on the fourthor fifth day after wounding, 7 had normal excretion; in all 7 excretionhad been low during the first 3 days after wounding. Three had had moderateinitial shock, 2 slight shock, and 2 none. Of the 8 patients in whom excretionwas low on the fourth or fifth day after wounding, 3 had been tested forthe first time during this period, and 5 are known to have had diminishedexcretion during the first 3 days. The degree of shock on hospital admissionin 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 diminishedexcretion 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 abnormalexcretion on the twelfth and fourteenth days after wounding, respectively.
With the exception of one patient (Case 107) who died with alkalosisand renal failure, all patients in whom excretion was low on initial testsshowed improvement in excretory capacity, reflected chiefly in abilityto excrete increased quantities of dye during the first 30 minutes, althoughthe total quantities excreted also increased with passage of time.
The time required for phenolsulfonphthalein excretory capacity to returnto normal was well correlated with urinary output, nonprotein nitrogenretention, 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 regainedrenal function, as measured by phenolsulfonphthalein excretion, most rapidly.
Summary, P.S.P. Test
Phenolsulfonphthalein excretory capacity was determined during the first3 days after wounding in 57 patients. The test was made after resuscitationhad been effected and, with the exception of 1 patient who was not operatedupon, after surgery had been completed. In 20 of these patients who hadhad neither initial shock nor hypotension, the average dye excretion wasnormal. In the remaining 37, all of whom had been in various degrees ofshock, with hypotension occurring in 27, the average dye excretion waslow, especially during the first 30 minutes. The amount of dye cleareddecreased as severity of
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previous shock increased. In patients who had had slight and moderateshock, average excretion was abnormal only in the first 30 minutes; inthose 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 fourteenthpostoperative days on 15 of 37 patients in whom initial excretion had beenfound low. In 14 of them dye excretion returned to normal during this time.In those patients in whom impairment was only mild, kidney function wasapparently normal by the fourth or fifth day. In patients in whom it wasmore severe (e.g., in recovery diuresis) renal insufficiency, as gagedby phenolsulfonphthalein excretory capacity, persisted much longer.
Renal Clearance Studies
The majority of the severely wounded patients who died exhibited evidenceof renal insufficiency (see Chapter V). Histologic examination of the kidneysof these patients showed damage predominantly in the lower nephron andrelatively little evidence of glomerular damage (see Chapter IX). The anatomicfindings immediately raised the question of how closely functional impairmentcorresponded with anatomic alterations. One obvious approach to solutionof this problem was utilization of clearance methods of measuring renalfunction. This was done in 11 patients--a small series but the largestwe could obtain after the materials necessary for performance of the testsbecame 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 ofthese substances is discussed in Appendix C. Quantities given and ratesof administration were essentially those suggested by Goldring and Chasis.3Indwelling, multiple-eyed catheters were routinely employed. The bladderwas washed with 10 to 30 cc. of isotonic salt solution at the end of eachcollection period, followed by 10 to 20 cc. of air to insure complete emptying.
Renal clearance findings together with other pertinent data on the 11individual patients are shown in Table 49. Five patients were studied withinthe first 31 hours after wounding, but not until resuscitation had beeneffected 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.
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1 severe initial shock. None of them had high azotemia (a plasma nonproteinnitrogen 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 hadoliguria for 1 day (Case 142), but it was slight and can be disregarded.
The remaining six patients were first studied between 3 and 30 daysafter wounding. All of them had high azotemia at some time during theircourse. One had no initial shock, two moderate, and three severe shock.In three patients clearances were first measured while renal failure wassevere and repeated after recovery diuresis had taken place. A fourth hadhad severe renal failure, but clearance tests were not made until 30 daysafter wounding, by which time he had recovery diuresis and his plasma nonproteinnitrogen was normal. The remaining two patients died 16 hours and 5 days,respectively, after clearance studies were done; in both uremia was presentat the time of death but in neither was it an immediate or contributorycause of death.
Results
Charts 14 through 16, in each of which all 11 cases are included, wereconstructed from mean normals4 5 6and average values listedin Table 49. The 5 patients who did not have high azotemia are representedby 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--onlythe initial observation is shown. Chart 17 shows these initial values inaddition 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 studiedduring the early postoperative period who had had severe initial shock.In two of these five glomerular filtration rate and effective plasma flowwere in the low normal ranges. Marked diminution of both components inthe three patients (Cases 133, 138, 150) with severe renal failure is evident.There were lesser degrees of impairment in the two in whom renal failurewas 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.
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CHART 14. RELATIONSHIPBETWEENAVERAGEEFFECTIVEPLASMAFLOWAND GLOMERULARFILTRATIONRATEIN 5 PATIENTSWITHOUT AND 6PATIENTS WITHRENALFAILURE
THE VALUES represented in thisand in the succeeding two charts were obtained from average values shownin Table 49. The diagonal line shows normal filtration fraction (CM/CPAH.The solid and semisolid symbols represent patients with high azotemia andvarious degrees of renal failure; the open figures patients who at no timehad azotemia.
(Cases 143 and 147), and in the one (Case 125) who had fairly well recoveredfrom renal failure. The tendency of glomerular filtration rate and effective
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TABLE 49.-SUMMARY OF RENAL CLEARANCE STUDIES IN 11 PATIENTS
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plasma flow each to diminish proportionately was demonstrated by therelatively normal filtration fractions (CM/CPAH)in most cases.
Maximum Tubular Excretory Capacity (TmPAH)-Table49 and Chart 15.-There is wide variation in this measurement whichmay represent the actual amount of actively functioning tubular tissue,and is hence related to the functional size of the kidneys. It was significantlylow 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 andeffective plasma flow but normal Tm (Case 139). Relating plasma flow tomaximum excretory capacity (CPAH/TmPAH) providessubstantially an expression of the quantity of plasma cleared per unitof functionally active tubular tissue. The diagonal line in the chart isthe normal ratio. Ratios significantly
CHART 15. RELATIONSHIPBETWEENAVERAGEEFFECTIVE PLASMAFLOWAND MAXIMAL
TUBULAREXCRETORYCAPACITY
THE SYMBOLS for the individualcases represented are explained on Chart 14. The diagonal line representsCPAH/TmPAH.
Variation is wide, but noteworthyperhaps is the fact that all but two patients had normal ratios or ratiosless than normal.
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CHART 16. RELATIONSHIPBETWEEN AVERAGE GLOMERULARFILTRATION RATE AND MAXIMAL
TUBULAR EXCRETORYCAPACITY
THERE IS an unexpected tendencyfor the ratio of CM/TmPAH to be below normal. Thesymbols used for individual
cases are the same as those ofCharts 14 and 15.
below normal presumably indicate relative renal ischemia. It may besignificant that this ratio was normal or below normal in nine patients,and that it was lowest in the patient tested shortly after he had recoveredfrom 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 ofglomerular function per unit of functioning tubular tissue. Ratios belownormal presumably indicate greater relative impairment of glomerular functionthan tubular, and high ratios the reverse. Nine of the 11 patients hadeither a normal or low ratio, a fact which, if significant, is difficultto explain in view of the anatomic lesion in this type of case.
Rate of Recovery as Gaged by CM,CPAH, andTmPAH-Table49 and Chart 17.-Findings in three patients (Cases 133, 138, and150) who had severe renal failure but recovered (see discussion of recoverydiuresis in Chapter V) are
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CHART 17. SEVERERENAL FAILURE AND SUBSEQUENTRECOVERYDIURESIS;RATE OF RECOVERY (Case 133)
NOTE (1) the relatively proportionatereduction in glomerular filtration rate, effective plasma flow, and maximumtubular
excretory capacity, and (2) similarrecovery rates for all three.
shown in Table 49 and Chart 17 (Case 133). Initial observations weremade during periods of maximum failure, subsequent ones after recoveryhad largely taken place. In general, on the basis of clearance measurements,all portions of the nephron were about equally affected; recovery likewiseoccurred at about an even rate in all portions. Function was apparentlycompletely restored in one patient (Case 133) 49 days after wounding andpartially so in another patient 26 days after wounding.
Summary, Renal Clearance
Renal clearance was measured in 11 patients in this study. Of 5 testedwithin 31 hours after wounding, findings were essentially normal in four.The fifth patient showed significantly low rates of glomerular filtrationand effective
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plasma flow, but normal maximum tubular excretory capacity. He was theonly one studied in the early postoperative period who had had severe initialshock.
Six patients in whom high azotemia (a plasma nonprotein nitrogen levelof 65 mg. per 100 cc. or higher) developed were studied in various stagesof renal failure. The results suggest that in this type of renal insufficiencyall portions of the nephron suffer functional impairment, and that allportions regenerate at about an equal rate if recovery ensues. Evidencehas been presented that a relative renal ischemia may exist, but the numberof 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 functionin many cases. Restriction of fluids during the first few postoperativedays was almost always inadvisable for the patients` welfare. Pituitrinwas therefore employed, using the accepted method of administering 0.5cc. of posterior pituitary extract (10 units) subcutaneously and collectingurine specimens 1 and 2 hours afterward. However, many of the patientsin whom we should like to have known concentrating ability were daily receivingconsiderable quantities of sodium chloride intravenously. Since the antidiuretichormone may be ineffective during saline administration, there was concernthat in a large number of cases the pituitrin test would be complicatedby recent administration of isotonic saline solution, but in most instanceswe did not feel justified in requesting that the saline solution be withheld.
A compromise regimen was therefore established in which all parenteralfluids were withheld for 7 or 8 hours before the pituitrin was administeredwhenever such restriction clearly would not be harmful in any way to thepatient. Under these conditions a value for normal concentrating abilityis difficult to state; we have assumed that a specific gravity of 1.025or higher represents normal integrity of tubular reabsorptive capacityfor water. Data on the 32 patients in whom concentrating ability of thekidneys was tested in this manner during the postoperative days indicatedare shown in Table 50.
Of the 17 patients in whom we assumed there was no impairment of concentratingability (that is, the specific gravity of one hourly specimen was 1.025or higher) during the first week after wounding, 8 had had moderate orsevere
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TABLE 50.-RESULTS OF URINECONCENTRATION TESTS EMPLOYINGPITUITRIN-32 CASES
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shock and hypotension on admission. In 2 of these 17, high azotemiasubsequently developed. Of the 9 patients with slightly decreased abilityto reabsorb water from the kidney tubules (specific gravity of urine 1.018to 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 patientswith marked impairment of concentrating ability, 4 had had moderate orsevere shock, and 4 hypotension. Severe and prolonged azotemia developedin 5 of these 6; they are discussed in the section on recovery diuresisin 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 thefirst test, rose to l.020 two and seven days later, respectively. In oneit increased from 1.017 to 1.022 in three days. One of these three patientsalso had high azotemia and oliguria, and two had normal output of urineand a plasma nonprotein nitrogen level under 65 mg. per 100 cubic centimeters.The remaining five patients had recovery diuresis, and after periods offrom 14 to 40 days still were unable to produce a concentrated urine.
Although the series was small, it suggests that the concentrating abilityof the kidneys may follow somewhat the same pattern as ability to excretephenolsulfonphthalein, mannitol, and sodium para-amino hippurate. Abilityto make a concentrated urine appeared to diminish within 2 days followingshock, and improve over a period of from 3 to 7 days, unless renal failurewas severe (recovery diuresis) in which case maximum tubular reabsorptionof water remained diminished for many days or even weeks. In two patients(Cases 125 and 133) specific gravity remained fixed even after clearanceof mannitol and sodium para-amino hippurate had returned to normal.
COMMENT
It has been demonstrated by Lauson, Bradley, and Cournand7that during shock glomerular filtration rate and effective plasma floware reduced. These workers have also advanced evidence that reduction inrenal blood flow is partially explained by active vasoconstriction of therenal 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.
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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 impairmentin kidney function may persist for some days after shock is relieved, eventhough the usually accepted signs of renal failure (suppression of urinaryoutput, nitrogen retention) may be meager. These patients probably rapidlyregain normal kidney function.
If the initial insult, whatever it might have been, was great, the resultingrenal insufficiency was much more severe and prolonged, and in a significantproportion of cases resulted in death in uremia. A few patients, however,did recover, with gradually increasing function over a period of days toweeks, as indicated by their progress in restoration of ability to excretephenolsulfonphthalein, improvement in the glomerular filtration rate, andby increased effective plasma flow, maximum tubular excretory capacity,and concentrating capacity of the urine.
Although the histologic picture in fatal cases might suggest a selectivefunctional impairment of the lower nephron, our studies indicated thatall functional components of the kidneys were about equally impaired. Glomerularfiltration rate and effective plasma flow were reduced in essentially proportionatedegrees in most of the patients we studied. That there may have been somerelative renal ischemia in these cases is suggested by the fact that inthe few patients on whom clearance tests were done, the ratio of CPAH/TmPAHtended to be low. One bit of evidence in favor of greater relative insultin the lower nephron may be cited from the two patients in whom abilityto concentrate urine was still much impaired after clearances had returnedto normal. Mannitol measures glomerular filtration; sodium para-amino hippurateis believed to be excreted by the proximal tubules. Urine concentrationtakes place primarily in the distal tubule: The question arises whetherthis lag in recovery of concentrating capacity is a manifestation of greaterrelative damage to the lower nephron. The discrepancies between the physiologicand anatomic findings could perhaps be explained by the production in thesepatients of renal vascular shunts, such as Trueta8 and his associateshave recently demonstrated in animals. It is impossible to state from ourdata 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.
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SUMMARY
Renal function in the wounded man was studied by measuring phenolsulfonphthaleinexcretory capacity in 57 patients; glomerular filtration rate, effectiveplasma flow, and maximal tubular excretory capacity of para-amino hippuricacid in 11 patients, and urine concentration, employing pituitrin, in 32patients. All studies were made after resuscitation had been effected,and in all surgical cases after operation had been completed. The resultswere qualitatively similar and indicated that functionally all portionsof the nephron were about equally impaired for a period of a few to manydays, depending on the severity of the initial insult which in most patientsparalleled the degree of shock on admission. Similarly, diminished renalfunction, as indicated by these tests, was associated with correspondingincreases in the level of plasma nonprotein nitrogen and with decreasesin urinary output. When recovery occurred, improvement of most of thesefunctions proceeded at about an equal rate.
These physiologic findings do not correspond with the histologic findingsin fatal cases, where the lesion was observed predominantly in the lowernephron. The fact that ability to produce a concentrated urine was impairedin a few patients long after phenolsulfonphthalein excretion, glomerularfiltration rate, effective plasma flow, and maximum tubular excretion ofPAH had returned to normal might suggest greater relative damage to thelower nephron.
CASES OF SPECIAL INTEREST IN THIS CHAPTER
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
