CHAPTER V
Clinical, Physiologic, and Biochemic Correlation inLower Nephron Nephrosis
The importance and frequent occurrence of renal failure in those battlecasualties who were severely wounded must be emphasized. In the precedingchapter the diagnosis of posttraumatic renal insufficiency was discussedfrom a clinicopathologic viewpoint. In this chapter an attempt will bemade to present a comprehensive picture of the physiologic and biochemicfeatures of the syndrome and their correlation with the clinical findings.
In studying these patients in whom renal insufficiency developed followingtrauma we have dealt with a unique group of individuals. They were nearlyall young men, and so far as was known, physiologically sound prior towounding. They had incurred severe wounds which almost immediately beganto cause changes in their internal environment. Because of the effectivenessof resuscitation and other early treatment, the wounds and the changesproduced were not severe enough to cause early death. These men withstoodoperation fairly well, largely because they had been adequately treatedpreoperatively, but beginning with the first day or two after operation(or after trauma, if no surgery was done) they began to show clinical andlaboratory evidence of inadequate renal function. The renal failure progressedrapidly and in most instances the patients either died in uremia within10 days or then began to show signs of improvement of renal function, suchas diuresis and clearance of nonprotein nitrogen, and subsequently recovered.
In selecting patients presumed to have diminished renal function, twomain criteria were utilized: the nonprotein nitrogen level in the bloodplasma, and the degree of urinary suppression. Much of the data presentedin this chapter will relate primarily to the patients with high azotemia,since this was a constant and generally reliable indication of renal insufficiency.In many instances the data
122
are also correlated with the degree of urinary suppression because alow urinary output provides a simple and useful clinical means of recognizingmany cases of impending renal failure. Our definitions of "high azotemia"and of oliguria and anuria have been given, and the diagnostic featuresof the syndrome were discussed in Chapter IV.
The incidence of high azotemia, oliguria, and anuria in our series isshown in Table 52. In 5 of the 186 patients no nonprotein nitrogen determinationswere made and in 50 the urinary output was unknown. Seventy-three of 181patients were found to have high azotemia. Thirty-three of 136 patientshad anuria for at least 24 hours, 45 oliguria (they did not reach anuriclevel at any time), and 58 had a normal output of urine. Of the patientswith high azotemia, 27 also had anuria and 29 oliguria.
TABLE 52.-PLASMA NONPROTEINNITROGEN LEVEL AND URINARYOUTPUT IN THE SEVERELY WOUNDED
Clinical Features
Case Fatality
Sixty-five of the 186 patients in the total series failed to survive.Of the 65 who died, 51, or 78 percent, were among those who had high azotemiaor urinary suppression or both. The serious implication of the onset ofthese conditions is well illustrated by Table 53. Of the 73 patients withhigh azotemia, 50, or 68 percent, died. Of 33 with anuria, 30, or 91 percent,died. This table likewise shows
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forcefully the importance of uremia as a primary cause of death in thesepatients; it was the primary cause of 34 (68 percent) of the deaths amongpatients with high azotemia and of 22 (73 percent) of the deaths amongpatients with anuria.
TABLE 53.-CASE FATALITYRATES AND TYPE OF DEATHIN ALL PATIENTS WITH AZOTEMIAAND/OR URINARY SUPPRESSION
Degree of Initial Shock
The relationship of the degree of shock on admission to subsequent developmentof renal failure is shown in Table 54. When the crush cases, a case oftrue transfusion incompatibility, and a case of sulfathiazole crystalluriain the group without shock are excluded, it becomes evident that a preponderanceof patients in whom signs of renal failure appeared were recognized ashaving had severe or moderate initial shock. With the above-mentioned casesexcluded, 86 percent of the azotemia group, 73 percent of the oliguriagroup, and 76 percent of the anuria group had had moderate or severe shockat the time of hospital admission. Many men may have had transient shock,even of several hours` duration, before hospital entry with no sign ofshock on entry. Our figures therefore are doubtless too low. It is not,however, clear that the severity of the renal lesion is entirely determinedby the degree of shock. This series includes a few patients (Cases 22,138, and 120) who, so far as we could determine, at no time had any appreciabledegree of shock yet who subsequently manifested renal insufficiency.
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TABLE 54.-RELATIONSHIP OFINITIAL SHOCK TO DEVELOPMENTOF RENAL INSUFFICIENCY
Survival Period after Wounding
The time of death after wounding was considered in 51 patients who hadrenal insufficiency (Table 55). Of these 51, uremia was the cause of deathin 35, a contributory cause in 3, and only coincidental in 13 patients.Of the 35 patients in whom uremia was the primary cause of death, 15, or43 percent, died in the first 5 days and 17, or 48.5 percent, in the second5 days--more than 91 percent within 10 days after wounding. Of the entiregroup of 51 fatalities, 94 percent (48 patients) died within the first10 days. The significance of this time factor will be illustrated in connectionwith the biochemic data and in the
TABLE 55.-PERIOD OF SURVIVALAFTER WOUNDING IN 51 PATIENTSWITH RENAL INSUFFICIENCY
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following chapter on therapy. Evidence will also be presented that ifpatients can be carried through this 10-day critical period, they standa fair chance of recovery. This point will be further discussed later;it emphasizes the importance of avoiding certain therapeutic errors whichcan result in death, such as overloading the circulatory system by administrationof too much fluid.
Type and Location of Wounds
The type and location of major wounds and injuries in patients withrenal insufficiency (as indicated by nonprotein nitrogen retention andurinary suppression) is shown in Table 56. In the former classification--thehigh azotemia group--peripheral wounds with fracture and intra-abdominalwounds are of equal frequency. In the latter, peripheral wounds predominatein the oliguria group whereas in the anuria group intra-abdominal woundsare somewhat more frequent. Thoracic wounds are third in all three groups.Wounds of the liver,
TABLE 56.-TYPE AND LOCATIONOF WOUNDS OR INJURIES INPATIENTS WITH RENAL INSUFFICIENCY
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kidneys, and urinary tract occurred, but not in a high percentage inany group.
Hypertension
Table 57 shows the number of patients having high azotemia who at sometime in their course also had a systolic blood pressure of 135 mm. Hg orhigher, or a diastolic pressure of 90 mm. Hg or higher. These figures representthe probable upper limits of normal for the age group into which our patientsfell. Blood pressures were recorded in 71 of 73 patients with high azotemia,67 being recorded within the first 7 days after wounding or injury, includingcrush injury. Hypertension developed in 44 patients, usually during thefirst week. In the few in whom it was first noted after this period, theprobability is that they also had an unobserved hypertension prior to thefirst determinations recorded. In general the blood pressure rose gradually,reaching a maximum between the third and sixth days after wounding. Thisagrees essentially with the time of maximum nitrogen retention in the blood.
Of the 27 patients who did not have hypertension, 20 died. Of these20, thirteen died within the first 4 days after wounding, three within6 days, and four between 6 and 10 days. Of those who died within a fewdays after wounding, many had never really recovered from shock. It seemsprobable that they would
TABLE 57.-INCIDENCE OF HYPERTENSIONIN PATIENTS WITH HIGHAZOTEMIA
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have developed hypertension if they had lived longer, especially thosein whom the primary cause of death was uremia.
Other Clinical Findings
Edema was observed in 23 of the 73 patients with high azotemia. Theedema varied in degree, but it was usually generalized, involving all extremitiesand the face. It was present in 18 patients who died. Three patients hadgeneralized convulsions. Eyegrounds were examined in 7 patients; 2 showedflame-shaped hemorrhages and 1 a small exudate. A pericardial frictionrub was heard in 1 patient who died of uremia, and pericarditis was foundon necropsy.
Biochemic and Physiologic Features
BLOOD
Biochemic Abnormalities
A large number of blood chemistry studies were made preoperatively andpostoperatively on the 73 patients with high azotemia. It was not possibleto make daily or even regular determinations on every patient, and thenumber of cases indicated in the various cells of the tables to followis conditioned by the available data. The plasma carbon-dioxide combiningpower, and the concentrations of plasma nonprotein nitrogen, chlorides,phosphate, protein, magnesium, phosphorus, creatinine, and uric acid, andof the serum sodium were determined. Average values are shown in Table58 A through G and Table 59. When more than 1 determination of any constituentwas made on any 1 patient during the postoperative periods specified inthe tables, only the most abnormal value was selected for inclusion inthe averages.
In both tables the data are presented in two ways: (1) on the basisof survival, and (2) on the basis of the daily output of urine. These findings,together with the changes in the urine (see Tables 75-77) to be discussedlater, reflect the typical biochemic and physiologic alterations whichoccurred in those of the severely wounded patients in whom renal insufficiencydeveloped. The data show the changes taking place during the acute phaseeither to the time of death or, in those who survived, through the recoveryphase as long as we could follow the case. Variations will be mentionedwhenever they are important.
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129
130
TABLE 58.-PHYSIOLOGIC ANDBIOCHEMIC FINDINGS IN PATIENTSWITH HIGH AZOTEMIA
C. Plasma Chlorides*
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TABLE 58.-PHYSIOLOGIC ANDBIOCHEMICFINDINGS IN PATIENTS WITH HIGHAZOTEMIA
D. Plasma Phosphate*
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TABLE 58.-PHYSIOLOGIC ANDBIOCHEMIC FINDINGS IN PATIENTSWITH HIGH AZOTEMIA
E. Plasma Protein*
133
TABLE 58.-PHYSIOLOGIC ANDBIOCHEMIC FINDINGS IN PATIENTSWITH HIGH AZOTEMIA
F. Serum Sodium*
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TABLE 58.-PHYSIOLOGIC ANDBIOCHEMIC FINDINGS IN PATIENTSWITH HIGH AZOTEMIA
G. Plasma Magnesium*
135
Nitrogenous Waste Products and Phosphorus
Nonprotein Nitrogen.-Averages of nonprotein nitrogen findingsare shown in Tables 58A and 59. Although the number is small and the variationgreat in some periods, giving rise to large standard errors, the data areadequate to give a fairly representative picture. Generally nitrogen retentionwas already significant by the first postoperative day, increased rapidlyduring the first 10 days, and then began to decline. This is illustratedin Chart 18, which has been constructed from averages shown in Table 58A,"All Cases."
CHART 18. PLASMANONPROTEIN NITROGEN INPATIENTS WITH HIGH AZOTEMIA
As previously discussed, most of the fatalities occurred in the first10 days, so the fall in nitrogen retention in the tenth through fifteenthdays chiefly represents patients who recovered. In general the nonproteinnitrogen level rose progressively to the day of death in those patientsdying primarily of uremia (Chart 19 and Table 60). However, two patients(Cases 66 and 93) who lived longer than 10 days after wounding (14 and13 days respectively) had begun to show some evidence of returning renalfunction. The importance of this fact in relation to therapy cannot betoo strongly emphasized: it is essential to avoid
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any measure that might precipitate death before this spontaneous recoverycan occur.
CHART 19. PLASMANITROGENOUS WASTE PRODUCTSAND PHOSPHORUS IN PATIENTS WHODIED OF UREMIA
Marked qualitative differences are clear between patients in the differentcategories shown in Tables 58, 59, and 60. In many instances the standarderror of the mean is large, indicating wide variation of values in thecases listed; also the number of cases in many categories is small. Differencesin degree of nitrogen
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retention seem to be evident, however, (1) between those who lived andthose who died of uremia, and (2) between those with a normal output ofurine and those with oliguria or anuria. The time of greatest retentionis essentially in the same periods as shown in Chart 18.
An attempt to determine whether the development of azotemia could becorrelated with the degree of initial shock was not successful. As wasmentioned previously, of the total number of patients who developed posttraumaticazotemia, oliguria, or anuria, a large proportion had had severe or moderateshock on hospital entry. A few patients who had no shock or only slightinitial shock (so far as we could determine) had subsequent renal insufficiency,and the renal failure was as severe as in those with previous moderateor severe shock. Similarly there was no evidence that nonprotein nitrogenretention was initially greater in patients who subsequently died of uremiaor who developed oliguria or anuria than it was in those whose renal failurewas less severe.
For those interested in further differences between categories of patientsand in day-to-day changes in the nonprotein nitrogen and other constituentsof the plasma, the detailed analyses in Tables 59 through 62 are included.The essential trends are illustrated in the charts; minor variations areevident in the tables. The lack of effect of ether anesthesia on nonproteinnitrogen levels was discussed in Chapter II.
Creatinine and Urea.-In general, creatinine rose in the plasmaat about the same rate as the nonprotein nitrogen (Chart 19). Also, aswith other nitrogenous products and the electrolytes, there was no correlationbetween the degree of initial shock and elevation of creatinine duringthe period of posttraumatic renal failure. The plasma urea nitrogen levelwas determined simultaneously with total nonprotein nitrogen and creatininein 15 cases (Table 63). Like creatinine, it rose approximately as the totalnonprotein nitrogen rose. The relationships of these three substances whennonprotein nitrogen was elevated are shown in the table. The averages wereobtained by using 38 determinations from a larger series on 15 patients,but including only those in which the nonprotein nitrogen was over 100milligrams per 100 cubic centimeters. When more than 1 determination wasincluded from the same patient, the samples were drawn at least 24 hoursapart.
Although all waste products which make up the total nonprotein nitrogenrose in our patients, they did not accumulate in exactly the same proportionsseen in the normal individual, if these figures represent a fair sample.However,
138
139
140
141
142
it would appear that both creatinine and urea make up a greater proportionof the total nonprotein nitrogen in patients with severe renal failurethan in the normal individual.
Excretion of Urea and Creatinine.-In two patients who died inthe first 6 postoperative days, 24-hour urea nitrogen and creatinine excretionwas measured. The relationships of the total amounts of these substancesin the urine to plasma nonprotein nitrogen levels, urine specific gravity,and output of urine in these two patients are shown in Table 64.
The relationship of rising plasma levels of nitrogenous waste productsto low or decreasing urinary excretion of these same substances is distinctlyshown. The fall in output and specific gravity of the urine is directlyrelated to these changes. Twenty-four hour specimens were examined alsoin two patients who had recovery diuresis and will be discussed under thatsubject later in this chapter. One of these patients also showed diminishedtotal excretion; the other was examined after his recovery and values wereessentially normal.
Phosphorus.-The characteristic retention of phosphorus in renalfailure was
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TABLE 60.-AVERAGE PLASMANITROGENOUS WASTE PRODUCTSAND PHOSPHORUS IN PATIENTS WHODIED OF UREMIA
also observed in our cases, and in general paralleled the degree ofnitrogen retention (see Chart 19 and Tables 58A, 58D, 59, 60, 61, and 62).In these patients with posttraumatic azotemia, phosphorus retention wasprimarily due to impaired ability to excrete that substance; whereas thehyperphosphatemia seen in patients in shock soon after wounding was possiblydue to release of phosphates secondary to muscle damage (Chapter I). Referenceto Tables 58 through 62 and to the individual case records shows that thepatients with the most severe renal damage had the greatest phosphorusretention.
Relationship of Calcium and Phosphorus.-Calcium and phosphorusdeterminations were made on 12 patients who had high azotemia. The well-knownreciprocal relationship of calcium and phosphorus was present in the majorityof these cases (Table 65).
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TABLE 61.-AVERAGE NONPROTEINNITROGEN AND ELECTROLYTES OFPLASMA IN PATIENTS IN
WHOMOLIGURIADEVELOPED
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TABLE 62.-AVERAGE NONPROTEINNITROGEN AND ELECTROLYTES OFPLASMA IN PATIENTS IN
WHOMANURIADEVELOPED
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TABLE 63.-RELATIONSHIP OFPLASMA TOTAL NONPROTEINNITROGEN, UREA NITROGEN,AND CREATININE IN 15 PATIENTS
TABLE 64.-RELATIONSHIP OFURINARY NITROGENOUS WASTEPRODUCTS AND URINARY EXCRETIONIN 2 FATAL CASES
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TABLE 65.-RELATIONSHIP OFCALCIUM AND PHOSPHORUS IN 12PATIENTS WITH HIGH AZOTEMIA
Uric Acid.-This substance, like phosphorus and creatinine, rosein patients with high azotemia as the nonprotein nitrogen did, and in roughlythe same proportion while retention of both progressed with renal failure(Chart 19 and Tables 59 and 60). Here also the number of determinationswas rather small in most categories, but the tendency for greatest retentionof uric acid in those patients who had the most severe renal insufficiencywill become apparent by in-
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spection of the tables and from the individual case records. The elevateduric acid seen in admission cases has been previously discussed and possiblemechanisms for it mentioned in Chapter I.
Summary-Nitrogenous Waste Products
The nitrogenous waste products and phosphorus of the blood plasma allshowed progressive retention as renal insufficiency which follows shockor trauma proceeded. In patients with high azotemia the maximum retentionwas observed between the sixth and tenth postoperative days. The majorityof deaths occurred during this period also. Average values for nitrogenouswaste products fell from the tenth to the fifteenth days, representinglargely patients who recovered. The few patients who died after the tenthday usually showed progressive nitrogen retention up to the day of death,but in a few a falling nonprotein nitrogen level and rising urine outputindicated beginning recovery even though they subsequently died of uremia.These time factors emphasize the importance from a therapeutic standpointof making every effort to carry the patient through the critical first10 days until the kidneys begin spontaneously to recover.
Acid-Basc Balance
Anions
Plasma Carbon-Dioxide Combining Power and Blood pH.-The onlygroup with a sufficient number of determinations of combining power fordependable averages was that of "All Cases" of high azotemia from Table58B. In these patients, initial low values were followed by a rise towardnormal (normal range: 24-31 mEq./L.) during the first 4 postoperative daysand a subsequent gradual fall during the next 12 days (Chart 20). A breakdownof these averages according to types of cases does not yield differenceswhich are statistically significant. However, in general, those patientswho had the most nitrogen retention, those who died in uremia, and thosewith oliguria or anuria tended to have the lowest values for carbon-dioxidecombining power. Conversely, the patients with the least nitrogen retention,those who survived and who had a normal output of urine, tended to havenormal values. There was no correlation of carbon-dioxide combining powerwith degree of shock after the preoperative day. The acidosis seen in patientswho were in shock when they were admitted to the hospital was discussedin Chapter I. Evidence that a low carbon-dioxide combining
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CHART 20. PLASMACARBON-DIOXIDE COMBININGPOWER IN HIGH AZOTEMIA
power was a result of diminished alkali reserve in these patients isonly indirect.
The pH of the venous blood was measured in five patients who simultaneouslyhad low carbon-dioxide combining power and renal failure. The results wereas follows:
|
Case No. |
Plasma CO2 Combining Power |
Blood pH |
|
69 |
23 |
7.39 |
|
90 |
20 |
7.37 |
|
93 |
16 |
7.31 |
|
112 |
20 |
7.04 |
|
133 |
21 |
7.32 |
From the limited number of cases in which a blood pH determination was done, and from the indirect evidence to be cited later, it seems likely that there was a metabolic acidosis in the majority of cases. If the low carbon-dioxide combining power had been due to respiratory alkalosis, one would expect to see clinical evidence of hyperventilation and possibly an alkaline urine, depending on the renal function. None of our patients had either. Furthermore, in such cases the blood pH, although probably in the normal range (7.38-7.48), would be in the upper limits of normal. Obviously we do not have enough pH determinations to draw any definite conclusions, and those we do have were made on venous
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CHART 21. HYDROGEN-IONCONCENTRATION OF URINE IN HIGHAZOTEMIA
blood, but they support the view that most of these patients were sufferingfrom a metabolic acidosis. This acidosis was not of the hyperchloremictype. For further discussion, see the following sections on chlorides andsodium.
The range of the pH of the urine in patients with high azotemia gaveat least a partial explanation for the acidosis; after the first postoperativeday none of the patients was able to produce a urine more acid than pHof 6.0 despite an increasingly severe acidosis. In those in whom renalfailure was most severe--those who died of uremia--this abnormality waseven more evident (Charts 20 and 21). The inference here is that thosemechanisms responsible for acidification of the urine, such as tubulartransfer of hydrogen ion, were impaired. This subject will be discussedfurther in the section on Urine; average urine pH is shown in Chart 21and Table 76. Measurements of urinary ammonia were too few to say whetherthe deficient formation of this base was also responsible for the acidosis.
Plasma Chlorides.-The relationship of the plasma chloride levelto the severity of renal failure is shown in Chart 22 and Table 58C. Theaverages of all patients with high azotemia show progressive hypochloremiathrough the first 10 postoperative days and normal values after this time(normal range:
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CHART 22. PLASMACHLORIDES IN HIGH AZOTEMIA
97.5-104). Of the patients who died in uremia, the average values showthat an extreme hypochloremia was reached by the tenth day; only one ofthese patients survived longer than that day. Average values for patientswho lived were only slightly low during the period of greatest nitrogenretention. Analysis of individual case records shows that the lowest plasmachloride levels usually occurred in those patients who died before thetenth day, and the rise in the level from the eleventh through the fifteenthday occurred largely in those patients who had a recovery diuresis or onlyminimal azotemia.
Relationship of Low Plasma Chloride Levels to Intake of Sodium Chloride.-Themechanism of the hypochloremia in these patients is not clear. Most ofthe patients with a low plasma chloride level were extremely ill and weretaking practically no food by mouth; hence their source of salt was almostentirely derived from that administered parenterally. In those patientswho presumably had the most severe renal lesions (those who died in uremia),there is a possible correlation between the quantity of parenteral sodiumchloride given and the plasma chloride levels (Table 66). The table showsthe influence of parenteral sodium chloride intake over a period of 3 dayson the subsequent plasma chloride level in 32 patients who died and in19 who survived. The patients were arbi-
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trarily divided into 2 groups: those with plasma chloride levels of100 milliequivalents per liter or higher, and those with levels below ahundred.
TABLE 66.-RELATIONSHIPOF PARENTERALINTAKE OF SODIUM CHLORIDEFOR 3 SUCCESSIVE DAYS TO SUBSEQUENTPLASMACHLORIDE LEVEL
Of 32 patients who died in uremia, 11 had plasma chlorides of 100 milliequivalentsper liter or higher up to the time of death. All of the 11 had receivedconsiderable parenteral sodium chloride in the previous 3 days. Twenty-oneof the 32 had low plasma chlorides, under 100 milliequivalents per liter;10 of these patients had received no chlorides parenterally during theprevious 3 days, and the remaining 11 had received on an average considerablyless salt than those in whom plasma chloride levels were found to be normalor high. It should be emphasized that this analysis of fatalities includesonly patients who died in uremia, that is, those in whom the maximum degreeof renal impairment could logically be expected.
Among 19 of 23 patients with high azotemia who lived, some relationshipof parenteral salt intake to low plasma chloride is also evident in thetable. In addition, these patients as a whole were not nearly so ill andit is likely that chloride intake by mouth was considerable, so the totalsalt intake probably largely exceeded parenteral salt intake. Examinationof the individual records of patients who developed severe renal failureand yet lived (see also the section on Recovery Diuresis to follow) indicatesthat hypochloremia was a part of the chemical picture in most such cases,e.g., Cases 60, 27, 125, but that it was to an appreciable
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degree associated with the sodium chloride intake. This relationshipto intake is also brought out in conjunction with the discussion of sodiumto follow.
Several exceptions to these generalizations were evident in individualcases. With apparently adequate salt intake, the chloride level was sometimeslow, even in patients in whom there was no loss of chloride through Wangensteendrainage or vomiting. In one patient with high azotemia and with all theother clinical features common to the syndrome of severe renal failure,the plasma chloride levels were abnormally high (Case 133), but in thisinstance salt intake had been excessive.
It is possible that the hypochloremia might have been due in part toa simple dilution of the chloride ion, since practically all of these patientshad an increased plasma volume. This will be discussed further in the sectionon Plasma Volume. No such connection is apparent, however, in Table 67which shows plasma volume and plasma chloride determinations done simultaneouslyin 18 patients who subsequently died of uremia. No correlation betweendegree of initial shock and plasma chloride level could be demonstrated.
TABLE 67.-PLASMA VOLUMEAND PLASMA CHLORIDE DETERMINATIONSIN 18 PATIENTS WHO DIED OFUREMIA
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Chloride Excretion.-Total chloride excretion was measured infive patients with high azotemia (Cases 104, 105, 107, 112, and 133). Ofthese, the two patients who died (Cases 105 and 107) had plasma chloridelevels which were low or falling. In both of these and in Case 112, chlorideexcretion was practically nil; chloride intake was probably inadequatein each. Two of them (Cases 107 and 112, to be discussed at greater lengthin Chapter VII) also had an alkalosis due to administration of excess alkali,chiefly sodium bicarbonate, in an attempt to alkalinize the urine. Twoof the three patients who lived had a recovery diuresis. Chloride excretionin one (Case 104) was essentially normal, but determinations were begunafter he had actually recovered. The other patient (Case 133) had hyperchloremia,but a high "threshold" for chloride excretion (see Table 78 and Chart 26).This case will be discussed further in the section on Recovery Diuresis.
Chloride concentration in single specimens of urine was measured in18 patients who died of uremia. In 9 determinations made on 8 patientswho had normal plasma chloride levels, the average urine chloride concentrationwas
72.5±10 milliequivalents per liter. In 21 determinations on10 patients with low plasma levels, it averaged 54.0±7.0milliequivalents per liter.
From these data it can, however, be concluded that in cases of renalfailure in our series the plasma chlorides in most cases tended to fallas renal failure progressed, the degree of hypochloremia depending to someextent on salt intake. The chloride excreted in the urine was measuredin too few cases to state that the hypochloremia was not due to excessiveexcretion of the chloride ion. No correlation between plasma chloride leveland increased plasma volume could be demonstrated, so the low levels, asfar as can be determined from our data, were not due to simple dilution.In addition to inadequate salt intake, there must be other factors contributingto hypochloremia.
Plasma Phosphate.-The variations in phosphorus have been discussedin more detail in the preceding section on nitrogenous waste products.The phosphates are mentioned here again only to indicate their relationto total acid-base balance. Reference to Table 58B-E shows that the averageplasma phosphates, when converted to milliequivalents, even when elevatedto twice normal or over, constitute but a small portion of the total anions;they clearly account for only a portion of the carbon dioxide displacedin those cases in which carbon-dioxide combining power is low.
Plasma Protein.-Plasma proteins have been converted to milliequivalentsin
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Table 58E. Inspection of these values in all categories shows a remarkableconstancy with very small standard errors of the mean. Although the proteinsrepresent a significant proportion of the total anions present, their importancein terms of change in acid-base balance is negligible.
Cations
Serum Sodium.-The number of sodium analyses (Table 58F) was smallin comparison with those of anions. However, by grouping all determinationsmade on patients with high azotemia between the second and tenth postoperativedays (or days after trauma) some interesting facts emerge (Table 68).
TABLE 68.-RELATIONSHIP OFSERUMSODIUM, PLASMA CHLORIDE,AND PLASMA CARBON-DIOXIDECOMBININGPOWER TO PARENTERALSODIUMAND CHLORIDE INTAKE IN HIGHAZOTEMIA-32 DETERMINATIONS IN26 PATIENTS
Thirty-two determinations were made on 26 patients. In 4 instances,2 determinations for the same patients on different days are included,and in one instance, 3 determinations on different days. Twenty-four ofthe determinations were among patients dying in uremia, 2 were done onpatients in whom uremia was contributory to death, and 1 on a patient inwhom uremia was coincident with death. Five determinations were made onpatients who survived, 4 of whom had severe renal failure. Nine of the14 determinations which were above 139 milliequivalents per liter representpatients dying primarily of uremia; 2 determinations, patients in whomuremia was contributory to death; 2 deter-
156
minations, patients who lived but had severe renal failure, and 1 determinationa patient with slight renal failure who survived. Fifteen of the 18 determinationsbelow 140 milliequivalents per liter represent patients dying primarilyof uremia, 1 a patient in whom it was coincident with death, and 2 patientswho survived but had severe renal failure.
Several facts seem evident from these data: 1. Serum sodium and plasmachloride concentrations were related to intake of these ions, regardlessof the severity of the renal insufficiency present. 2. The acidosis, asreflected by the low carbon-dioxide combining power, was equally severeregardless of whether the sodium or chloride levels were normal or low.3. The outcome was the same in both the normal and low groups; there isno direct evidence that the diminished sodium and chloride concentrationsaffected the course of the syndrome.
The cause of the acidosis in these cases is not clear. If the acidosiswere due to loss of total base, one might expect a lower carbon-dioxidelevel in the low-sodium group; if due to substitution of chloride for carbondioxide, the plasma chlorides should be high. As stated before, phosphateswere not sufficiently elevated to account for the change entirely in termsof base equivalence. Proteins remained constant and essentially normal.Sulfates and organic acids were not measured; these two components mightaccount for some of the discrepancies evident in our data.
Plasma Magnesium.-There were too few determinations of plasmamagnesium to be significant (Table 58G). Because of this, 14 determinationsmade between the second and tenth postoperative days in 13 cases (two determinationson the same patient on different days are included) were averaged and were2.3±0.1 milliequivalents per liter. The nonprotein nitrogen determinationsdone simultaneously on these 13 patients averaged 164±22mg. per 100 cubic centimeters. If these few determinations are significant,there was no evidence of abnormal magnesium metabolism in this type ofrenal insufficiency.
Serum Potassium.-Determinations of this substance were made inonly seven patients (Cases 78, 80, 107, 112, 133, 135, and 138). In twoof these (Cases 78 and 80) the values were 9.1 and 9.8 milliequivalentsper liter respectively after several days of anuria or oliguria and justprior to death. In three (Cases 133, 135, and 138) they varied between6.2 and 7.0 milliequivalents per liter. In the remaining two (Cases 107and 112) the values were normal (3.9-5.3). Analysis of these cases showedthat hyperpotassemia occurred only when urine volume was greatly decreased.
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Serum Calcium.-This was discussed in the section on NitrogenousWaste Products and Phosphorus.
Summary-Acid-Base Balance
From the data presented it is apparent that in lower nephron nephrosisresulting from shock or trauma, the most characteristic electrolyte abnormalityconsists of a progressive, fairly severe acidosis. Hypochloremia was alsoa frequent but not constant finding, one which we have been unable to explainadequately. Phosphate retention contributes to the acidosis. Serum cationdeterminations were few. Sodium concentrations followed no constant pattern.Potassium was found to be elevated at the time the patients had oliguriaor anuria.
Physiologic Abnormalities
Plasma and Blood Volume
Plasma volume was determined in 23 patients at a time when they hadposttraumatic renal insufficiency. The results were striking and of practicalimportance, for they indicated that increase in plasma volume was a partof the abnormal physiologic picture. Nineteen of these patients died and4 survived through the mechanism of recovery diuresis. Average plasma volumedeterminations are shown in Tables 69 and 70, the former for all casesand the latter for fatal cases. Tables 71, 72, and 73 list the individualplasma and blood volume changes and related data on each of the 23 patients.
Relationship of Plasma Volume to Fluid Intake.-Referring firstto Tables
TABLE 69.-AVERAGE PLASMAVOLUME CHANGES* IN 23 PATIENTSWITH RENAL INSUFFICIENCY
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69 and 70, it is evident that the average plasma volume for the entiregroup was increased significantly above the calculated normal after developmentof renal insufficiency, the average increase for all 23 cases being 43.3±5.7percent. In the 19 fatal cases the average increase was 41.6±6.6percent. The fatal cases were further analyzed as to the quantity of intravenousfluid administered. Average increases for the 15 patients who receivedan average of 1 liter or more of fluid intravenously daily (Group A, Table70) were much greater than for the 4 patients who received less than 1liter daily (Group B, in Table 70). Analysis of Tables 71 and 72, fromwhich the averages in Table 70 were computed, shows that no patient inGroup A and only 1 patient in Group B had a normal or subnormal plasmavolume after development of renal insufficiency. In this patient (Case136) there is some reason to question whether deficient circulating bloodvolume was adequately replaced, and hence whether he ever really recoveredfrom shock during the 3 days he survived after wounding. The four patientswho survived all showed increased plasma volume (Table 73).
TABLE 70.-AVERAGE PLASMAVOLUME INCREASE* IN 19 PATIENTSWITH FATAL RENAL INSUFFICIENCY
Table 74 represents further analysis of all 23 cases. In 22 of themplasma volume was found to be increased above the calculated normal whenrenal insufficiency developed. The one exception, a patient (Case 136)who showed a subnormal plasma volume, probably had not been adequatelyresuscitated, as stated above. Eighteen of the 22 patients with increaseshad received parenterally an average of 1 liter or more of fluid, crystalloidor colloid, daily. In 10 of the
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22 patients multiple determinations were made and 8 of them showed progressiveincreases in plasma volume as renal failure became more severe. Of the2 whose plasma volume did not increase further as renal failure progressed,one (Case 69, Table 71) was in Group A in which average fluid intake washigh. His plasma volume was increased approximately 23 percent over normalon both
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TABLE 72.-PLASMA AND BLOODVOLUME CHANGES1 IN FATALPOSTTRAUMATIC RENAL INSUFFICIENCY
Group B: Patients who Received an Average of Less than 1 Literof Intravenous Fluids (Crystalloid or Colloid) Daily
the second and ninth days after crushing injury. The other (Case 118,Table 72) was in Group B, those with restricted fluid intake. His increasedplasma volume actually diminished although he subsequently died in uremia.
Among those who had increased plasma volumes were the four patientswho had a recovery diuresis and survived. In three of them plasma volumefirst increased and then decreased as diuresis proceeded and nitrogenouswaste products were excreted (Table 73). The progress of the plasma volumechanges in relation to the plasma nonprotein nitrogen in these cases isshown in Chart 27. The fourth patient (Case 150) had his first determinationafter diuresis had begun although he still had severe renal failure andan increased plasma volume.
Relationship of Plasma Volume to Plasma Protein Concentration, HematocritLevel, and Total Blood Volume.-The relationships of plasma volume toplasma protein concentration, hematocrit value, and total blood volumeare evident in Tables 71, 72, and 73. There were considerable individualvariations, but in general it can be stated that an expected coincidentdecrease in plasma protein concentration as the plasma volume rose duringrenal insufficiency was not usually demonstrated. Thus of the eight patientsin whom the already increased plasma volume was known to rise, there wereno significant changes in plasma protein concentration in five (three ofwhom received blood between measurements);
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TABLE 73.-PLASMA AND BLOODVOLUME CHANGES1 IN4 PATIENTS WITH POSTTRAUMATICRENAL INSUFFICIENCY AND SUBSEQUENTRECOVERY DIURESIS
TABLE 74.-TRENDOF PLASMA VOLUME CHANGESDURING POSTTRAUMATIC RENAL INSUFFICIENCYIN 23 PATIENTS
there was an increase in one, and a decrease in only two. Explanationfor the absence of a dilution phenomenon is not evident from our data.One can only
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postulate that in such cases plasma protein was being mobilized fromprotein sources elsewhere in the body.
The hematocrit level in the eight patients in whom plasma volume increasedprogressively (as shown by serial determinations) rose in one who receivedblood between measurements, was unchanged in three, two of whom receivedblood between measurements, and fell in four, one of whom received bloodbetween measurements. Although the total blood volumes were also increased,the increments clearly were a reflection of the increase in the plasmavolume, and because of the low hematocrit level in most cases, they werenot as strikingly increased as was the plasma volume.
These data indicate, then, that in posttraumatic renal failure, totalcirculating plasma volume is increased. This must be due largely to theinability of the kidneys to excrete adequate water. However, because theplasma protein concentration did not usually diminish as plasma volumeincreased, it is evident that the sole explanation is not simply that hydremiaexists. There would seem to be also unexplained extrarenal factors interferingwith maintenance of a normal extracellular fluid volume. The practicalimportance of these observations is self-evident. Administration of excessivequantities of fluids to these patients who already have increased extracellularfluid volume can probably do nothing toward stimulating the kidneys toexcrete; it can cause fatal pulmonary edema.
Summary-Plasma and Blood Volume
Plasma volume was determined in 23 patients in whom posttraumatic renalinsufficiency developed, 19 of whom died. Averaging all 23 cases, therewas an increase over the calculated normal plasma volume of 43.3 percent,and of 41.6 percent in the fatal cases. Considering the patients individually,there was only one in whom plasma volume was less than normal after signsof renal impairment appeared, and there was good reason to believe thatthis patient had never been adequately resuscitated from shock. Comparisonof the plasma volume with simultaneous plasma protein levels indicatesthat there was an increase in total circulating plasma and not simply anincrease in proportion of water in the plasma; i.e., in general, plasmaprotein did not decrease with increasing plasma volume. In those patientsin whom serial determinations were made, including several who had a recoverydiuresis, the time of maximum increase in plasma volume coincided withthat of maximum azotemia, and in those who recovered, plasma volume andplasma nonprotein nitrogen diminished at parallel rates.
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URINE
Specific Gravity
One of the most striking and constant physiologic abnormalities observedin posttraumatic renal insufficiency was impairment of ability of the renaltubules to reabsorb water. Within a day or two postoperatively, those patientswho developed renal impairment, almost without exception, lost the powerto make a concentrated urine regardless of the amount they were excreting(Chart 23 and Tables 75 and 77). The averages in the tables and chart werecalculated from the specific gravities observed in routine specimens, usuallythe first morning one. They do not, then, represent true concentrationtests, but there are several factors which indicate that the values observed,in most cases, were those of practically maximum concentrating ability:(1) Concentration tests were done later on patients who recovered, whenit was deemed safe to do them. In these patients, even after the retainednitrogenous products had been cleared and output had returned to normal,specific gravity remained fixed and low. (2) Many of the specimens weretaken when the output of urine was very low and hence
CHART 23. URINESPECIFIC GRAVITY IN PATIENTSWITH HIGH AZOTEMIA
Figures from "Anuria and Oliguria" grouping, Table 75.
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TABLE 75.-AVERAGE SPECIFICGRAVITY OF THE URINE IN PATIENTSWITH HIGH AZOTEMIA*
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when the kidneys were theoretically concentrating urine to the maximumof their ability. (3) In many of the patients, particularly those who diedin uremia, fluids were sharply restricted, usually to about 1 liter a day.This could be further reason for assuming that the average urine specimenwould be concentrated if the kidneys were capable of making it so; on theother hand, this argument may be rendered untenable by the fact that plasmavolume was probably increased in all cases. (4) Twenty-four hour urinespecimens were collected from five patients in whom renal failure developed.In these the specific gravity of the total specimens showed the same trend,even though plasma nonprotein nitrogen was rising, and in three cases totaloutput of urine was diminishing.
It will be shown in the section on Recovery Diuresis that in those patientswho did recover, the nitrogenous waste products were cleared because ofan increasing output of urine but the urine specific gravity remained fixedat a low level. In summary, it appears from our data that in this syndromeone of the earliest functional derangements of the kidney to occur, andprobably one of the last to disappear when recovery takes place, is theability to concentrate the urine.
Hydrogen-Ion Concentration
The tendency of the acidity of the urine to decrease as systemic acidosisand renal failure progress has been previously discussed (see PlasmaCarbon-Dioxide Combining Power under Acid-Base Balance, Chart 21, andTables 76 and 77). From our meager data on measurement of titratable acidityand ammonia of the urine (see the section on Recovery Diuresis), it isprobable that the mechanism of this failure to make a very acid urine isassociated with a decrease in titratable acidity and thus is similar tothat seen in most types of renal failure. Inability of the kidneys to producea urine of maximum alkalinity, if presented with a surplus of base, alsoseems to be a feature of the syndrome (see Chapter VII) and again is similarto the situation occasionally seen in other types of kidney disease.
There is good evidence1 that acidification of the urine byactive transfer of hydrogen ions, as well as ammonia production is accomplishedby the distal
1PITTS, R. F.; LOTSPEICH, W. D.; SCHIESS, W. A., and AYER, J. L.: The renal regulation of acid-base balance in man. I. The nature of the mechanism for acidifying the urine. J. Clin. Investigation 27: 48-56, January 1948. SCHIESS, W. A.; AYER, J. L.; LOTSPEICH, W. D., and PITTS, R. F.: The renal regulation of acid-base balance in man. II. Factors affecting the excretion of titratable acid by the normal human subject. Ibid. 57-64.
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TABLE 76.-AVERAGE pH OFTHE URINE IN PATIENTS WITHHIGH AZOTEMIA*
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tubular cells. This provides further correlation, perhaps, of functionalwith anatomic findings in patients suffering from lower nephron nephrosisfollowing shock or trauma.
TABLE 77.-AVERAGE SPECIFICGRAVITY AND pH OF URINEIN PATIENTS WITH OLIGURIA ORANURIA
Proteinuria and Pigment Excretion
As was pointed out in Chapter IV, all patients with proved renal lesionshad proteinuria, and this finding was also a constant one in all patientswith posttraumatic renal insufficiency. It was not, however, a specificfinding, for it was absent in only 14 of the entire series of casualtiesstudied. The relationship of pigment excretion in the urine to posttraumaticrenal insufficiency will be discussed in Chapter VIII.
Summary-Changes in the Urine
The most striking change in the urine was the fixation of specific gravityat low levels within a day or two after the onset of renal failure followingshock or trauma. This impairment of maximum reabsorptive capacity of waterby the renal tubules persisted after other evidence of kidney damage disappearedin those patients who recovered. Inability to manufacture a highly acidurine in
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the presence of metabolic acidosis was also a constant feature in thepatients studied.
Recovery Diuresis
The arbitrary choice of 65 mg. per 100 cc. or higher concentration ofnonprotein nitrogen in the plasma as an index of renal insufficiency inthis series of cases has been discussed. Of the 73 patients included inour "high azotemia" group, 23 (32 percent) lived. Those who survived maybe further classified according to the degree of renal impairment theyexhibited: Twelve had apparently only minimal interference with renal function,with a rapid return to normal after transient nitrogen retention. We wereunable to follow one patient with a nonprotein nitrogen level greater than65 mg. per 100 cc. who lived and so do not know what degree of renal insufficiencyhe ultimately had. Ten had even greater evidence of renal impairment andtheir course conformed with the syndrome we have designated as recoverydiuresis.
The characteristic features of this syndrome are:
1. A nonprotein nitrogen level greater than 100 milligrams per 100 cubic centimeters.
2. Oliguria or anuria, followed by a substantial diuresis resultingin clearance of nitrogenous waste products and return to normal of theelectrolyte pattern.
3. Impaired ability to concentrate the urine.
4. Hypertension (systolic blood pressure above 135 millimeters of mercury;diastolic above 90).
Of the 10 patients exhibiting this syndrome, 9 showed at least three and most of them all four of these characteristics. The tenth patient (Case 44) was observed during a period when the laboratory was not functioning, so his blood and urine could not be examined, but clinically he displayed the characteristics of the syndrome.
This small group of cases is of great interest and practical importance.One would like to know why these patients recovered whereas the majorityof those with renal insufficiency died, and whether in their course ortreatment there are any clues which might lead to more effective treatmentthan has been found to the present. Detailed data on a few typical cases(see Charts 25 and 26),
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together with pertinent clinical and physiologic findings in the groupas a whole, are considered of value here. (The 10 cases were Numbers 27,30, 43, 44, 60, 104, 125, 133, 138, and 150.)
Clinical Features
The degree of initial shock was essentially the same for these 10 patientsas for the entire group having renal failure. Three patients had had severeshock, 5 moderate, 1 slight, and 1 no shock. As in other instances, itis entirely possible that there may have been considerable shock in all10, but so far as we could determine at the time of admission, they mustbe classified as above.
Five of the 10 patients had multiple major wounds. The major woundsin the entire group were: 6 peripheral with fracture, 4 thoracic, 4 intra-abdominal,and one thoraco-abdominal. One patient had a contusion of the bladder.There were no wounds of the liver or kidney.
The time of onset of oliguria in relation to wounding and operation,and the duration of suppression of urinary output are of interest. Unfortunatelythe day-to-day records are not as accurate as one would like. Many of thesepatients were seen in field hospitals during periods of great militaryactivity, when the press of work made it very difficult to make such observations.We have no record of output of urine until the first postoperative dayin any of the cases. Eight of the 10 patients are known to have had atleast 1 day of oliguria or anuria between the first and sixth postoperativedays. Records of output of urine were not kept for the remaining 2 patientsat the time they probably had oliguria, but questioning of ward personneland of the patients suggested very strongly that they too had had oliguriaduring this period. The duration of oliguria ranged from 1 to 4 days. Therefollowed then a period of gradually increasing output of urine, reachingin some cases 5 or 6 liters a day. The plasma nonprotein nitrogen leveldid not, as a rule, begin to decrease until several days after diuresishad begun.
Because of the increase in plasma volume during the period of increasingazotemia, it might be expected that total fluid output would exceed intakeduring the diuresis period. This clearly occurred in two cases (Case 60(Chart 24) and Case 150). In the remaining eight cases it was impossibleto demonstrate this fact from the figures available, for the records keptgave only an approximate estimate of total water balance; they did notaccount for water lost by perspiration, respiration, or with the stools.Since the plasma volume returned
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to normal and the edema subsided as diuresis proceeded, it is logicalto assume that total fluid output did exceed intake until equilibrium wasreestablished.
All these patients had hypertension, by our definition. In general theblood pressure was highest at the time of the most severe nitrogen retentionand the
CHART 24. RELATIONSHIPOF FLUID INTAKE AND OUTPUTIN A PATIENT WITH RECOVERYDIURESIS (CASE 60)
Output exceeded intake from theeighth day. If extrarenal losses were shown, output would have exceededintake after the fourth day.
CHART 25. COURSEOF A PATIENT WITH RECOVERYDIURESIS (CASE 60)
Chart 25. Recovery diuresisoccurred in this patient following an initial period of renal insufficiencydue to severe traumatic shock and great blood loss. Note: (1) Initial periodof oliguria and diminished renal function as evidenced by low phenolsulfonphthaleinexcretion with fixed urine specific gravity which persisted throughoutthe period of observation. (2) The gradual increase in urinary output duringthe first week accompanied by rising blood pressure, rising plasma nonproteinnitrogen concentration, falling carbon-dioxide combining power and plasmachlorides. (3) The fall in nonprotein nitrogen occurring only several daysafter adequate urinary output, accompanied by improvement of phenolsulfonphthaleinexcretion, rising carbon-dioxide combining power and plasma chloride levels,and return of the blood pressure toward normal. See page 171.
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elevation was significant, with levels ranging from 150 to 170 mm. Hgsystolic and from 90 to 110 diastolic. Likewise, as diuresis proceededand the nonprotein nitrogen levels fell, blood pressures returned to normal.One patient was evacuated to the rear before his hypertension had subsidedand we were unable to obtain subsequent blood-pressure determinations.
Two patients (Cases 44 and 150) had generalized convulsions on the eighthand ninth postoperative days respectively. In one, the convulsions furnishedthe first clue to the attending medical officers that renal failure waspresent. One of these patients also had a small retinal hemorrhage in thefundus of one eye. Eyegrounds were examined in three other patients inthe group and found to be normal. Four patients had clinical edema.
Blood Chemistry
The abnormal chemical pattern in this selected group of cases was essentiallysimilar to that described in the preceding section. Chart 25 representsthe course of the patient cited in Chart 24 and demonstrates the essentialfeatures seen in all such cases.
This man, who had had a period of severe initial shock, had oliguriafor 1 day. Renal function, as measured by phenolsulfonphthalein excretionand the urine concentration test, was greatly impaired by the first postoperativeday. A gradual increase in output of urine followed. Despite diuresis,however, the nonprotein nitrogen continued to rise for the first 7 days-apparentlybecause, with a fixed specific gravity of the urine, the kidneys were notat first able to clear sufficient nitrogen. Blood pressure rose and fellapproximately with the nitrogen retention. Electrolytes followed the patternalready described but returned to normal as renal function improved. Thepatient`s inability to make an acid urine in the presence of a mild acidosisis evident from study of the chart. When the patient was evacuated on thefifteenth postoperative day, renal function was still reduced
CHART 26. COURSEOF A PATIENT WITH RECOVERYDIURESIS (CASE 133)
Chart 26. There was an excessiveintake of sodium chloride during the previous 10 days, which is not shownon the chart. Note: (1) The unusually high serum sodium and plasma chloridelevels. (2) A relatively low urinary chloride excretion during the periodof maximum hyperchloremia and the extremely low excretion during the lastdays of the observation, although significant hyperchloremia persisted.(3) The slowly falling plasma nonprotein nitrogen level, although urinaryoutput was over 2 liters a day during most of the period studied. Seepage 173.
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despite normal chemical findings in the blood.2 Results ofblood chemistry and urine examinations, made in eight of the nine otherpatients, followed essentially the same pattern.
The time of maximum nitrogen retention varied; five patients had theirhighest nonprotein nitrogen level between the third and ninth days aftertrauma, and the remaining four between the tenth and thirteenth days. Theperiod of time required for recovery of renal function varied from 6 to25 days.
As mentioned earlier, hypochloremia was not as prominent a feature inthese patients as in those who died in uremia, but it was present to somedegree (plasma chlorides under 100 milliequivalents per liter) in fivepatients. One patient (Case 133), on the other hand, following a high intakeof sodium chloride, had a pronounced hyperchloremia (plasma chlorides 144milliequivalents per liter) about the time of greatest nitrogen retention(Chart 26 and Table 79).
Plasma Volume
Four patients with recovery diuresis in whom the plasma volume was measuredshowed a significant increase over the calculated normal. It was greatestat the time of maximum nitrogen retention and decreased as diuresis proceeded.Three patients (Cases 60, 133, and 138, Chart 27) were discussed in thepreceding section on Plasma and Blood Volume. A fourth patient (Case 150,Table 73) still had a significant elevation in plasma volume when firststudied on the twelfth postoperative day after diuresis had begun.
Urinary Findings
Specific Gravity.-Five patients, following administration ofpituitrin, were unable to concentrate urine above 1.015 as long as theywere followed (up to 49 days postoperatively in one instance). One patientwith very transient nitrogen retention could concentrate to 1.020 by thethirteenth day. Concentration tests were not done in the other four patients,but several specimens in three of them were uniformly dilute. In one (Case30), two routine specimens taken at the time of maximum nitrogen retentionwere 1.019 and 1.023.
Twenty-four Hour Urine Analyses and Related Findings in Two Patients.-Examinationsof 24-hour urine specimens were made in two patients who had
2Studies made 10 months later in the United States showed normal kidney function.
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CHART 27. PLASMAVOLUME AND PLASMA NONPROTEINNITROGEN CONCENTRATION IN 3
PATIENTS WITH RECOVERYDIURESIS
(CASES 60, 133, AND138)
recovery diuresis. In Case 133 the collections were started just atthe end of the recovery period. Table 78 lists the findings in one of thesepatients (Case 104) along with plasma determinations made on the same days.From these data a few conclusions could be drawn regarding this one patient:(1) Titratable acidity values were rather low, considering low plasma carbon-dioxidecombining power during the first 3 days of collection. (2) Ammonia productionwas normal. (3) Chloride excretion and sodium chloride intake were normal.Plasma chloride values were normal. (4) Excretion of urea was high thefirst
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day and accompanied a fall in plasma nonprotein nitrogen to normal.
Table 79 and Chart 26 show comparable findings on the other patient(Case 133). Ammonia and titratable acidity determinations of the urinein this case were not numerous enough and varied too widely to draw anyconclusions regarding acid-base regulation. Excretion of urea and creatininewas about what would be expected in a normal individual, but not sufficientto clear the retained nitrogen rapidly. Toward the end of the 10-day periodduring which 24-hour urine collections were made, plasma levels of ureanitrogen and creatinine be-
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gan to fall. Clearance rates of these substances, however, were diminishedduring the entire period of observation.
The relationship of serum sodium, plasma carbon-dioxide combining power,fluid and sodium chloride intake, urinary output, and urinary excretionof chloride in this same patient are also shown. After a high intake ofsodium chloride, sodium and chloride retention developed. Plasma carbon-dioxidecombining power fell, in this instance partially as a result of hyperchloremia.Chloride excretion was relatively low considering the high plasma chloridelevel. As the plasma chloride level fell, chloride excretion decreasedto negligible amounts during the last 4 days, even though the plasma chloridelevel was still unusually high. High serum sodium accompanied the hyperchloremia.There is in this case evidence of a high renal "threshold" for both sodiumand chloride excretion.
The course and essential features in this patient were characteristicof recovery diuresis, but he exhibited most unusual electrolyte abnormalities.Although he had an increased plasma volume (Chart 27), there were alsomarked hypernatremia and hyperchloremia. An elevated serum sodium is mostunusual except in the presence of dehydration, which, if the measurementsof plasma volume can be accepted, was not present in this patient. Furtherevidence of inability of the renal tubules to reabsorb maximum amountsof water is seen here in the dilute urines of total specimens in both Cases104 and 133 during periods of high nitrogen retention.
Renal Clearance Tests and Phenolsulfonphthalein Excretion
The results of renal clearance and phenolsulfonphthalein excretion testsin patients with recovery diuresis were discussed in Chapter III. Briefly,in three such patients in whom clearance measurements were made, all functionalcomponents of the kidney were diminished when first observed and graduallyreturned toward normal over a period of several days or weeks. Similarevidence of functional impairment and subsequent improvement was seen inthree additional patients with recovery diuresis on whom phenolsulfonphthaleinexcretory capacity tests were made.
Summary-Recovery Diuresis
Of the 23 patients with posttraumatic renal insufficiency who lived,10 exhibited certain features which conform to the syndrome designatedas recovery
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diuresis; namely, (1) nonprotein nitrogen greater than 100 mg. per 100cc., (2) oliguria or anuria followed by diuresis and fall in nonproteinnitrogen, (3) low and fixed urinary specific gravity, and (4) hypertension.Their clinical course and physiologic and biochemic changes were entirelysimilar to those demonstrated in patients who died and were found at necropsyto have had lower nephron nephrosis. This group of patients demonstrates,then, that recovery from this type of renal disease can occur spontaneouslyif the patient survives the first critical 10 days after onset of renalfailure.
SUMMARY
In earlier chapters the changes that began to occur in the internalenvironment soon after a man had been wounded were described. The effectsof these early changes upon the kidney have been reported in this and thepreceding chapter. Following severe trauma, accompanied usually by shock,a man could be adequately resuscitated and successfully operated upon.The latent renal incompetency which might develop in this man, who hadnormal kidneys at the time he was wounded, usually did not become manifestuntil two or three days later. At this time there appeared signs of failureon the part of the kidneys to withstand the initial insult, the effectsof which his body had thus far resisted with fair success.
The first clinical sign of impending renal failure usually was suppressionof urinary output. Of 73 patients with "high azotemia" (a plasma nonproteinnitrogen concentration of 65 mg. per 100 cc. or higher at some time duringtheir course), 27 had anuria (urinary output of less than 100 cc. in any24-hour period) and 29 had oliguria (output of from 100 to 600 cc. in a24-hour period).
The case fatality rate was high. Fifty patients (69 percent) of the73 with high azotemia died. Twenty-one (47 percent) of 45 who had oliguria,and 30 (91 percent) of 33 with anuria had a fatal outcome.
Initial shock--if special types of cases such as crush injuries, reactionto incompatible blood transfusion, and sulfathiazole crystalluria are excluded--wasobserved in a large proportion of the cases. Eighty-two percent of thosewho had high azotemia, and, in another category, 73 percent of those whohad oliguria and 69 percent of those who had anuria had been in moderateor severe initial shock. These figures are undoubtedly too low, for manymen probably had been in shock before we saw them.
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Death occurred within 10 days after wounding in 48 (94 percent) of 51patients who died of posttraumatic renal insufficiency. Apparently if thewounded man can withstand this critical 10-day period, recovery of renalfunction begins and he may survive. In a few patients there was evidenceof returning renal function toward the end of their course, even thoughthey died in uremia. The importance of this fact cannot be overemphasized,for a therapeutic error (such as overloading the circulatory system byfluid administration) during this critical period may cause a fatal outcomebefore natural recovery can take place.
Hypertension (at least 135 mm. Hg systolic and at least 90 mm. Hg diastolic)occurred in 62 percent of the patients with high azotemia, and in 79 percentof those in this group who died in uremia. In many of the fatal cases inwhich hypertension did not develop, death occurred within 4 days afterwounding. Had these patients survived longer, probably they too would havehad hypertension.
The important biochemic and physiologic abnormalities in the blood resultingfrom posttraumatic renal insufficiency were found to be nitrogen and phosphorusretention, acidosis, hypochloremia, and increase in the plasma volume.These blood and plasma changes reflect rapidly diminishing renal function,as indicated by: (1) inability to concentrate the urine; (2) frequent failureto make a highly acid or alkaline urine in the presence of metabolic acidosisor alkalosis; (3) diminished glomerular filtration rate and renal bloodflow, and (4) decreased phenolsulfonphthalein and maximum tubular excretorycapacity of para-amino hippuric acid.
Nonprotein nitrogen, urea nitrogen, creatinine, uric acid, and phosphoruslevels in the plasma rose as renal failure progressed during the first10 days after wounding. Most observations after this period were on patientswho recovered. The level of these waste products fell between the tenthand fifteenth days.
A progressive, fairly severe acidosis was characteristic, manifestedby falling plasma carbon-dioxide combining power as renal failure advanced.Loss of ability to make a highly acid urine in most cases suggests thatthe acidosis was partially to be explained by impairment of the mechanismwhich produces an acid urine. A few observations also indicated, as expected,an impairment of ammonia production by the renal tubules. There was alsogood evidence that removal of sodium by excretion as sodium bicarbonatewas poorly accomplished
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in those cases in which alkalosis resulted from administration of largequantities of sodium.
Hypochloremia was severe and progressive, if all fatal cases are averaged.Correlation of the plasma chloride level and sodium chloride intake, however,demonstrated that the low chlorides were to some degree a result of inadequatesalt intake. Serum sodium levels showed similar correlation. There wasno difference in case fatality between the group with hypochloremia andthose with normal plasma chloride levels. One patient with renal failurehad severe sodium and chloride retention following a high salt intake.Intake, however, does not entirely explain variations in plasma chloridelevels. No correlation with degree of plasma volume increase was apparent,but it is suggested that some interference with water and sodium chlorideequilibrium was present in addition to the demonstrated relation to intake.
Phosphates in terms of acid equivalence, contributed toward but didnot entirely account for the acidosis. Plasma proteins, if converted tomilliequivalents, were normal and constant. Sulfates and organic acidswere not measured and possibly account for discrepancies in our anion determinations.
Cation determinations were few. It has already been stated that sodiumlevels were partially correlated with salt intake. Magnesium was not significantlyelevated in most cases. Potassium was determined in only a few cases, butthe results suggest that hyperpotassemia was probably a feature of thesyndrome. Calcium followed a reciprocal relationship with rising phosphoruslevels in the few cases in which such determinations were made.
Total plasma volume was significantly elevated in 22 of 23 patientswith posttraumatic renal insufficiency. Nineteen of these 23 died. Threepatients with severe renal failure in whom a recovery diuresis developedhad plasma volume increases that reached a maximum at the time of greatestnitrogen retention and decreased after diuresis. The degree of increaseof the plasma volume was clearly related to fluid intake. The water retentionappeared to be largely a result of administration of more fluid than theimpaired kidneys could excrete. Comparison of plasma volume with totalblood volume indicated that it was the plasma which was increased, ratherthan all elements of the blood. The expected dilution of plasma proteinswas not demonstrated in most cases. The practical importance of this increasein plasma volume has been mentioned.
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Ability to concentrate the urine diminished rapidly as the syndromeof posttraumatic renal insufficiency progressed, and specific gravity becamefixed in all patients with a severe degree of renal failure. In patientswho recovered it was the last of the kidney functions of those measuredto return to normal. Since urine concentration is accomplished by the distaltubular cells, whereas mannitol, para-amino hippuric acid, and phenolsulfonphthaleinreflect glomerular and proximal tubular function, the lag in recovery ofwater-reabsorptive capacity may point to greater relative functional impairmentof the lower nephron.
Ten patients of the 73 who had high azotemia exhibited all of the featuresof severe renal failure and subsequently a diuresis developed and theyrecovered. The course of these patients followed a pattern which has beentermed the "syndrome of recovery diuresis." This small group re-emphasizesthe importance of avoiding early fatal therapeutic errors (such as overloadingthe circulatory system with fluid) thereby affording the kidneys an opportunityto recover spontaneously.
