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Chapter V

Contents

CHAPTER V

Clinical, Physiologic, and Biochemic Correlation in Lower Nephron Nephrosis

The importance and frequent occurrence of renal failure in those battle casualties who were severely wounded must be emphasized. In the preceding chapter the diagnosis of posttraumatic renal insufficiency was discussed from a clinicopathologic viewpoint. In this chapter an attempt will be made to present a comprehensive picture of the physiologic and biochemic features of the syndrome and their correlation with the clinical findings.

In studying these patients in whom renal insufficiency developed following trauma we have dealt with a unique group of individuals. They were nearly all young men, and so far as was known, physiologically sound prior to wounding. They had incurred severe wounds which almost immediately began to cause changes in their internal environment. Because of the effectiveness of resuscitation and other early treatment, the wounds and the changes produced were not severe enough to cause early death. These men withstood operation fairly well, largely because they had been adequately treated preoperatively, but beginning with the first day or two after operation (or after trauma, if no surgery was done) they began to show clinical and laboratory evidence of inadequate renal function. The renal failure progressed rapidly and in most instances the patients either died in uremia within 10 days or then began to show signs of improvement of renal function, such as diuresis and clearance of nonprotein nitrogen, and subsequently recovered.

In selecting patients presumed to have diminished renal function, two main criteria were utilized: the nonprotein nitrogen level in the blood plasma, and the degree of urinary suppression. Much of the data presented in 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


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are also correlated with the degree of urinary suppression because a low urinary output provides a simple and useful clinical means of recognizing many cases of impending renal failure. Our definitions of "high azotemia" and of oliguria and anuria have been given, and the diagnostic features of the syndrome were discussed in Chapter IV.

The incidence of high azotemia, oliguria, and anuria in our series is shown in Table 52. In 5 of the 186 patients no nonprotein nitrogen determinations were made and in 50 the urinary output was unknown. Seventy-three of 181 patients were found to have high azotemia. Thirty-three of 136 patients had anuria for at least 24 hours, 45 oliguria (they did not reach anuric level at any time), and 58 had a normal output of urine. Of the patients with high azotemia, 27 also had anuria and 29 oliguria.

TABLE 52.-PLASMA NONPROTEIN NITROGEN LEVEL AND URINARY OUTPUT 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 azotemia or urinary suppression or both. The serious implication of the onset of these conditions is well illustrated by Table 53. Of the 73 patients with high 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 these patients; it was the primary cause of 34 (68 percent) of the deaths among patients with high azotemia and of 22 (73 percent) of the deaths among patients with anuria.

TABLE 53.-CASE FATALITY RATES AND TYPE OF DEATH IN ALL PATIENTS WITH AZOTEMIA AND/OR URINARY SUPPRESSION
Degree of Initial Shock

The relationship of the degree of shock on admission to subsequent development of renal failure is shown in Table 54. When the crush cases, a case of true transfusion incompatibility, and a case of sulfathiazole crystalluria in the group without shock are excluded, it becomes evident that a preponderance of patients in whom signs of renal failure appeared were recognized as having had severe or moderate initial shock. With the above-mentioned cases excluded, 86 percent of the azotemia group, 73 percent of the oliguria group, and 76 percent of the anuria group had had moderate or severe shock at the time of hospital admission. Many men may have had transient shock, even of several hours' duration, before hospital entry with no sign of shock on entry. Our figures therefore are doubtless too low. It is not, however, clear that the severity of the renal lesion is entirely determined by 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 appreciable degree of shock yet who subsequently manifested renal insufficiency.


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TABLE 54.-RELATIONSHIP OF INITIAL SHOCK TO DEVELOPMENT OF RENAL INSUFFICIENCY
Survival Period after Wounding

The time of death after wounding was considered in 51 patients who had renal insufficiency (Table 55). Of these 51, uremia was the cause of death in 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, or 43 percent, died in the first 5 days and 17, or 48.5 percent, in the second 5 days--more than 91 percent within 10 days after wounding. Of the entire group of 51 fatalities, 94 percent (48 patients) died within the first 10 days. The significance of this time factor will be illustrated in connection with the biochemic data and in the

TABLE 55.-PERIOD OF SURVIVAL AFTER WOUNDING IN 51 PATIENTS WITH RENAL INSUFFICIENCY


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following chapter on therapy. Evidence will also be presented that if patients can be carried through this 10-day critical period, they stand a fair chance of recovery. This point will be further discussed later; it emphasizes the importance of avoiding certain therapeutic errors which can result in death, such as overloading the circulatory system by administration of too much fluid.

Type and Location of Wounds

The type and location of major wounds and injuries in patients with renal insufficiency (as indicated by nonprotein nitrogen retention and urinary suppression) is shown in Table 56. In the former classification--the high azotemia group--peripheral wounds with fracture and intra-abdominal wounds are of equal frequency. In the latter, peripheral wounds predominate in the oliguria group whereas in the anuria group intra-abdominal wounds are somewhat more frequent. Thoracic wounds are third in all three groups. Wounds of the liver,

TABLE 56.-TYPE AND LOCATION OF WOUNDS OR INJURIES IN PATIENTS WITH RENAL INSUFFICIENCY


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kidneys, and urinary tract occurred, but not in a high percentage in any group.

Hypertension

Table 57 shows the number of patients having high azotemia who at some time in their course also had a systolic blood pressure of 135 mm. Hg or higher, or a diastolic pressure of 90 mm. Hg or higher. These figures represent the probable upper limits of normal for the age group into which our patients fell. Blood pressures were recorded in 71 of 73 patients with high azotemia, 67 being recorded within the first 7 days after wounding or injury, including crush injury. Hypertension developed in 44 patients, usually during the first week. In the few in whom it was first noted after this period, the probability is that they also had an unobserved hypertension prior to the first determinations recorded. In general the blood pressure rose gradually, reaching a maximum between the third and sixth days after wounding. This agrees essentially with the time of maximum nitrogen retention in the blood.

Of the 27 patients who did not have hypertension, 20 died. Of these 20, thirteen died within the first 4 days after wounding, three within 6 days, and four between 6 and 10 days. Of those who died within a few days after wounding, many had never really recovered from shock. It seems probable that they would

TABLE 57.-INCIDENCE OF HYPERTENSION IN PATIENTS WITH HIGH AZOTEMIA


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have developed hypertension if they had lived longer, especially those in whom the primary cause of death was uremia.

Other Clinical Findings

Edema was observed in 23 of the 73 patients with high azotemia. The edema varied in degree, but it was usually generalized, involving all extremities and the face. It was present in 18 patients who died. Three patients had generalized convulsions. Eyegrounds were examined in 7 patients; 2 showed flame-shaped hemorrhages and 1 a small exudate. A pericardial friction rub was heard in 1 patient who died of uremia, and pericarditis was found on necropsy.

Biochemic and Physiologic Features

BLOOD

Biochemic Abnormalities

A large number of blood chemistry studies were made preoperatively and postoperatively on the 73 patients with high azotemia. It was not possible to make daily or even regular determinations on every patient, and the number of cases indicated in the various cells of the tables to follow is conditioned by the available data. The plasma carbon-dioxide combining power, and the concentrations of plasma nonprotein nitrogen, chlorides, phosphate, protein, magnesium, phosphorus, creatinine, and uric acid, and of the serum sodium were determined. Average values are shown in Table 58 A through G and Table 59. When more than 1 determination of any constituent was made on any 1 patient during the postoperative periods specified in the tables, only the most abnormal value was selected for inclusion in the averages.

In both tables the data are presented in two ways: (1) on the basis of 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 discussed later, reflect the typical biochemic and physiologic alterations which occurred in those of the severely wounded patients in whom renal insufficiency developed. The data show the changes taking place during the acute phase either to the time of death or, in those who survived, through the recovery phase as long as we could follow the case. Variations will be mentioned whenever they are important.


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TABLE 58.-PHYSIOLOGIC AND BIOCHEMIC FINDINGS IN PATIENTS WITH HIGH AZOTEMIA*
A. Plasma Nonprotein Nitrogen**


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TABLE 58.-PHYSIOLOGIC AND BIOCHEMIC FINDINGS IN PATIENTS WITH HIGH AZOTEMIA
B. Plasma Carbon-Dioxide Combining Power*


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TABLE 58.-PHYSIOLOGIC AND BIOCHEMIC FINDINGS IN PATIENTS WITH HIGH AZOTEMIA
C. Plasma Chlorides*


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TABLE 58.-PHYSIOLOGIC AND BIOCHEMIC FINDINGS IN PATIENTS WITH HIGH AZOTEMIA
D. Plasma Phosphate*


132

TABLE 58.-PHYSIOLOGIC AND BIOCHEMIC FINDINGS IN PATIENTS WITH HIGH AZOTEMIA
E. Plasma Protein*


133

TABLE 58.-PHYSIOLOGIC AND BIOCHEMIC FINDINGS IN PATIENTS WITH HIGH AZOTEMIA
F. Serum Sodium*


134

TABLE 58.-PHYSIOLOGIC AND BIOCHEMIC FINDINGS IN PATIENTS WITH HIGH AZOTEMIA
G. Plasma Magnesium*


135

Nitrogenous Waste Products and Phosphorus

Nonprotein Nitrogen.-Averages of nonprotein nitrogen findings are shown in Tables 58A and 59. Although the number is small and the variation great in some periods, giving rise to large standard errors, the data are adequate to give a fairly representative picture. Generally nitrogen retention was already significant by the first postoperative day, increased rapidly during the first 10 days, and then began to decline. This is illustrated in Chart 18, which has been constructed from averages shown in Table 58A, "All Cases."

CHART 18. PLASMA NONPROTEIN NITROGEN IN PATIENTS WITH HIGH AZOTEMIA

As previously discussed, most of the fatalities occurred in the first 10 days, so the fall in nitrogen retention in the tenth through fifteenth days chiefly represents patients who recovered. In general the nonprotein nitrogen level rose progressively to the day of death in those patients dying primarily of uremia (Chart 19 and Table 60). However, two patients (Cases 66 and 93) who lived longer than 10 days after wounding (14 and 13 days respectively) had begun to show some evidence of returning renal function. The importance of this fact in relation to therapy cannot be too strongly emphasized: it is essential to avoid


136

any measure that might precipitate death before this spontaneous recovery can occur.

CHART 19. PLASMA NITROGENOUS WASTE PRODUCTS AND PHOSPHORUS IN PATIENTS WHO DIED OF UREMIA
Marked qualitative differences are clear between patients in the different categories shown in Tables 58, 59, and 60. In many instances the standard error of the mean is large, indicating wide variation of values in the cases listed; also the number of cases in many categories is small. Differences in degree of nitrogen


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retention seem to be evident, however, (1) between those who lived and those who died of uremia, and (2) between those with a normal output of urine and those with oliguria or anuria. The time of greatest retention is essentially in the same periods as shown in Chart 18.

An attempt to determine whether the development of azotemia could be correlated with the degree of initial shock was not successful. As was mentioned previously, of the total number of patients who developed posttraumatic azotemia, oliguria, or anuria, a large proportion had had severe or moderate shock on hospital entry. A few patients who had no shock or only slight initial shock (so far as we could determine) had subsequent renal insufficiency, and the renal failure was as severe as in those with previous moderate or severe shock. Similarly there was no evidence that nonprotein nitrogen retention was initially greater in patients who subsequently died of uremia or who developed oliguria or anuria than it was in those whose renal failure was less severe.

For those interested in further differences between categories of patients and in day-to-day changes in the nonprotein nitrogen and other constituents of the plasma, the detailed analyses in Tables 59 through 62 are included. The essential trends are illustrated in the charts; minor variations are evident in the tables. The lack of effect of ether anesthesia on nonprotein nitrogen levels was discussed in Chapter II.

Creatinine and Urea.-In general, creatinine rose in the plasma at about the same rate as the nonprotein nitrogen (Chart 19). Also, as with other nitrogenous products and the electrolytes, there was no correlation between the degree of initial shock and elevation of creatinine during the period of posttraumatic renal failure. The plasma urea nitrogen level was determined simultaneously with total nonprotein nitrogen and creatinine in 15 cases (Table 63). Like creatinine, it rose approximately as the total nonprotein nitrogen rose. The relationships of these three substances when nonprotein nitrogen was elevated are shown in the table. The averages were obtained by using 38 determinations from a larger series on 15 patients, but including only those in which the nonprotein nitrogen was over 100 milligrams per 100 cubic centimeters. When more than 1 determination was included from the same patient, the samples were drawn at least 24 hours apart.

Although all waste products which make up the total nonprotein nitrogen rose in our patients, they did not accumulate in exactly the same proportions seen in the normal individual, if these figures represent a fair sample. However,


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TABLE 59.-AVERAGE PLASMA NITROGENOUS WASTE PRODUCTS AND PHOSPHORUS IN HIGH AZOTEMIA
PREOPERATIVE PERIOD
FIRST POSTOPERATIVE DAY


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TABLE 59.-AVERAGE PLASMA NITROGENOUS WASTE PRODUCTS AND PHOSPHORUS IN HIGH AZOTEMIA-Continued
SECOND POSTOPERATIVE DAY
THIRD POSTOPERATIVE DAY


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TABLE 59.-AVERAGE PLASMA NITROGENOUS WASTE PRODUCTS AND PHOSPHORUS IN HIGH AZOTEMIA-Continued
FOURTH POSTOPERATIVE DAY
FIFTH POSTOPERATIVE DAY


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TABLE 59.-AVERAGE PLASMA NITROGENOUS WASTE PRODUCTS AND PHOSPHORUS IN HIGH AZOTEMIA-Continued
SIXTH POSTOPERATIVE DAY
SEVENTH POSTOPERATIVE DAY


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TABLE 59.-AVERAGE PLASMA NITROGENOUS WASTE PRODUCTS AND PHOSPHORUS IN HIGH AZOTEMIA-Continued
EIGHTH THROUGH TENTH POSTOPERATIVE DAYS

it would appear that both creatinine and urea make up a greater proportion of the total nonprotein nitrogen in patients with severe renal failure than in the normal individual.

Excretion of Urea and Creatinine.-In two patients who died in the first 6 postoperative days, 24-hour urea nitrogen and creatinine excretion was measured. The relationships of the total amounts of these substances in 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 products to low or decreasing urinary excretion of these same substances is distinctly shown. The fall in output and specific gravity of the urine is directly related to these changes. Twenty-four hour specimens were examined also in two patients who had recovery diuresis and will be discussed under that subject later in this chapter. One of these patients also showed diminished total excretion; the other was examined after his recovery and values were essentially normal.

Phosphorus.-The characteristic retention of phosphorus in renal failure was


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TABLE 60.-AVERAGE PLASMA NITROGENOUS WASTE PRODUCTS AND PHOSPHORUS IN PATIENTS WHO DIED OF UREMIA
also observed in our cases, and in general paralleled the degree of nitrogen retention (see Chart 19 and Tables 58A, 58D, 59, 60, 61, and 62). In these patients with posttraumatic azotemia, phosphorus retention was primarily due to impaired ability to excrete that substance; whereas the hyperphosphatemia seen in patients in shock soon after wounding was possibly due to release of phosphates secondary to muscle damage (Chapter I). Reference to Tables 58 through 62 and to the individual case records shows that the patients with the most severe renal damage had the greatest phosphorus retention.

Relationship of Calcium and Phosphorus.-Calcium and phosphorus determinations were made on 12 patients who had high azotemia. The well-known reciprocal relationship of calcium and phosphorus was present in the majority of these cases (Table 65).


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TABLE 61.-AVERAGE NONPROTEIN NITROGEN AND ELECTROLYTES OF PLASMA IN PATIENTS IN
WHOM OLIGURIA DEVELOPED


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TABLE 62.-AVERAGE NONPROTEIN NITROGEN AND ELECTROLYTES OF PLASMA IN PATIENTS IN
WHOM ANURIA DEVELOPED


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TABLE 63.-RELATIONSHIP OF PLASMA TOTAL NONPROTEIN NITROGEN, UREA NITROGEN, AND CREATININE IN 15 PATIENTS
 TABLE 64.-RELATIONSHIP OF URINARY NITROGENOUS WASTE PRODUCTS AND URINARY EXCRETION IN 2 FATAL CASES


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TABLE 65.-RELATIONSHIP OF CALCIUM AND PHOSPHORUS IN 12 PATIENTS WITH HIGH AZOTEMIA
 Uric Acid.-This substance, like phosphorus and creatinine, rose in patients with high azotemia as the nonprotein nitrogen did, and in roughly the same proportion while retention of both progressed with renal failure (Chart 19 and Tables 59 and 60). Here also the number of determinations was rather small in most categories, but the tendency for greatest retention of uric acid in those patients who had the most severe renal insufficiency will become apparent by in-


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spection of the tables and from the individual case records. The elevated uric acid seen in admission cases has been previously discussed and possible mechanisms for it mentioned in Chapter I.

Summary-Nitrogenous Waste Products

The nitrogenous waste products and phosphorus of the blood plasma all showed progressive retention as renal insufficiency which follows shock or trauma proceeded. In patients with high azotemia the maximum retention was observed between the sixth and tenth postoperative days. The majority of deaths occurred during this period also. Average values for nitrogenous waste products fell from the tenth to the fifteenth days, representing largely patients who recovered. The few patients who died after the tenth day usually showed progressive nitrogen retention up to the day of death, but in a few a falling nonprotein nitrogen level and rising urine output indicated beginning recovery even though they subsequently died of uremia. These time factors emphasize the importance from a therapeutic standpoint of making every effort to carry the patient through the critical first 10 days until the kidneys begin spontaneously to recover.

Acid-Basc Balance

Anions

Plasma Carbon-Dioxide Combining Power and Blood pH.-The only group with a sufficient number of determinations of combining power for dependable averages was that of "All Cases" of high azotemia from Table 58B. In these patients, initial low values were followed by a rise toward normal (normal range: 24-31 mEq./L.) during the first 4 postoperative days and a subsequent gradual fall during the next 12 days (Chart 20). A breakdown of these averages according to types of cases does not yield differences which are statistically significant. However, in general, those patients who had the most nitrogen retention, those who died in uremia, and those with oliguria or anuria tended to have the lowest values for carbon-dioxide combining power. Conversely, the patients with the least nitrogen retention, those who survived and who had a normal output of urine, tended to have normal values. There was no correlation of carbon-dioxide combining power with degree of shock after the preoperative day. The acidosis seen in patients who were in shock when they were admitted to the hospital was discussed in Chapter I. Evidence that a low carbon-dioxide combining


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CHART 20. PLASMA CARBON-DIOXIDE COMBINING POWER IN HIGH AZOTEMIA

power was a result of diminished alkali reserve in these patients is only indirect.

The pH of the venous blood was measured in five patients who simultaneously had low carbon-dioxide combining power and renal failure. The results were as follows:

Case No.

Plasma CO2 Combining Power 
(mEq./L.)

Blood pH
(venous)

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-ION CONCENTRATION OF URINE IN HIGH AZOTEMIA

blood, but they support the view that most of these patients were suffering from a metabolic acidosis. This acidosis was not of the hyperchloremic type. For further discussion, see the following sections on chlorides and sodium.

The range of the pH of the urine in patients with high azotemia gave at least a partial explanation for the acidosis; after the first postoperative day none of the patients was able to produce a urine more acid than pH of 6.0 despite an increasingly severe acidosis. In those in whom renal failure was most severe--those who died of uremia--this abnormality was even more evident (Charts 20 and 21). The inference here is that those mechanisms responsible for acidification of the urine, such as tubular transfer of hydrogen ion, were impaired. This subject will be discussed further in the section on Urine; average urine pH is shown in Chart 21 and Table 76. Measurements of urinary ammonia were too few to say whether the deficient formation of this base was also responsible for the acidosis.

Plasma Chlorides.-The relationship of the plasma chloride level to the severity of renal failure is shown in Chart 22 and Table 58C. The averages of all patients with high azotemia show progressive hypochloremia through the first 10 postoperative days and normal values after this time (normal range:


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CHART 22. PLASMA CHLORIDES IN HIGH AZOTEMIA

97.5-104). Of the patients who died in uremia, the average values show that an extreme hypochloremia was reached by the tenth day; only one of these patients survived longer than that day. Average values for patients who lived were only slightly low during the period of greatest nitrogen retention. Analysis of individual case records shows that the lowest plasma chloride levels usually occurred in those patients who died before the tenth day, and the rise in the level from the eleventh through the fifteenth day occurred largely in those patients who had a recovery diuresis or only minimal azotemia.

Relationship of Low Plasma Chloride Levels to Intake of Sodium Chloride.-The mechanism of the hypochloremia in these patients is not clear. Most of the patients with a low plasma chloride level were extremely ill and were taking practically no food by mouth; hence their source of salt was almost entirely derived from that administered parenterally. In those patients who presumably had the most severe renal lesions (those who died in uremia), there is a possible correlation between the quantity of parenteral sodium chloride given and the plasma chloride levels (Table 66). The table shows the influence of parenteral sodium chloride intake over a period of 3 days on the subsequent plasma chloride level in 32 patients who died and in 19 who survived. The patients were arbi-


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trarily divided into 2 groups: those with plasma chloride levels of 100 milliequivalents per liter or higher, and those with levels below a hundred.

TABLE 66.-RELATIONSHIPOF PARENTERAL INTAKE OF SODIUM CHLORIDE FOR 3 SUCCESSIVE DAYS TO SUBSEQUENT PLASMA CHLORIDE LEVEL
Of 32 patients who died in uremia, 11 had plasma chlorides of 100 milliequivalents per liter or higher up to the time of death. All of the 11 had received considerable parenteral sodium chloride in the previous 3 days. Twenty-one of the 32 had low plasma chlorides, under 100 milliequivalents per liter; 10 of these patients had received no chlorides parenterally during the previous 3 days, and the remaining 11 had received on an average considerably less salt than those in whom plasma chloride levels were found to be normal or high. It should be emphasized that this analysis of fatalities includes only patients who died in uremia, that is, those in whom the maximum degree of renal impairment could logically be expected.

Among 19 of 23 patients with high azotemia who lived, some relationship of parenteral salt intake to low plasma chloride is also evident in the table. In addition, these patients as a whole were not nearly so ill and it is likely that chloride intake by mouth was considerable, so the total salt intake probably largely exceeded parenteral salt intake. Examination of the individual records of patients who developed severe renal failure and yet lived (see also the section on Recovery Diuresis to follow) indicates that 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


153

degree associated with the sodium chloride intake. This relationship to intake is also brought out in conjunction with the discussion of sodium to follow.

Several exceptions to these generalizations were evident in individual cases. With apparently adequate salt intake, the chloride level was sometimes low, even in patients in whom there was no loss of chloride through Wangensteen drainage or vomiting. In one patient with high azotemia and with all the other clinical features common to the syndrome of severe renal failure, the plasma chloride levels were abnormally high (Case 133), but in this instance salt intake had been excessive.

It is possible that the hypochloremia might have been due in part to a simple dilution of the chloride ion, since practically all of these patients had an increased plasma volume. This will be discussed further in the section on Plasma Volume. No such connection is apparent, however, in Table 67 which shows plasma volume and plasma chloride determinations done simultaneously in 18 patients who subsequently died of uremia. No correlation between degree of initial shock and plasma chloride level could be demonstrated.

TABLE 67.-PLASMA VOLUME AND PLASMA CHLORIDE DETERMINATIONS IN 18 PATIENTS WHO DIED OF UREMIA


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Chloride Excretion.-Total chloride excretion was measured in five patients with high azotemia (Cases 104, 105, 107, 112, and 133). Of these, the two patients who died (Cases 105 and 107) had plasma chloride levels which were low or falling. In both of these and in Case 112, chloride excretion was practically nil; chloride intake was probably inadequate in each. Two of them (Cases 107 and 112, to be discussed at greater length in Chapter VII) also had an alkalosis due to administration of excess alkali, chiefly sodium bicarbonate, in an attempt to alkalinize the urine. Two of the three patients who lived had a recovery diuresis. Chloride excretion in one (Case 104) was essentially normal, but determinations were begun after 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 in 18 patients who died of uremia. In 9 determinations made on 8 patients who had normal plasma chloride levels, the average urine chloride concentration was
72.5±10 milliequivalents per liter. In 21 determinations on 10 patients with low plasma levels, it averaged 54.0±7.0 milliequivalents per liter.

From these data it can, however, be concluded that in cases of renal failure in our series the plasma chlorides in most cases tended to fall as renal failure progressed, the degree of hypochloremia depending to some extent on salt intake. The chloride excreted in the urine was measured in too few cases to state that the hypochloremia was not due to excessive excretion of the chloride ion. No correlation between plasma chloride level and increased plasma volume could be demonstrated, so the low levels, as far as can be determined from our data, were not due to simple dilution. In addition to inadequate salt intake, there must be other factors contributing to hypochloremia.

Plasma Phosphate.-The variations in phosphorus have been discussed in more detail in the preceding section on nitrogenous waste products. The phosphates are mentioned here again only to indicate their relation to total acid-base balance. Reference to Table 58B-E shows that the average plasma phosphates, when converted to milliequivalents, even when elevated to twice normal or over, constitute but a small portion of the total anions; they clearly account for only a portion of the carbon dioxide displaced in those cases in which carbon-dioxide combining power is low.

Plasma Protein.-Plasma proteins have been converted to milliequivalents in


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Table 58E. Inspection of these values in all categories shows a remarkable constancy with very small standard errors of the mean. Although the proteins represent a significant proportion of the total anions present, their importance in terms of change in acid-base balance is negligible.

Cations

Serum Sodium.-The number of sodium analyses (Table 58F) was small in comparison with those of anions. However, by grouping all determinations made on patients with high azotemia between the second and tenth postoperative days (or days after trauma) some interesting facts emerge (Table 68).

TABLE 68.-RELATIONSHIP OF SERUM SODIUM, PLASMA CHLORIDE, AND PLASMA CARBON-DIOXIDE COMBINING POWER TO PARENTERAL SODIUM AND CHLORIDE INTAKE IN HIGH AZOTEMIA-32 DETERMINATIONS IN 26 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 of the determinations were among patients dying in uremia, 2 were done on patients in whom uremia was contributory to death, and 1 on a patient in whom uremia was coincident with death. Five determinations were made on patients who survived, 4 of whom had severe renal failure. Nine of the 14 determinations which were above 139 milliequivalents per liter represent patients dying primarily of uremia; 2 determinations, patients in whom uremia was contributory to death; 2 deter-


156

minations, patients who lived but had severe renal failure, and 1 determination a patient with slight renal failure who survived. Fifteen of the 18 determinations below 140 milliequivalents per liter represent patients dying primarily of uremia, 1 a patient in whom it was coincident with death, and 2 patients who survived but had severe renal failure.

Several facts seem evident from these data: 1. Serum sodium and plasma chloride concentrations were related to intake of these ions, regardless of the severity of the renal insufficiency present. 2. The acidosis, as reflected by the low carbon-dioxide combining power, was equally severe regardless 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 is no direct evidence that the diminished sodium and chloride concentrations affected the course of the syndrome.

The cause of the acidosis in these cases is not clear. If the acidosis were due to loss of total base, one might expect a lower carbon-dioxide level in the low-sodium group; if due to substitution of chloride for carbon dioxide, the plasma chlorides should be high. As stated before, phosphates were not sufficiently elevated to account for the change entirely in terms of base equivalence. Proteins remained constant and essentially normal. Sulfates and organic acids were not measured; these two components might account for some of the discrepancies evident in our data.

Plasma Magnesium.-There were too few determinations of plasma magnesium to be significant (Table 58G). Because of this, 14 determinations made between the second and tenth postoperative days in 13 cases (two determinations on the same patient on different days are included) were averaged and were 2.3±0.1 milliequivalents per liter. The nonprotein nitrogen determinations done simultaneously on these 13 patients averaged 164±22 mg. per 100 cubic centimeters. If these few determinations are significant, there was no evidence of abnormal magnesium metabolism in this type of renal insufficiency.

Serum Potassium.-Determinations of this substance were made in only seven patients (Cases 78, 80, 107, 112, 133, 135, and 138). In two of these (Cases 78 and 80) the values were 9.1 and 9.8 milliequivalents per liter respectively after several days of anuria or oliguria and just prior to death. In three (Cases 133, 135, and 138) they varied between 6.2 and 7.0 milliequivalents per liter. In the remaining two (Cases 107 and 112) the values were normal (3.9-5.3). Analysis of these cases showed that hyperpotassemia occurred only when urine volume was greatly decreased.


157

Serum Calcium.-This was discussed in the section on Nitrogenous Waste Products and Phosphorus.

Summary-Acid-Base Balance

From the data presented it is apparent that in lower nephron nephrosis resulting from shock or trauma, the most characteristic electrolyte abnormality consists of a progressive, fairly severe acidosis. Hypochloremia was also a frequent but not constant finding, one which we have been unable to explain adequately. Phosphate retention contributes to the acidosis. Serum cation determinations were few. Sodium concentrations followed no constant pattern. Potassium was found to be elevated at the time the patients had oliguria or anuria.

Physiologic Abnormalities

Plasma and Blood Volume

Plasma volume was determined in 23 patients at a time when they had posttraumatic renal insufficiency. The results were striking and of practical importance, for they indicated that increase in plasma volume was a part of the abnormal physiologic picture. Nineteen of these patients died and 4 survived through the mechanism of recovery diuresis. Average plasma volume determinations are shown in Tables 69 and 70, the former for all cases and the latter for fatal cases. Tables 71, 72, and 73 list the individual plasma and blood volume changes and related data on each of the 23 patients.

Relationship of Plasma Volume to Fluid Intake.-Referring first to Tables

TABLE 69.-AVERAGE PLASMA VOLUME CHANGES* IN 23 PATIENTS WITH RENAL INSUFFICIENCY


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69 and 70, it is evident that the average plasma volume for the entire group was increased significantly above the calculated normal after development of renal insufficiency, the average increase for all 23 cases being 43.3±5.7 percent. In the 19 fatal cases the average increase was 41.6±6.6 percent. The fatal cases were further analyzed as to the quantity of intravenous fluid administered. Average increases for the 15 patients who received an average of 1 liter or more of fluid intravenously daily (Group A, Table 70) were much greater than for the 4 patients who received less than 1 liter daily (Group B, in Table 70). Analysis of Tables 71 and 72, from which the averages in Table 70 were computed, shows that no patient in Group A and only 1 patient in Group B had a normal or subnormal plasma volume after development of renal insufficiency. In this patient (Case 136) there is some reason to question whether deficient circulating blood volume was adequately replaced, and hence whether he ever really recovered from shock during the 3 days he survived after wounding. The four patients who survived all showed increased plasma volume (Table 73).

TABLE 70.-AVERAGE PLASMA VOLUME INCREASE* IN 19 PATIENTS WITH FATAL RENAL INSUFFICIENCY
Table 74 represents further analysis of all 23 cases. In 22 of them plasma volume was found to be increased above the calculated normal when renal insufficiency developed. The one exception, a patient (Case 136) who showed a subnormal plasma volume, probably had not been adequately resuscitated, as stated above. Eighteen of the 22 patients with increases had received parenterally an average of 1 liter or more of fluid, crystalloid or colloid, daily. In 10 of the


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TABLE 71.-PLASMA AND BLOOD VOLUME CHANGES1 IN FATAL POSTTRAUMATIC RENAL INSUFFIENCY
Group A
: Patients who Received an Average of 1 Liter or More of Intravenous Fluids (Crystalloid or Colloid) Daily

22 patients multiple determinations were made and 8 of them showed progressive increases in plasma volume as renal failure became more severe. Of the 2 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 was high. His plasma volume was increased approximately 23 percent over normal on both


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TABLE 72.-PLASMA AND BLOOD VOLUME CHANGES1 IN FATAL POSTTRAUMATIC RENAL INSUFFICIENCY
Group B
: Patients who Received an Average of Less than 1 Liter of 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 increased plasma volume actually diminished although he subsequently died in uremia.

Among those who had increased plasma volumes were the four patients who had a recovery diuresis and survived. In three of them plasma volume first increased and then decreased as diuresis proceeded and nitrogenous waste products were excreted (Table 73). The progress of the plasma volume changes in relation to the plasma nonprotein nitrogen in these cases is shown in Chart 27. The fourth patient (Case 150) had his first determination after diuresis had begun although he still had severe renal failure and an increased plasma volume.

Relationship of Plasma Volume to Plasma Protein Concentration, Hematocrit Level, and Total Blood Volume.-The relationships of plasma volume to plasma protein concentration, hematocrit value, and total blood volume are evident in Tables 71, 72, and 73. There were considerable individual variations, but in general it can be stated that an expected coincident decrease in plasma protein concentration as the plasma volume rose during renal insufficiency was not usually demonstrated. Thus of the eight patients in whom the already increased plasma volume was known to rise, there were no significant changes in plasma protein concentration in five (three of whom received blood between measurements);


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TABLE 73.-PLASMA AND BLOOD VOLUME CHANGES1 IN 4 PATIENTS WITH POSTTRAUMATIC RENAL INSUFFICIENCY AND SUBSEQUENT RECOVERY DIURESIS
 TABLE 74.-TREND OF PLASMA VOLUME CHANGES DURING POSTTRAUMATIC RENAL INSUFFICIENCY IN 23 PATIENTS

there was an increase in one, and a decrease in only two. Explanation for 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 from protein sources elsewhere in the body.

The hematocrit level in the eight patients in whom plasma volume increased progressively (as shown by serial determinations) rose in one who received blood between measurements, was unchanged in three, two of whom received blood between measurements, and fell in four, one of whom received blood between measurements. Although the total blood volumes were also increased, the increments clearly were a reflection of the increase in the plasma volume, and because of the low hematocrit level in most cases, they were not as strikingly increased as was the plasma volume.

These data indicate, then, that in posttraumatic renal failure, total circulating plasma volume is increased. This must be due largely to the inability of the kidneys to excrete adequate water. However, because the plasma protein concentration did not usually diminish as plasma volume increased, it is evident that the sole explanation is not simply that hydremia exists. There would seem to be also unexplained extrarenal factors interfering with maintenance of a normal extracellular fluid volume. The practical importance of these observations is self-evident. Administration of excessive quantities of fluids to these patients who already have increased extracellular fluid volume can probably do nothing toward stimulating the kidneys to excrete; it can cause fatal pulmonary edema.

Summary-Plasma and Blood Volume

Plasma volume was determined in 23 patients in whom posttraumatic renal insufficiency developed, 19 of whom died. Averaging all 23 cases, there was 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 signs of renal impairment appeared, and there was good reason to believe that this patient had never been adequately resuscitated from shock. Comparison of the plasma volume with simultaneous plasma protein levels indicates that there was an increase in total circulating plasma and not simply an increase in proportion of water in the plasma; i.e., in general, plasma protein did not decrease with increasing plasma volume. In those patients in whom serial determinations were made, including several who had a recovery diuresis, the time of maximum increase in plasma volume coincided with that of maximum azotemia, and in those who recovered, plasma volume and plasma nonprotein nitrogen diminished at parallel rates.


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URINE

Specific Gravity

One of the most striking and constant physiologic abnormalities observed in posttraumatic renal insufficiency was impairment of ability of the renal tubules to reabsorb water. Within a day or two postoperatively, those patients who developed renal impairment, almost without exception, lost the power to 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 were calculated from the specific gravities observed in routine specimens, usually the first morning one. They do not, then, represent true concentration tests, 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, when it was deemed safe to do them. In these patients, even after the retained nitrogenous products had been cleared and output had returned to normal, specific gravity remained fixed and low. (2) Many of the specimens were taken when the output of urine was very low and hence

CHART 23. URINE SPECIFIC GRAVITY IN PATIENTS WITH HIGH AZOTEMIA

Figures from "Anuria and Oliguria" grouping, Table 75.


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TABLE 75.-AVERAGE SPECIFIC GRAVITY OF THE URINE IN PATIENTS WITH HIGH AZOTEMIA*


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when the kidneys were theoretically concentrating urine to the maximum of their ability. (3) In many of the patients, particularly those who died in uremia, fluids were sharply restricted, usually to about 1 liter a day. This could be further reason for assuming that the average urine specimen would be concentrated if the kidneys were capable of making it so; on the other hand, this argument may be rendered untenable by the fact that plasma volume was probably increased in all cases. (4) Twenty-four hour urine specimens 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 total output of urine was diminishing.

It will be shown in the section on Recovery Diuresis that in those patients who did recover, the nitrogenous waste products were cleared because of an increasing output of urine but the urine specific gravity remained fixed at a low level. In summary, it appears from our data that in this syndrome one of the earliest functional derangements of the kidney to occur, and probably one of the last to disappear when recovery takes place, is the ability to concentrate the urine.

Hydrogen-Ion Concentration

The tendency of the acidity of the urine to decrease as systemic acidosis and renal failure progress has been previously discussed (see Plasma Carbon-Dioxide Combining Power under Acid-Base Balance, Chart 21, and Tables 76 and 77). From our meager data on measurement of titratable acidity and ammonia of the urine (see the section on Recovery Diuresis), it is probable that the mechanism of this failure to make a very acid urine is associated with a decrease in titratable acidity and thus is similar to that seen in most types of renal failure. Inability of the kidneys to produce a urine of maximum alkalinity, if presented with a surplus of base, also seems to be a feature of the syndrome (see Chapter VII) and again is similar to the situation occasionally seen in other types of kidney disease.

There is good evidence1 that acidification of the urine by active transfer of hydrogen ions, as well as ammonia production is accomplished by 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 OF THE URINE IN PATIENTS WITH HIGH AZOTEMIA*


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tubular cells. This provides further correlation, perhaps, of functional with anatomic findings in patients suffering from lower nephron nephrosis following shock or trauma.

TABLE 77.-AVERAGE SPECIFIC GRAVITY AND pH OF URINE IN PATIENTS WITH OLIGURIA OR ANURIA
Proteinuria and Pigment Excretion

As was pointed out in Chapter IV, all patients with proved renal lesions had proteinuria, and this finding was also a constant one in all patients with posttraumatic renal insufficiency. It was not, however, a specific finding, for it was absent in only 14 of the entire series of casualties studied. The relationship of pigment excretion in the urine to posttraumatic renal insufficiency will be discussed in Chapter VIII.

Summary-Changes in the Urine

The most striking change in the urine was the fixation of specific gravity at low levels within a day or two after the onset of renal failure following shock or trauma. This impairment of maximum reabsorptive capacity of water by the renal tubules persisted after other evidence of kidney damage disappeared in those patients who recovered. Inability to manufacture a highly acid urine in


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the presence of metabolic acidosis was also a constant feature in the patients studied.

Recovery Diuresis

The arbitrary choice of 65 mg. per 100 cc. or higher concentration of nonprotein nitrogen in the plasma as an index of renal insufficiency in this series of cases has been discussed. Of the 73 patients included in our "high azotemia" group, 23 (32 percent) lived. Those who survived may be further classified according to the degree of renal impairment they exhibited: Twelve had apparently only minimal interference with renal function, with a rapid return to normal after transient nitrogen retention. We were unable to follow one patient with a nonprotein nitrogen level greater than 65 mg. per 100 cc. who lived and so do not know what degree of renal insufficiency he ultimately had. Ten had even greater evidence of renal impairment and their course conformed with the syndrome we have designated as recovery diuresis.

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 resulting in clearance of nitrogenous waste products and return to normal of the electrolyte 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 majority of those with renal insufficiency died, and whether in their course or treatment there are any clues which might lead to more effective treatment than 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 group as 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 patients as for the entire group having renal failure. Three patients had had severe shock, 5 moderate, 1 slight, and 1 no shock. As in other instances, it is entirely possible that there may have been considerable shock in all 10, but so far as we could determine at the time of admission, they must be classified as above.

Five of the 10 patients had multiple major wounds. The major wounds in 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. Unfortunately the day-to-day records are not as accurate as one would like. Many of these patients were seen in field hospitals during periods of great military activity, 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 day in any of the cases. Eight of the 10 patients are known to have had at least 1 day of oliguria or anuria between the first and sixth postoperative days. Records of output of urine were not kept for the remaining 2 patients at the time they probably had oliguria, but questioning of ward personnel and of the patients suggested very strongly that they too had had oliguria during this period. The duration of oliguria ranged from 1 to 4 days. There followed then a period of gradually increasing output of urine, reaching in some cases 5 or 6 liters a day. The plasma nonprotein nitrogen level did not, as a rule, begin to decrease until several days after diuresis had begun.

Because of the increase in plasma volume during the period of increasing azotemia, it might be expected that total fluid output would exceed intake during the diuresis period. This clearly occurred in two cases (Case 60 (Chart 24) and Case 150). In the remaining eight cases it was impossible to demonstrate this fact from the figures available, for the records kept gave only an approximate estimate of total water balance; they did not account 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 logical to assume that total fluid output did exceed intake until equilibrium was reestablished.

All these patients had hypertension, by our definition. In general the blood pressure was highest at the time of the most severe nitrogen retention and the

CHART 24. RELATIONSHIP OF FLUID INTAKE AND OUTPUT IN A PATIENT WITH RECOVERY DIURESIS (CASE 60)
Output exceeded intake from the eighth day. If extrarenal losses were shown, output would have exceeded intake after the fourth day.

CHART 25. COURSE OF A PATIENT WITH RECOVERY DIURESIS (CASE 60)
Chart 25
. Recovery diuresis occurred in this patient following an initial period of renal insufficiency due to severe traumatic shock and great blood loss. Note: (1) Initial period of oliguria and diminished renal function as evidenced by low phenolsulfonphthalein excretion with fixed urine specific gravity which persisted throughout the period of observation. (2) The gradual increase in urinary output during the first week accompanied by rising blood pressure, rising plasma nonprotein nitrogen concentration, falling carbon-dioxide combining power and plasma chlorides. (3) The fall in nonprotein nitrogen occurring only several days after adequate urinary output, accompanied by improvement of phenolsulfonphthalein excretion, rising carbon-dioxide combining power and plasma chloride levels, and return of the blood pressure toward normal. See page 171.


172-173

elevation was significant, with levels ranging from 150 to 170 mm. Hg systolic and from 90 to 110 diastolic. Likewise, as diuresis proceeded and the nonprotein nitrogen levels fell, blood pressures returned to normal. One patient was evacuated to the rear before his hypertension had subsided and we were unable to obtain subsequent blood-pressure determinations.

Two patients (Cases 44 and 150) had generalized convulsions on the eighth and ninth postoperative days respectively. In one, the convulsions furnished the first clue to the attending medical officers that renal failure was present. One of these patients also had a small retinal hemorrhage in the fundus of one eye. Eyegrounds were examined in three other patients in the group and found to be normal. Four patients had clinical edema.

Blood Chemistry

The abnormal chemical pattern in this selected group of cases was essentially similar to that described in the preceding section. Chart 25 represents the course of the patient cited in Chart 24 and demonstrates the essential features seen in all such cases.

This man, who had had a period of severe initial shock, had oliguria for 1 day. Renal function, as measured by phenolsulfonphthalein excretion and the urine concentration test, was greatly impaired by the first postoperative day. A gradual increase in output of urine followed. Despite diuresis, however, the nonprotein nitrogen continued to rise for the first 7 days-apparently because, with a fixed specific gravity of the urine, the kidneys were not at first able to clear sufficient nitrogen. Blood pressure rose and fell approximately with the nitrogen retention. Electrolytes followed the pattern already described but returned to normal as renal function improved. The patient's inability to make an acid urine in the presence of a mild acidosis is evident from study of the chart. When the patient was evacuated on the fifteenth postoperative day, renal function was still reduced

CHART 26. COURSE OF A PATIENT WITH RECOVERY DIURESIS (CASE 133)
Chart 26. There was an excessive intake of sodium chloride during the previous 10 days, which is not shown on the chart. Note: (1) The unusually high serum sodium and plasma chloride levels. (2) A relatively low urinary chloride excretion during the period of maximum hyperchloremia and the extremely low excretion during the last days of the observation, although significant hyperchloremia persisted. (3) The slowly falling plasma nonprotein nitrogen level, although urinary output was over 2 liters a day during most of the period studied. See page 173.


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despite normal chemical findings in the blood.2 Results of blood chemistry and urine examinations, made in eight of the nine other patients, followed essentially the same pattern.

The time of maximum nitrogen retention varied; five patients had their highest nonprotein nitrogen level between the third and ninth days after trauma, and the remaining four between the tenth and thirteenth days. The period of time required for recovery of renal function varied from 6 to 25 days.

As mentioned earlier, hypochloremia was not as prominent a feature in these patients as in those who died in uremia, but it was present to some degree (plasma chlorides under 100 milliequivalents per liter) in five patients. One patient (Case 133), on the other hand, following a high intake of sodium chloride, had a pronounced hyperchloremia (plasma chlorides 144 milliequivalents 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 measured showed a significant increase over the calculated normal. It was greatest at the time of maximum nitrogen retention and decreased as diuresis proceeded. Three patients (Cases 60, 133, and 138, Chart 27) were discussed in the preceding section on Plasma and Blood Volume. A fourth patient (Case 150, Table 73) still had a significant elevation in plasma volume when first studied on the twelfth postoperative day after diuresis had begun.

Urinary Findings

Specific Gravity.-Five patients, following administration of pituitrin, were unable to concentrate urine above 1.015 as long as they were followed (up to 49 days postoperatively in one instance). One patient with very transient nitrogen retention could concentrate to 1.020 by the thirteenth day. Concentration tests were not done in the other four patients, but several specimens in three of them were uniformly dilute. In one (Case 30), two routine specimens taken at the time of maximum nitrogen retention were 1.019 and 1.023.

Twenty-four Hour Urine Analyses and Related Findings in Two Patients.-Examinations of 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. PLASMA VOLUME AND PLASMA NONPROTEIN NITROGEN CONCENTRATION IN 3
PATIENTS WITH RECOVERY DIURESIS
(CASES 60, 133, AND 138)
 recovery diuresis. In Case 133 the collections were started just at the end of the recovery period. Table 78 lists the findings in one of these patients (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-dioxide combining power during the first 3 days of collection. (2) Ammonia production was normal. (3) Chloride excretion and sodium chloride intake were normal. Plasma chloride values were normal. (4) Excretion of urea was high the first


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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 urine in this case were not numerous enough and varied too widely to draw any conclusions regarding acid-base regulation. Excretion of urea and creatinine was about what would be expected in a normal individual, but not sufficient to clear the retained nitrogen rapidly. Toward the end of the 10-day period during which 24-hour urine collections were made, plasma levels of urea nitrogen and creatinine be-

TABLE 78.-RELATIONSHIP OF 24-HOUR URINALYSES AND PLASMA BIOCHEMIC FINDINGS IN A PATIENT WITH RECOVERY DIURESIS (Case 104)


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gan to fall. Clearance rates of these substances, however, were diminished during the entire period of observation.

The relationship of serum sodium, plasma carbon-dioxide combining power, fluid and sodium chloride intake, urinary output, and urinary excretion of chloride in this same patient are also shown. After a high intake of sodium chloride, sodium and chloride retention developed. Plasma carbon-dioxide combining power fell, in this instance partially as a result of hyperchloremia. Chloride excretion was relatively low considering the high plasma chloride level. As the plasma chloride level fell, chloride excretion decreased to negligible amounts during the last 4 days, even though the plasma chloride level was still unusually high. High serum sodium accompanied the hyperchloremia. There is in this case evidence of a high renal "threshold" for both sodium and chloride excretion.

The course and essential features in this patient were characteristic of recovery diuresis, but he exhibited most unusual electrolyte abnormalities. Although he had an increased plasma volume (Chart 27), there were also marked hypernatremia and hyperchloremia. An elevated serum sodium is most unusual except in the presence of dehydration, which, if the measurements of plasma volume can be accepted, was not present in this patient. Further evidence of inability of the renal tubules to reabsorb maximum amounts of water is seen here in the dilute urines of total specimens in both Cases 104 and 133 during periods of high nitrogen retention.

Renal Clearance Tests and Phenolsulfonphthalein Excretion

The results of renal clearance and phenolsulfonphthalein excretion tests in patients with recovery diuresis were discussed in Chapter III. Briefly, in three such patients in whom clearance measurements were made, all functional components of the kidney were diminished when first observed and gradually returned toward normal over a period of several days or weeks. Similar evidence of functional impairment and subsequent improvement was seen in three additional patients with recovery diuresis on whom phenolsulfonphthalein excretory 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 designated as recovery


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TABLE 79.-RELATIONSHIP OF 24-HOUR URINALYSES AND PLASMA BIOCHEMIC FINDINGS IN A PATIENT WITH RECOVERY DIURESIS (Case 133)


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TABLE 79.-RELATIONSHIP OF 24-HOUR URINALYSES AND PLASMA BIOCHEMIC FINDINGS IN A PATIENT WITH RECOVERY DIURESIS (CASE 133)-Continued


180

diuresis; namely, (1) nonprotein nitrogen greater than 100 mg. per 100 cc., (2) oliguria or anuria followed by diuresis and fall in nonprotein nitrogen, (3) low and fixed urinary specific gravity, and (4) hypertension. Their clinical course and physiologic and biochemic changes were entirely similar to those demonstrated in patients who died and were found at necropsy to have had lower nephron nephrosis. This group of patients demonstrates, then, that recovery from this type of renal disease can occur spontaneously if the patient survives the first critical 10 days after onset of renal failure.

SUMMARY

In earlier chapters the changes that began to occur in the internal environment soon after a man had been wounded were described. The effects of these early changes upon the kidney have been reported in this and the preceding 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 had normal kidneys at the time he was wounded, usually did not become manifest until two or three days later. At this time there appeared signs of failure on the part of the kidneys to withstand the initial insult, the effects of which his body had thus far resisted with fair success.

The first clinical sign of impending renal failure usually was suppression of urinary output. Of 73 patients with "high azotemia" (a plasma nonprotein nitrogen concentration of 65 mg. per 100 cc. or higher at some time during their course), 27 had anuria (urinary output of less than 100 cc. in any 24-hour period) and 29 had oliguria (output of from 100 to 600 cc. in a 24-hour period).

The case fatality rate was high. Fifty patients (69 percent) of the 73 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, reaction to incompatible blood transfusion, and sulfathiazole crystalluria are excluded--was observed in a large proportion of the cases. Eighty-two percent of those who had high azotemia, and, in another category, 73 percent of those who had oliguria and 69 percent of those who had anuria had been in moderate or severe initial shock. These figures are undoubtedly too low, for many men 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 51 patients who died of posttraumatic renal insufficiency. Apparently if the wounded man can withstand this critical 10-day period, recovery of renal function begins and he may survive. In a few patients there was evidence of returning renal function toward the end of their course, even though they died in uremia. The importance of this fact cannot be overemphasized, for a therapeutic error (such as overloading the circulatory system by fluid administration) during this critical period may cause a fatal outcome before 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 percent of those in this group who died in uremia. In many of the fatal cases in which hypertension did not develop, death occurred within 4 days after wounding. Had these patients survived longer, probably they too would have had hypertension.

The important biochemic and physiologic abnormalities in the blood resulting from posttraumatic renal insufficiency were found to be nitrogen and phosphorus retention, 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 failure to make a highly acid or alkaline urine in the presence of metabolic acidosis or alkalosis; (3) diminished glomerular filtration rate and renal blood flow, and (4) decreased phenolsulfonphthalein and maximum tubular excretory capacity of para-amino hippuric acid.

Nonprotein nitrogen, urea nitrogen, creatinine, uric acid, and phosphorus levels in the plasma rose as renal failure progressed during the first 10 days after wounding. Most observations after this period were on patients who recovered. The level of these waste products fell between the tenth and fifteenth days.

A progressive, fairly severe acidosis was characteristic, manifested by falling plasma carbon-dioxide combining power as renal failure advanced. Loss of ability to make a highly acid urine in most cases suggests that the acidosis was partially to be explained by impairment of the mechanism which produces an acid urine. A few observations also indicated, as expected, an impairment of ammonia production by the renal tubules. There was also good evidence that removal of sodium by excretion as sodium bicarbonate was poorly accomplished


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in those cases in which alkalosis resulted from administration of large quantities 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 inadequate salt intake. Serum sodium levels showed similar correlation. There was no difference in case fatality between the group with hypochloremia and those with normal plasma chloride levels. One patient with renal failure had severe sodium and chloride retention following a high salt intake. Intake, however, does not entirely explain variations in plasma chloride levels. No correlation with degree of plasma volume increase was apparent, but it is suggested that some interference with water and sodium chloride equilibrium was present in addition to the demonstrated relation to intake.

Phosphates in terms of acid equivalence, contributed toward but did not entirely account for the acidosis. Plasma proteins, if converted to milliequivalents, were normal and constant. Sulfates and organic acids were not measured and possibly account for discrepancies in our anion determinations.

Cation determinations were few. It has already been stated that sodium levels were partially correlated with salt intake. Magnesium was not significantly elevated in most cases. Potassium was determined in only a few cases, but the results suggest that hyperpotassemia was probably a feature of the syndrome. Calcium followed a reciprocal relationship with rising phosphorus levels in the few cases in which such determinations were made.

Total plasma volume was significantly elevated in 22 of 23 patients with posttraumatic renal insufficiency. Nineteen of these 23 died. Three patients with severe renal failure in whom a recovery diuresis developed had plasma volume increases that reached a maximum at the time of greatest nitrogen retention and decreased after diuresis. The degree of increase of the plasma volume was clearly related to fluid intake. The water retention appeared to be largely a result of administration of more fluid than the impaired kidneys could excrete. Comparison of plasma volume with total blood volume indicated that it was the plasma which was increased, rather than all elements of the blood. The expected dilution of plasma proteins was not demonstrated in most cases. The practical importance of this increase in plasma volume has been mentioned.


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Ability to concentrate the urine diminished rapidly as the syndrome of posttraumatic renal insufficiency progressed, and specific gravity became fixed in all patients with a severe degree of renal failure. In patients who recovered it was the last of the kidney functions of those measured to return to normal. Since urine concentration is accomplished by the distal tubular cells, whereas mannitol, para-amino hippuric acid, and phenolsulfonphthalein reflect glomerular and proximal tubular function, the lag in recovery of water-reabsorptive capacity may point to greater relative functional impairment of the lower nephron.

Ten patients of the 73 who had high azotemia exhibited all of the features of severe renal failure and subsequently a diuresis developed and they recovered. The course of these patients followed a pattern which has been termed the "syndrome of recovery diuresis." This small group re-emphasizes the importance of avoiding early fatal therapeutic errors (such as overloading the circulatory system with fluid) thereby affording the kidneys an opportunity to recover spontaneously.

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