U.S. Army Medical Department, Office of Medical History
Skip Navigation, go to content

HISTORY OF THE OFFICE OF MEDICAL HISTORY

AMEDD BIOGRAPHIES

AMEDD CORPS HISTORY

BOOKS AND DOCUMENTS

HISTORICAL ART WORK & IMAGES

MEDICAL MEMOIRS

AMEDD MEDAL OF HONOR RECIPIENTS External Link, Opens in New Window

ORGANIZATIONAL HISTORIES

THE SURGEONS GENERAL

ANNUAL REPORTS OF THE SURGEON GENERAL

AMEDD UNIT PATCHES AND LINEAGE

THE AMEDD HISTORIAN NEWSLETTER

Chapter VIII

Contents

CHAPTER VIII

Pigment Mobilization in Severely Wounded Men

It was shown in Chapter IV that severely wounded men commonly excrete heme-containing pigments, either hemoglobin or myoglobin, in the urine and that such excretion was constantly observed in patients destined to develop the syndrome of posttraumatic renal insufficiency. In Chapter IX the significance of pigment excretion will be further emphasized by demonstrating that pigment precipitation in the lower segments of the nephrons was a constant feature of the renal lesion observed in fatal cases. The importance of pigment mobilization, its transport via the plasma to the kidneys, and its excretion in the urine was therefore obvious early in our investigations, and the present chapter will be devoted to presentation of the available data and discussion of their significance.

Materials and Methods

We were severely handicapped by the lack of a spectroscope of sufficient sensitivity to distinguish between the closely similar spectrums of hemoglobin and myoglobin, and even if a suitable instrument had been available it is doubtful if it could have been utilized under field conditions. We resorted therefore to use of the benzidine method, which gave a color reaction strong enough to read in a Coleman Junior spectrophotometer in a dilution of 1 milligram of benzidine-positive material per 100 cubic centimeters. The method did not, however, permit distinction between myoglobin and hemoglobin in plasma, so throughout this chapter the term "plasma hemoglobin" is used to indicate the total amount of benzidine-reacting material, though in many instances a significant proportion was undoubtedly myoglobin. A further small fraction of the total was probably contributed by nonspecific oxydases, but it is improbable


202

that this was large enough to affect comparative results. Under these conditions, results of the test were always positive for "hemoglobin," ranging from 6 to 12 mg. per 100 cc. in the majority of initial samples and also in samples procured during convalescence. We therefore considered values up to 12 mg. per 100 cc. as being within normal range.

In the urine it did prove possible to distinguish between the two pigments within certain limits by taking advantage of the greater stability of myoglobin in alkaline solutions. By cautiously alkalinizing the urine, hemoglobin could be converted to alkaline hematin and precipitated while the greater portion of the myoglobin remained in solution. Tests with known mixtures of the two pigments showed that the separation was approximately 80-percent effective, and analyses of normal and decolorized muscles from patients who died of the crush syndrome provided further confirmation of the validity of the method. When enough pigment for quantitative determination was present in a urine specimen, this method was applied. Values of "myoglobin" that were less than 20 percent of the hemoglobin present were considered negative; findings of 20 percent or more were recorded as myoglobin. Details of the methods used will be found in Appendix C.

Determinations of plasma "hemoglobin" and of urine hemoglobin and myoglobin were made routinely upon all patients in the series from whom suitable specimens could be obtained. In some instances high plasma values were undoubtedly due to hemolysis incurred in taking samples of blood. Great care was used in cleaning and drying needles and syringes and in the technique of venepuncture, but needles and syringes were not paraffinized. In certain patients injury to the kidney or other portion of the urinary tract resulted in gross hematuria, and urine hemoglobin levels in these cases were considered valueless; however, if myoglobin was discovered in such specimens, it was recorded.

Bank Blood

Since hemolysis is inevitable in stored blood, many samples of bank blood, taken at the time the blood was given out for transfusion to our patients, were analyzed. The plasma hemoglobin and the blood sugar levels were determined, the latter in order to check upon the effectiveness of added dextrose as a preservative. Confirmation of the serologic blood group of the bank blood was not attempted because the triple check used in the theater blood bank was as ac-


203

curate as any method we could have tried. We did, however, take the precaution of checking the blood group of the recipient whenever possible since the "dog tags" were known to be approximately 8-percent erroneous, and since the grouping was often too difficult for hospital technicians because of the large quantities of group O blood that some patients had already received before the first test-specimen was obtained.

Few Rh factor determinations were made because very little typing serum was available. All patients, however, who were conscious at the time of observation were carefully questioned regarding previous transfusion and answers were uniformly negative. Previous sensitization was therefore improbable, and the short duration of the period of transfusion therapy--from 1 to 3 days--made active sensitization of no importance in our problem.

Specifications of Bank Blood.-Blood given to patients in this study was derived from the theater blood bank in all but two instances.1 All bank blood was group O and the plasma agglutinins against A and B cells had been determined. If these were below 1:64, the blood was labeled Universal Donor; if above this level, O-Blood, for Use in O-Recipients Only. The blood had been drawn into sodium citrate, and dextrose had been added to give a concentration approximating 0.3 percent. Blood was stored at all times, including periods of transportation, in refrigerators at approximately 8° Centigrade. It was never used after the tenth day.

Analyses of Bank Blood.-Since all blood samples contain cells of varying maturity, progressive hemolysis is inevitable in all stored specimens. This is apparent in Chart 29 and Table 84 which show average plasma hemoglobin levels at the time of transfusion in 213 samples of blood from 2 to 10 days old. The rate compares favorably with Gibson's2 figures based on storage in A-C-D solution. In occasional samples, usually those from 6 to 8 days old, considerable hemolysis was evidenced by plasma hemoglobin levels from 100 to 300 mg. per

    1Case 9 was an example of a transfusion accident--A blood to an O recipient. The patient was seen in consultation at a neighboring hospital and was studied for comparison only. The second patient (Case 22) belonged to group A. He received three transfusions of bank blood in a forward hospital and subsequently was given 2 units of group A blood at a general hospital. He had already given evidence of renal insufficiency before the type-specific blood was administered.
    2GIBSON, J. G., 2nd; EVANS, R. D.; AUB, J. C.; SACK, T., and PEACOCK, W. C.: The post-transfusion survival of preserved human erythrocytes stored as whole blood or in resuspension, after removal of plasma, by means of two isotopes of radioactive iron. J. Clin. Investigation 26: 715-738, July 1947.


204

CHART 29. RELATIONSHIP BETWEEN FREE PLASMA HEMOGLOBIN AND AGE OF STORED BLOOD-213 SAMPLES
 100 cc. (see Charts 30, 31, and 32). The average levels in samples from 5 to 8 days old, the age period of most of the blood used, were in the range from 38 to 50 milligrams per 100 cubic centimeters.

The possible effect of blood transfusions on the level of free hemoglobin in the blood plasma of the recipients is made readily apparent by a few simple calculations. Since the average amount of free hemoglobin in the bank blood at the time of transfusion was approximately 40 mg. per 100 cc., and 500 cc. of blood was the amount per unit, each patient receiving a unit of blood received at the time 200 mg. of free hemoglobin. Our patients received an average of 4.2 units of blood, or 840 mg. of hemoglobin, and in the fatal cases an average of 7.3 units, or 1,460 mg. of hemoglobin was given. Seven patients received from 10 to 14 units, or 2,000 to 2,800 mg. of free hemoglobin. Assuming an average blood volume to be 5,000 cc., such quantities of infused hemoglobin could have resulted in plasma levels of free hemoglobin in the patients of 16 to 58 mg.


205

per 100 cubic centimeters. It must not be forgotten, however, that these approximations are based on the assumption that all infused free hemoglobin would remain in the circulating plasma. This would certainly not be true, since in many patients significant quantities would be excreted in the urine and in all instances some would escape with the plasma into traumatized tissues.

TABLE 84.-RELATIONSHIP OF AVERAGE PLASMA HEMOGLOBIN LEVEL TO AGE OF STORED BLOOD-213 ANALYSES
Charts 30 through 33 show the relationship between hemolysis and sugar levels in the stored blood. It is evident that most instances of extreme hemolysis occurred in blood samples with low sugar levels. Table 85 and Chart 33 show average sugar levels in relationship to age of the blood. The chart shows that the sugar level was well maintained until the seventh day and dropped sharply thereafter.

TABLE 85.-RELATIONSHIP OF AVERAGE BLOOD SUGAR TO AGE OF STORED BLOOD-223 SAMPLES
 


206

CHART 30. Relationship between Plasma Hemoglobin and Blood Sugar in Blood Stored 6 Days-52 Samples

CHART 31. Relationship between Plasma Hemoglobin and Blood Sugar in Blood Stored 7 Days

CHART 32. Relationship between Plasma Hemoglobin and Blood Sugar in Blood Stored 8 Days

CHART 33. Relationship between Blood Sugar and Age of Stored Blood-223 Samples


207

Plasma "Hemoglobin" Levels in Wounded Men

The pattern of plasma "hemoglobin" (benzidine-reacting material) levels in severely traumatized men is shown in Charts 34 through 37. In Chart 34, based upon findings in 133 patients, the mean plasma hemoglobin level for each day after injury is plotted. From an initial figure of 10 mg. per 100 cc., it climbs in 72 hours to 17.3 mg., then slowly falls in the course of the next 13 days to a level of 3 mg. per 100 cc. of plasma. Chart 35 shows daily mean levels of 64 patients who had high azotemia, over half of whom died. The curve is essentially similar, though the peak is higher and is delayed 24 hours. In Chart 36 only the fatal cases with histologically proved pigment nephropathy are shown, exclusive of crush cases. In this group the peak is sharp and high, occurring at 24 hours and attaining a maximum of 36.8 mg. per 100 cubic centimeters. This figure is still far below the generally accepted threshold level of 135 mg. per 100 cc. at which a normal kidney begins to excrete hemoglobin.3 4 5

The plasma bilirubin level as determined by the van den Bergh diazo test has also been plotted on these charts, omitting cases of direct liver trauma. As would be expected, the bilirubin curve roughly paralleled that of hemoglobin but its peak occurred from 3 to 4 days later. Strict parallelism could not be expected since the bilirubin level is also affected by efficiency of liver function; evidence of liver injury in these patients is presented in Chapters II and XII.

In considering the significance of the plasma hemoglobin levels, two possible relationships at once come to mind: does the level depend upon the severity of shock? or upon the quantity of blood the patient was given? The answer is not obvious since the patients with the most severe shock usually received the most blood. Available evidence compiled from the first specimen of blood obtained for analysis is presented in Table 86. The following cases have been excluded: all crush cases, in which benzidine-reacting pigment in the plasma

    3GILLIGAN, D. R., and BLUMGART, H. L.: March hemoglobinuria; studies of clinical characteristics, blood metabolism and mechanism, with observations on three new cases, and review of the literature. Medicine 20: 341-395, September 1941.
    4GILLIGAN, D. R.; ALTSCHULE, M. D., and KATERSKY, E. M.: Studies of hemoglobinemia and hemoglobinuria produced in man by intravenous injection of hemoglobin solutions. J. Clin. Investigation 20: 177-187, March 1941.
    5OTTENBERG, R., and FOX, C. L., JR.: Rate of removal of hemoglobin from circulation and its renal threshold in human beings. Am. J. Physiol. 123: 516-525, August 1938.


208

TABLE 86.-MEAN PLASMA "HEMOGLOBIN" LEVELS IN RELATION TO SHOCK AND QUANTITY OF
TRANSFUSED BLOOD-76 CASES

 


209

CHART 34. AVERAGE LEVELS OF PLASMA "HEMOGLOBIN" AND BILIRUBIN RELATED TO TIME FROM WOUNDING IN 133 SEVERELY WOUNDED PATIENTS

may be assumed to have been predominantly myoglobin, all cases in which the initial specimen was not obtained within 3 days of injury, and Case 37 with several plasma hemoglobin levels above two hundred. This figure was so completely out of line with all other cases that a unique and unexplained mecha-


210

CHART 35. AVERAGE LEVELS OF PLASMA "HEMOGLOBIN" AND BILIRUBIN RELATED TO TIME FROM WOUNDING IN 64 PATIENTS WITH HIGH AZOTEMIA

nism of hemolysis must be assumed. Seventy-six cases were available for analysis after these exclusions.

In compiling the table, the patients were divided into three groups: (1) those who had received no blood transfusion prior to drawing of the first blood specimen for analysis; (2) those who had received small to moderate amounts of blood-from 1 to 3 units or 500 to 1,500 cc.--and (3) recipients of large quan-


211

CHART 36. AVERAGE LEVELS OF PLASMA "HEMOGLOBIN" AND BILIRUBIN RELATED TO TIME FROM WOUNDING IN 33 PATIENTS WITH PIGMENT NEPHROPATHY AT NECROPSY

tities of blood--from 4 to 14 units or 2 to 7 liters. Shock had been estimated in three grades of severity, and there were a few patients without shock. The


212

CHART 37. AVERAGE LEVELS OF PLASMA "HEMOGLOBIN" AND BILIRUBIN RELATED TO TIME FROM WOUNDING IN 107 PATIENTS OF BLOOD GROUPS A OR O
number of cases in some shock categories was so small, however, that only two categories were utilized: (1) patients with no shock or only slight shock (the minimal-shock" group), and (2) patients with moderate or severe degrees of shock. Data are shown separately for blood samples drawn within 24 hours of injury and those taken from 24 to 96 hours after injury.

It is apparent from inspection of the table that plasma hemoglobin levels


213

during the first 24 hours after injury showed no elevation which could be attributed either to shock or to infusion of bank blood. The mean plasma hemoglobin level for the entire group examined within 24 hours of injury was 9.6 mg. per 100 cc. of plasma, a normal figure for the technique used (See Materials and Methods). The mean for the moderate-and-severe shock group (8.8) was actually lower than the mean (11.7) of the minimal-shock group. More surprising are comparisons based on the quantity of transfused blood. The plasma hemoglobin levels actually appear to decline from a mean of 11.1 mg. per 100 cc. in the 14 patients who had received no blood to 9.2 in 22 patients who had had from 1 to 3 transfusions, and a minimum level of 7.5 in the 5 patients who had received the largest quantities of blood--from 4 to 14 units. These apparently paradoxical differences are not statistically significant, but it is clear that in this study no evidence emerged to indicate that during the first 24 hours after injury infused hemoglobin from stored blood produced any rise in plasma hemoglobin concentration.

In the succeeding 3 days, from 24 to 96 hours after injury, some rise in plasma hemoglobin was usually apparent. The average for the 35 cases in this category was 16.9 mg. per 100 cc. of plasma. Once again no evidence was obtained that shock per se produced any mobilization of hemoglobin. The mean of 17.3 mg. per 100 cc. for the moderate-and-severe shock group is not appreciably greater than the 16 mg.-figure for the minimal-shock category. In contrast to the findings in the first 24 hours, however, there does appear to be evidence that the plasma hemoglobin level rose in proportion to the quantity of transfused blood. It rose from a mean of 9.2 mg. per 100 cc. in the patients who had received no blood, to 15.1 in those who had received from 1 to 3 units, and to 20.5 in the patients treated with 4 or more transfusions. The difference between the first and third of these means, 11.3, is more than three times the standard error of 3.08.

In summary, the initial plasma free-hemoglobin levels of 76 wounded men who had had various degrees of shock, and who had received from none to 14 units of bank blood before the first sample of plasma was obtained for analysis, showed no rise in plasma hemoglobin concentration within 4 days after injury that could be attributed to the state of shock. During the first 24 hours after injury, the plasma hemoglobin concentration was surprisingly constant regardless of the amount of blood the patients had received. Hemoglobin in solution in the plasma of the infused bank blood was therefore not sufficient


214

to raise the plasma hemoglobin level of the recipient. After the first 24 hours, plasma hemoglobin levels did rise in the majority of patients. This rise could not be correlated with the degree of shock but did show an apparently significant correlation with the amount of transfused blood. Such a delayed hemolytic action could be due either to nonspecific, accelerated hemolysis of the infused group O red cells or to hemolysis of the recipients' red cells from accumulation of infused iso-agglutinins. Evidence bearing upon this possibility will be presented in the following section.

Iso-Agglutinins

Relationship to Pigment Nephropathy

In Chart 37, the mean plasma hemoglobin level of 56 patients belonging to blood-group A is compared with that of 51 patients belonging to blood-group O. A distinct peak in the former curve on the third and fourth days after injury is apparent. On the third day the mean level in the A group was 24 mg. of hemoglobin per 100 cc. of plasma as compared with 10 mg. per 100 cc. for the O group at the same period. The difference is large enough to indicate some degree of hemolysis due to a-agglutinins. No reason is apparent for the rather surprising delayed rise in plasma hemoglobin concentration in the O group, which appears on the eighth day. The precipitate character of this peak, with its sudden rise and drop and the lack of equivalent rise in the plasma bilirubin, suggests that this may reasonably be ascribed to inadequate sampling or technical error.

Relationship to Lower Nephron Nephrosis

If hemolysis due to iso-agglutinins in plasma or bank blood were of importance in the pathogenesis of lower nephron nephrosis, the lesion should have appeared with greater frequency in our patients of blood-groups A, B, and AB than in those of group O, since all transfusions, with the two exceptions previously noted, were of O blood. No evidence was obtained of any relationship of blood group to case fatality or to development of renal insufficiency.

Blood grouping in the 186 patients in the study was checked in our laboratory in 137 instances. The distribution of blood groups among these 137 patients is


215

shown in Table 87, both for all cases and for fatalities. It is evident that in both categories the distribution approximates closely the usual figures for a sample of the American population. Equally negative evidence of any effect of blood group is shown when the fatal cases of lower nephron nephrosis are considered. Blood group was known in 37 such cases which are shown on the table. It is evident that the distribution again approximates that of an average population.

TABLE 87.-DISTRIBUTION OF BLOOD GROUPS (CHECKED) AMONG ALL PATIENTS,1 THOSE DYING FROM ALL CAUSES, AND THOSE DYING FROM RENAL FAILURE
 

Hemoglobinuria and Myoglobinuria in Wounded Men

Relationship of Plasma Hemoglobin Levels to Excretion of Hemoglobin in the Urine

Excretion of hemoglobin in the urine is dependent upon two factors: the concentration of hemoglobin in the blood plasma and the permeability of the glomerular filter. As has already been pointed out, only one patient, Case 37, (crush cases excluded) showed a plasma hemoglobin concentration above 135 mg. per 100 cc., the usually-accepted threshold level for hemoglobinuria. An altered permeability of the glomeruli must therefore be assumed in all other patients manifesting hemoglobinuria. If the increase in permeability was more


216

or less constant, it might be expected that the degree of hemoglobinuria would be influenced by the level of plasma hemoglobin. If the alteration in permeability was variable, no such relationship would be demonstrable.

The concentrations of hemoglobin in plasma and urine are compared in Table 88 for 21 cases in which the two determinations were made upon samples collected at approximately the same time. The possibility that the urine might have been retained within the bladder for many hours before voiding could not always be excluded. No evidence of correlation is present, and the Spearman rank order coefficient of correlation (rho) is 0.03, indicating only chance relationship between the two series of figures.

TABLE 88.-COMPARISON OF HEMOGLOBIN CONCENTRATION IN PLASMA AND URINE IN 21 CASES
Excretion of Myoglobin in the Urine

Analyses for hemoglobin and myoglobin in the urine were carried out in 42 cases in which measurable amounts of benzidine-positive material were present. Myoglobin was positively identified in 19 cases and was the dominant pigment in nine. (Comparison was impossible in 5 of these because wounds of the urinary tract made urine hemoglobin figures unreliable.) In 8 additional cases the test for myoglobin was positive but the proportion found was so small (from 10 to 20 percent of the benzidine-reacting material) that the results were classed as doubtful and were disregarded. The analyses in the remaining 15 cases were recorded as definitely negative (myoglobin from 0 to 10 percent).


217

The 19 positive cases are listed in Table 89 together with the degree of shock, the concentration of myoglobin and hemoglobin in the urine, the level of benzidine-positive material in the blood plasma, and the major clinical diagnoses.

TABLE 89.-OCCURRENCE OF MYOGLOBINURIA AND CORRELATIVE FINDINGS IN 19 SEVERELY WOUNDED PATIENTS
Inspection of this table reveals several points of interest. As in the case of hemoglobinuria, it is obvious that there is no correlation between the level of benzidine-positive material in the plasma and the amount of myoglobin excreted in the urine. For example, in Case 38 only 4.3 mg. per 100 cc. were found


218

in the plasma, while the urine contained the enormous concentration of 420 mg. per 100 cubic centimeters. In Case 78, a patient with crush syndrome, the situation was reversed. The plasma concentration was 920 mg. per 100 cc., the maximal figure of the entire series, whereas the urine contained barely enough to measure--only 2.5 milligrams.

If the myoglobinuric cases are considered as a whole, the degree of myoglobinuria shows no relationship to the severity of shock. In the "minimal-shock" group (as previously defined), the concentrations of myoglobin in the urine ranged from 2.5 to 588.0 mg. per 100 cubic centimeters. In the moderate-and-severe shock group, the range was from 1 to 420 mg. per 100 cubic centimeters. The average of seven cases in the minimal-shock group was 321 mg. in comparison with 63.7 mg. for the more severe-shock group, but with such wide variation in the data the averages are meaningless.

TABLE 90.-RELATIONSHIP OF MUSCLE NECROSIS TO SHOCK IN 19 PATIENTS WITH MYOGLOBINURIA
When the nature of the major injury or lesion in these myoglobinuric cases is taken into consideration, however, an interesting correlation does become apparent. The cases fall readily into two groups: those with extensive necrosis of skeletal muscle (either ischemic or infectious) and those without such muscle necrosis. They are so listed, with the estimated degrees of shock, in Table 90.

Five of nine patients with extensive necrosis of skeletal muscles showed minimal or no clinical evidence of shock; in those without extensive muscle


219

necrosis, in contrast, eight were in the moderate-and-severe shock group and only two in the minimal-shock group. One of the latter, Case 74, with extensive burns showed sufficient hemoconcentration to suggest a more severe grade of shock than was clinically apparent. These findings strongly suggest, on the one hand, that myoglobin is rarely liberated in the absence of shock unless there has been extensive necrosis of skeletal muscle, and on the other, that in the presence of severe shock, there is some mechanism for its mobilization other than muscle necrosis.

Relationship of Hemoglobinuria to Myoglobinuria

Attempts to correlate the variety of pigment excreted in the urine with the type of injury or lesion provided extremely puzzling results, as may be seen from the tabulation to follow in which cases have been classified by the predominant pigment, though many of them showed simultaneous excretion of both pigments. Because of the frequency of multiple injuries, the same case has often been included under more than one heading. Cases of trauma to the urinary tract have been excluded from the hemoglobinuric but not from the myoglobinuric category.

Type of injury or complication

Number predominantly hemoglobin

Number predominantly myoglobin

Crush syndrome

2

3

Wounds of extremity

19

5

Major vascular interruption

11

3

Clostridial myositis

1

2

Urinary tract injury

---

2

Liver injury

4

1

Abdominal wound

11

3

Peritonitis

4

3

Burn

0

1

Volvulus

0

1


It is at once evident that any type of injury may be associated with either hemoglobinuria or myoglobinuria and that in most types, except the crush syndrome and in clostridial myositis, the former is by far the more common. It is noteworthy that in two typical crush cases no evidence of myoglobin excretion was obtained (see Chapter XI). Neither massive trauma to the extremities nor interruption of a major vessel, with consequent ischemic necrosis of muscle,


220

usually resulted in predominant myoglobinuria, and in two of the three patients in whom it did appear, a successful arterial anastomosis had re-established circulation of the leg before myoglobinuria was observed. In three patients (Case 70, extensive but superficial burns; Case 38, volvulus, and Case 9, mismatched transfusion) injury of voluntary muscle can be absolutely excluded. In considering the findings, however, it must be remembered first that our test for myoglobinuria was crude and results were recorded as positive only when considerable quantities of myoglobin were present, and second that myoglobin is rapidly excreted in the absence of renal insufficiency and the loss of a single urine specimen might cause a falsely negative result.

TABLE 91.-GREATEST CONCENTRATIONS1 OF HEMOGLOBIN AND MYOGLOBIN OBSERVEDIN THE URINE
 One final comparison is of interest. In Table 91 the 12 patients showing the highest concentrations of hemoglobin and the 12 with the highest myoglobin concentrations are listed. As before, cases of trauma to the urinary tract have been eliminated from the hemoglobinuric category. It is apparent from these figures that myoglobinuria was frequently massive whereas hemoglobinuria was rarely so when cases of direct trauma to the urinary tract are eliminated. It is also noteworthy that four cases (Cases 38, 70, 74, and 93) appear in both lists, suggesting that the conditions for the liberation of myoglobin and of hemoglobin may not be unrelated.


221

SUMMARY

The concentration of benzidine-reacting heme pigment in the blood plasma (recorded as plasma hemoglobin) and the individual concentrations of hemoglobin and myoglobin in the urine were measured in our patients to determine the extent of pigment mobilization. These data, together with determinations of plasma hemoglobin in the bank blood administered to the patients, were analyzed in an attempt to determine the mechanism of pigment mobilization in the body and of pigment excretion by the kidney.

It was found that the bank blood used in therapy was in a satisfactory state of preservation, with an average of only 43 mg. of free hemoglobin per 100 cc. of plasma at the moment of utilization. Even in patients who received as many as 10 to 14 transfusions, the plasma "hemoglobin" levels of the recipients showed in the first 24 hours no elevation which could be attributed to free hemoglobin in the transfused blood. Comparison of the plasma hemoglobin concentrations with the degree of shock in 76 patients showed no evidence that shock itself induced any immediate increase in plasma hemoglobin concentration.

Twenty-four hours after injury, however, a progressive rise in plasma hemoglobin began to be apparent which reached a peak between 48 and 72 hours and then slowly dropped to normal over a period of 2 weeks. This peak was approximately twice as high (36.8 mg. per 100 cc.) in 33 cases of fatal nephropathy as in the series as a whole (17.3 mg. per 100 cc.) and occurred only 24 hours after wounding. No evidence was obtained that it was higher in patients with severe shock than in those without shock or with only minimal shock. It was, however, significantly higher in patients who had received multiple transfusions than in those who had received no blood.

Evidence that this delayed rise in plasma hemoglobin was largely due to iso-agglutinins was afforded by comparison of group A and group O recipients. In 56 of the former, the mean plasma hemoglobin on the third day was 24 mg. per 100 cc., whereas in a sample of 51 group O recipients the corresponding level was only 10.2 milligrams. This difference was of no significance, however, in the development of pigment nephropathy as shown by the percentage distribution of blood groups among the nephropathies, which was essentially identical with the distribution of blood groups in the entire series of cases studied by the Board and with an average sampling of the American population.

In 21 cases in which plasma hemoglobin levels were obtained at approxi-


222

mately the same time that the first urine specimen was voided, the concentrations of pigment in the two fluids were compared. No evidence of correlation was found. It was concluded that the threshold of hemoglobin excretion in wounded men must vary over a wide range.

Myoglobin was positively identified in the urine of 19 patients in the series and these cases were subjected to special scrutiny. As in the case of hemoglobin, no correlation was found between the concentrations of benzidine-reacting pigment in the plasma and of myoglobin in the urine.

With the exception of clear-cut cases of the crush syndrome, excretion of myoglobin could not be predicted from the nature of the patient's injury or its complications. It was rarely seen in wounds of the extremities, even those associated with extensive necrosis of muscle, unless they were complicated by clostridial myositis, or, as in two cases, circulation was re-established after a period of ischemia by a successful arterial anastomosis. It was sometimes very severe in patients with little or no muscle damage. When muscle damage was extensive, the mobilization and excretion of myoglobin appeared to be independent of the development of shock. When there was insignificant or no muscle injury, myoglobinuria was rarely found in the absence of moderate or severe shock.

Two further observations are noteworthy though their significance is not apparent. Myoglobinuria was frequently massive, hemoglobinuria rarely so in the absence of injury to the urinary tract. Myoglobinuria and hemoglobinuria of significant degree frequently occurred in the same patient, suggesting a common but undiscovered mechanism.

CONCLUSIONS

1. Neither the development of shock nor the therapeutic use of multiple transfusions of group O bank blood produced immediate elevation of the plasma "hemoglobin" levels in severely wounded men.

2. The delayed rise in mean plasma "hemoglobin" for the series as a whole in the period from 24 to 96 hours was largely attributable to iso-agglutinins in the O bank blood, since it was absent in a sample of 51 O recipients.

3. Mean plasma "hemoglobin" concentrations were higher in the patients in whom pigment nephrosis developed than in other wounded men but were still far below the threshold level at which the normal kidney excretes hemoglobin.


223

A depression of the threshold for hemoglobin excretion must be assumed.

4. The lack of correlation between concentrations of benzidine-reacting pigment in the plasma and of hemoglobin or myoglobin in the urine suggests that this alteration of threshold was variable.

5. The irregularity with which extensive muscle injury was followed by myoglobinuria indicates that some factor other than necrosis of muscle cells is involved. This factor is not shock and appears to be the maintenance or re-establishment of the circulation in the involved muscles.

6. In a small number of cases severe myoglobinuria developed in the absence of demonstrable muscle injury. The almost constant presence of moderate or severe shock in such cases suggests the possibility of diffuse ischemic injury of muscle which is not morphologically recognizable.

7. The fact that severe myoglobinuria and severe hemoglobinuria were often observed in the same patient suggests the possibility of a common mechanism.

RETURN TO TABLE OF CONTENTS