Medical Science Publication No. 4, Volume 1

THE EFFECT OF SEVERE BATTLE INJURY AND OF POST-TRAUMATIC RENAL FAILURE ON RESISTANCE TO INFECTION*

MAJOR HENRY H. BALCH, Jr., MC, USAR

Introduction

Acute infection remains one of the serious complications of severely wounded soldiers. Its incidence, in terms of total casualties in Korea, was probably low; possibly 20 percent of the severely wounded who were resuscitated had complicating infection. About 5 percent of severely injured develop acute renal failure, and the incidence of infection is high in this group also. There are several reasons why severely wounded casualties may be more prone to infection-these include such things as the degree of tissue damage, the amount of bacterial contamination, delay in initial and subsequent surgical treatment, errors in judgment, etc.

The purpose of today's presentation is to discuss the possibility that severely wounded casualties and those with acute renal failure may be more prone to infection because of some breakdown in basic body defense.

There are several natural mechanisms of body defense following bacterial penetration. The microorganisms may be trapped or eliminated by lymph nodes draining the area. Cells of the reticuloendothelial system or wandering phagocytes may ingest and destroy pathogens. This process is much more effective if specific antibody is present. In addition, natural and specific antibody (globulin) participates in the lysis of a number of bacterial species and also neutralizes the products of others. A group of proteins found in normal serum which have been called complement possess several properties of importance in antibacterial defense; these include a capacity to kill bacteria sensitized by antibody and to render the microorganisms more susceptible to phagocytosis. If a defect in globulin synthesis or a depression of reticuloendothelial cell function or leukocyte activity follows severe injury, the defense effort might be impeded seriously and such patients become prone to infection.

*Presented 21 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington, D. C.

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In this investigation I attempted to measure the phagocytic activity of circulating leukocytes, the serum complement levels and the capacity of a patient to synthesize specific antibody, and then I tried to correlate the findings with the clinical course and with the presence or absence of infection. The methods were simple. For phagocytosis we took fresh specimens of blood and counted the number of neutrophils; we mixed a known number of neutrophils with a known number of pathogenic Staphylococci, rotated these in a 37° C. incubator, and at a fixed interval we counted the number of neutrophils which had ingested organisms, and so estimated their activity. Complement was assayed by measuring the least amount of plasma which would hemolyze specifically sensitized sheep red cells. The capacity to synthesize antibody was determined by measuring the response to the booster injection of tetanus toxoid immediately following wounding. The series was small because only severely wounded patients were studied.

Phagocytosis

Table 1 shows the number of neutrophils which ingested Staphylococci in 2 groups of patients, 6 nonwounded and 12 lightly wounded; 94 percent of the neutrophils from nonwounded and 88 percent from the lightly wounded showed staphylococcal ingestion. These differences could have been due to chance; therefore, neutrophils from the lightly wounded group appear to have been just as active as were those from individuals not exposed to combat conditions.

Table 1. Phagocytosis Related to Injury

Table 2 records phagocytosis from two groups of severely wounded patients; those without oliguria and those with oliguria. The only real abnormality in this table is the figure 68.4 percent in the group of patients without oliguria, who were studied within the first 24 hours of wounding. That group showed a significant depression in the ability of neutrophils to ingest Staphylococci. But, as the days went by, the neutrophils appeared normally active again. Neutrophils from patients with post-traumatic renal insufficiency appeared to posses  normal activity.

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Table 2. Phagocytosis Related to Injury

Table 3 shows some data of interest in connection with white cell counts, and neutrophil activity immediately following the administration of very large transfusions. There were eight patients, the volumes of blood used in resuscitation ranged from 5 to 26 liters, and a few of them had a liter or so of dextran also. It is of interest that the white blood counts were high although the bank blood contained very few white blood cells, especially neutrophils. There was an

Table 3. Leukocyte Count and Mean Ingestion of Staphylococci by Neutrophils Immediately Following Large Blood Transfusions

*Volumes of blood are reported on a cumulative basis.

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elevation in the percentage of neutrophils in the blood from these patients; but as I have already pointed out, on this first post-wound day, in this severely wounded group, there was a depression in the activity of these neutrophils. In two of these patients we found no significant drop in neutrophil activity. I have no explanation for the observed depression in neutrophil activity in the other patients. The subsequent recovery in phagocytic activity within 2 or 3 days of injury may have been the result of the outpouring of new neutrophils from the bone marrow. It is of interest that two of the patients who received the largest volumes of blood showed no depression of neutrophil activity, which suggests that the depression was not due to factors added by the bank blood, such as citrate. I do not have any data on neutrophil activity before resuscitation was commenced so I do not have any information on neutrophil activity immediately after severe injury.

The observed depression in neutrophil activity might possibly have been a manifestation of adrenal cortical hyperactivity. Others have reported finding a depression in the phagocytosis of opsonized pneumococci in a few patients under ACTH or cortisone therapy, but we did not find any fall in staphylococcal ingestion in a few nonwounded patients on ACTH therapy. Others too, in animals, have not found any depression of either reticoloendothelial cell function in rats treated with cortisone or of macrophage activity in tissue culture exposed to Kendall's compounds E or A. So, this depression in neutrophil activity in the first few hours after injury remains an interesting observation as yet unexplained.

Figure 1 shows the mean percentage neutrophil activity in two groups of patients. On the left are patients without oliguria and on the right those with oliguria. The differences in the groups could have been due to chance. Neutrophil activity in the blood of two individuals in the nonoliguric group showed a depression. The barred lines represent patients who died of uncontrolled infection. The other patients either had infection which was controlled or did not have significant infection. A number of these died, as you can see. We were not able to find any particular difference between neutrophil activity over the entire course of illness in the two groups.

Complement

Table 4 records complement activity from the blood of lightly wounded and seriously wounded patients without oliguria. These are recorded as the dilutions of plasma required to hemolyze a standard volume of sensitized red cells. The values for the lightly wounded are probably normal. Complement titers in seriously wounded patients without oliguria were not significantly different.

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FIGURE 1.

Table 4. Complement Activity in Plasma of Battle Casualties
End Point=100 Percent Hemolysis

Table 5 shows complement titers in 12 patients with post-traumatic renal insufficiency. And again, the levels of complement on the various post-wound days were not significantly different from those found in the control series. We had four isolated samples from different patients which showed no complement activity, but they did not follow any consistent pattern. Complement may vary in different dis-

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Table 5. Complement Activity in Plasma of Battle Casualties
End Point=100 Percent Hemolysis

Seriously wounded with Oliguria, 12 patients, post-wound day

eases in an unpredictable fashion. If these zero levels had been consistently present over several days, I would have considered them of importance, but the finding of apparently normal complement activity on the preceding and following days makes me hesitate to interpret this as a significant observation.

The finding of probable normal complement activity in most cases following acute hemorrhage or trauma under the conditions of this study agrees with observations of others, on the effect of hemorrhage on complement levels in animals. The removal of 50 to 83 percent of circulating complement from dogs by repeated plasmaphoresis has been reported to be followed by a return of normal serum titer within 24 hours. In guinea pigs restoration of complement occurred within 4 to 6 hours after removal by severe hemorrhage. It is probable that complement continually enters the intravascular compartment by diffusion from tissues or by the lymphatics.

Antibody

Figure 2 records antibody synthesis in two patients without renal failure. This type of study is difficult in severely wounded patients because of the need for repeated observations, so the series was small. The figure shows the antibody response of two patients with severe injury. The response of two normal controls is also recorded. The secondary immune response to a specific antigen in normal adults may not appear for 6 days or perhaps longer; therefore, the response observed in the 2 nonoliguric casualties studied cannot be said to be abnormal. One patient had not responded by the seventh day, but he had been in severe shock so there may have been either a loss or a delay in the absorption of antigen, and so a delay in the subsequent synthesis of antitoxin.

Figure 3 shows the antitoxin response of five patients with post-traumatic renal insufficiency. It is quite clear from this figure that

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FIGURE 2.

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FIGURE 3.

patients with acute renal failure may synthesize antibody in a comparable manner to control subjects. One of these patients failed to produce any detectable antitoxin until the sixth day when it began to rise,

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at which point the patient died. Again, it cannot be said that this was abnormal.

The finding of normal antibody synthesis in severely wounded casualties is not surprising. In previous observations we showed that moribund patients retained the capacity to synthesize specific antibody as well as or better than healthy subjects. Furthermore, observations on guinea pigs have shown that a response to antigenic stimulation occurred after protracted exposure to cold, after the production of severe clostridial myositis, and after attempts to block the reticuloendothelial system with large amounts of India ink. The absence of a detectable increase in circulating antitoxin until about the sixth or seventh post-wound day in three of the patients is of interest. There has been considerable discussion about the desirability of administering prophylactic tetanus antitoxin to previously immunized casualties instead of toxoid at the time of injury. This was the practice of the British Army in World War II because of the possibility that the response to the booster dose of tetanus toxoid might not be sufficiently rapid to protect in cases of tetanus with a short incubation period. Miller and Ryan have recently advised the injection in opposite extremities of prophylactic antitoxin and toxoid to previously immunized patients who have sustained shock or who have massively contaminated wounds. The data in this study lend some support to that proposal which might be particularly important if the level of circulating antitoxin in a patient happened to be low.

I would like now to present briefly two cases, one without post-traumatic renal insufficiency and the other with it.

First, a Marine who sustained a land mine injury resulting in a bilateral traumatic amputation of the lower extremities and a compound fracture of the right humerus. His wounds were dèbrided initially but at the evacuation hospital a re-amputation was required because of myositis in the stumps. His subsequent course was reasonably satisfactory and he was evacuated to Japan and the wounds have since undergone successful secondary closure. Figure 4 shows some of the clinical data. The daily white counts and phagocytic activity showed no depression. Daily complement levels, except for one, were within the normal range, and tetanus antitoxin rose from 0.35 unit per ml. to 1.23 units per ml. This patient represents an injured casualty who had extensive initial surgery, but developed myositis in the amputation stumps which was controlled by surgery. He did not have any apparent defect in antibacterial defense.

The other was a patient who had sustained a mortar injury of the left buttock penetrating through to the pelvis. On examination at the evacuation hospital it was obvious that the wound had been inadequately dèbrided. The incision was small, large areas of muscle

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FIGURE 4.

were not viable and, moreover, the patient's I. D. card was in the wound. An extensive dèbridement of the buttock muscle was done. He had a clostridial-like myositis of his left lower leg which required a supracondylar amputation. In addition, he had renal insufficiency. He developed a septicemia which we think was the final cause of death. We found no focus of infection at autopsy other than the surface infection of the buttock. The following figure (fig. 5) presents data on the chemotherapy used in an attempt to control the paracolon septicemia. White blood cell counts were elevated, and phagocytosis and complement levels were relatively normal. There was a rise in tetanus antitoxin from 0.13 unit per ml. to 0.35 unit per ml. The data on ati-bacterial defense from this patient look quite similar to those from the previous patient. Yet, he developed septicemia and the other did not. One had a myositis in an extremity which we were able to re-amputate completely and so obtain a cure. The other had

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FIGURE 5.

extensive pelvic injury which we were not able to dèbride to our satisfaction.

In conclusion, then, I found that neutrophils from a few severely wounded patients show decreased activity. In addition, there may be a delay in the appearance of tetanus antitoxin following the administration of a booster dose of toxoid to such patients. Apart from that, I found no evidence that severely injured casualties with or without post-traumatic renal insufficiency were more susceptible to infection because of some breakdown in antibacterial defense mechanisms. On

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the other hand, the other evidence I have gathered suggests that the combination of extensive trauma with bacterial contamination plus less than optimal surgical therapy will explain why infection developed in many of the cases.