Medical Science Publication No. 4, Volume 1
THE EFFECT OF SEVERE BATTLE INJURY AND OF POST-TRAUMATICRENAL FAILURE ON RESISTANCE TO INFECTION*
MAJOR HENRY H. BALCH,Jr., MC, USAR
Introduction
Acute infection remains one of the serious complications of severelywounded soldiers. Its incidence, in terms of total casualties in Korea,was probably low; possibly 20 percent of the severely wounded who wereresuscitated had complicating infection. About 5 percent of severely injureddevelop acute renal failure, and the incidence of infection is high inthis group also. There are several reasons why severely wounded casualtiesmay be more prone to infection-these include such things as the degreeof tissue damage, the amount of bacterial contamination, delay in initialand subsequent surgical treatment, errors in judgment, etc.
The purpose of today's presentation is to discuss the possibility thatseverely wounded casualties and those with acute renal failure may be moreprone to infection because of some breakdown in basic body defense.
There are several natural mechanisms of body defense following bacterialpenetration. The microorganisms may be trapped or eliminated by lymph nodesdraining the area. Cells of the reticuloendothelial system or wanderingphagocytes may ingest and destroy pathogens. This process is much moreeffective if specific antibody is present. In addition, natural and specificantibody (globulin) participates in the lysis of a number of bacterialspecies and also neutralizes the products of others. A group of proteinsfound in normal serum which have been called complement possess severalproperties of importance in antibacterial defense; these include a capacityto kill bacteria sensitized by antibody and to render the microorganismsmore susceptible to phagocytosis. If a defect in globulin synthesis ora depression of reticuloendothelial cell function or leukocyte activityfollows severe injury, the defense effort might be impeded seriously andsuch patients become prone to infection.
*Presented 21 April1954, to the Course on Recent Advances in Medicine and Surgery, Army MedicalService Graduate School, Walter Reed Army Medical Center, Washington, D.C.
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In this investigation I attempted to measure the phagocytic activityof circulating leukocytes, the serum complement levels and the capacityof a patient to synthesize specific antibody, and then I tried to correlatethe findings with the clinical course and with the presence or absenceof infection. The methods were simple. For phagocytosis we took fresh specimensof blood and counted the number of neutrophils; we mixed a known numberof neutrophils with a known number of pathogenic Staphylococci, rotatedthese in a 37° C. incubator, and at a fixed interval we counted thenumber of neutrophils which had ingested organisms, and so estimated theiractivity. Complement was assayed by measuring the least amount of plasmawhich would hemolyze specifically sensitized sheep red cells. The capacityto synthesize antibody was determined by measuring the response to thebooster injection of tetanus toxoid immediately following wounding. Theseries was small because only severely wounded patients were studied.
Phagocytosis
Table 1 shows the number of neutrophils which ingested Staphylococciin 2 groups of patients, 6 nonwounded and 12 lightly wounded; 94 percentof the neutrophils from nonwounded and 88 percent from the lightly woundedshowed staphylococcal ingestion. These differences could have been dueto chance; therefore, neutrophils from the lightly wounded group appearto have been just as active as were those from individuals not exposedto combat conditions.
Table 1. Phagocytosis Related to Injury
Postwound day | Number of subjects | Percent neutrophils showing ingestion | Standard error of means | |
Nonwounded | 0-1 | 6 | 94. 4 | ±2. 18 |
Lightly wounded | 0-1 | 12 | 88. 2 | ±2. 5 |
Table 2 records phagocytosis from two groups of severely wounded patients;those without oliguria and those with oliguria. The only real abnormalityin this table is the figure 68.4 percent in the group of patients withoutoliguria, who were studied within the first 24 hours of wounding. Thatgroup showed a significant depression in the ability of neutrophils toingest Staphylococci. But, as the days went by, the neutrophils appearednormally active again. Neutrophils from patients with post-traumatic renalinsufficiency appeared to posses normal activity.
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Table 2. Phagocytosis Related to Injury
Post-wound day | Number of subjects | Percent neutrophils showing ingestion | Standard error of means |
Severely Wounded without Clinical Post-traumaticRenal Insufficiency | |||
0-1 | 6 | 68. 4 | ±5. 5 |
1-2 | 5 | 61. 2 | ±12. 1 |
2-3 | 4 | 81 | ±4. 2 |
3-4 | 5 | 82 | ±5. 4 |
Severely Wounded with Post-traumatic RenalInsufficiency | |||
1-2 | 5 | 83. 6 | ±3. 7 |
2-3 | 8 | 82 | ±1. 7 |
3-4 | 6 | 83 | ±2. 1 |
Table 3 shows some data of interest in connection with white cell counts,and neutrophil activity immediately following the administration of verylarge transfusions. There were eight patients, the volumes of blood usedin resuscitation ranged from 5 to 26 liters, and a few of them had a literor so of dextran also. It is of interest that the white blood counts werehigh although the bank blood contained very few white blood cells, especiallyneutrophils. There was an
Table 3. Leukocyte Count and Mean Ingestionof Staphylococci by Neutrophils Immediately Following Large Blood Transfusions
Patient number | Post-wound day | Volume blood used in resuscitation | Volume dextran used in resuscitation | WBC per cu. mm. | Percent neutrophils | Percent neutrophils containing Staphylococci |
| L | L | ||||
3 | 1-2 | 5 | 1. 9 | 15,400 | 73 | 56 |
4 | 1-2 | 5 | ----- | 14,000 | 81 | 18 |
15 | 0-1 | 7 | 0. 5 | 13,250 | 72 | 66 |
16 | 0-1 | 7. 5 | ----- | 14,650 | 70 | 56 |
21 | 0-1 | 8. 5 | 1. 0 | 16,800 | 79 | 62 |
26 | 0-1 | *5. 5 | 1. 0 | 15,800 | 76 | 56 |
| 0-1 | 10 | ----- | 13,400 | 66 | 62 |
| 0-1 | 12 | ----- | 16,600 | 72 | 74 |
| 0-1 | 13 | ----- | 15,300 | 74 | 70 |
27 | 0-1 | *12 | ----- | 9,850 | 80 | 88 |
| 0-1 | 23 | ----- | 11,850 | 77 | 90 |
28 | 0-1 | 26 | ----- | 5,500 | 70 | 82 |
*Volumes of blood are reported on a cumulativebasis.
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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 thisseverely wounded group, there was a depression in the activity of theseneutrophils. In two of these patients we found no significant drop in neutrophilactivity. I have no explanation for the observed depression in neutrophilactivity in the other patients. The subsequent recovery in phagocytic activitywithin 2 or 3 days of injury may have been the result of the outpouringof new neutrophils from the bone marrow. It is of interest that two ofthe patients who received the largest volumes of blood showed no depressionof neutrophil activity, which suggests that the depression was not dueto factors added by the bank blood, such as citrate. I do not have anydata on neutrophil activity before resuscitation was commenced so I donot have any information on neutrophil activity immediately after severeinjury.
The observed depression in neutrophil activity might possibly have beena manifestation of adrenal cortical hyperactivity. Others have reportedfinding a depression in the phagocytosis of opsonized pneumococci in afew patients under ACTH or cortisone therapy, but we did not find any fallin staphylococcal ingestion in a few nonwounded patients on ACTH therapy.Others too, in animals, have not found any depression of either reticoloendothelialcell function in rats treated with cortisone or of macrophage activityin tissue culture exposed to Kendall's compounds E or A. So, this depressionin neutrophil activity in the first few hours after injury remains an interestingobservation as yet unexplained.
Figure 1 shows the mean percentage neutrophil activity in two groupsof patients. On the left are patients without oliguria and on the rightthose with oliguria. The differences in the groups could have been dueto chance. Neutrophil activity in the blood of two individuals in the nonoliguricgroup showed a depression. The barred lines represent patients who diedof uncontrolled infection. The other patients either had infection whichwas controlled or did not have significant infection. A number of thesedied, as you can see. We were not able to find any particular differencebetween neutrophil activity over the entire course of illness in the twogroups.
Complement
Table 4 records complement activity from the blood of lightly woundedand seriously wounded patients without oliguria. These are recorded asthe dilutions of plasma required to hemolyze a standard volume of sensitizedred cells. The values for the lightly wounded are probably normal. Complementtiters in seriously wounded patients without oliguria were not significantlydifferent.
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Table 4. Complement Activity in Plasma of BattleCasualties
End Point=100 Percent Hemolysis
Lightly wounded | Seriously wounded without oliguria | ||||||
17 patients | 14 patients | ||||||
Post-wound day | |||||||
Titer (reciprocal) | 0-1 number of patients | Number of patients | |||||
0 | 1 | 2 | 3 | 4 | 5 | ||
64 | -- | -- | -- | -- | 1 | -- | -- |
32 | 12 | 1 | 2 | -- | 2 | 1 | 1 |
16 | 5 | 5 | 4 | -- | 2 | 1 | -- |
8 | -- | 1 | 2 | 3 | 1 | -- | 1 |
4 | -- | 1 | -- | -- | -- | -- | -- |
Table 5 shows complement titers in 12 patients with post-traumatic renalinsufficiency. And again, the levels of complement on the various post-wounddays were not significantly different from those found in the control series.We had four isolated samples from different patients which showed no complementactivity, but they did not follow any consistent pattern. Complement mayvary in different dis-
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Table 5. Complement Activity in Plasma of BattleCasualties
End Point=100 Percent Hemolysis
Seriously wounded with Oliguria, 12 patients,post-wound day
| Number of Patients | ||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 | |
32 | ----- | 1 | 1 | 1 | 2 | 1 | ----- |
16 | 1 | 1 | 3 | 3 | ----- | 1 | ----- |
8 | 1 | 1 | 1 | ----- | 2 | ----- | 1 |
4 | ----- | ----- | ----- | ----- | ----- | ----- | ----- |
<1 | 2 | ----- | ----- | ----- | ----- | ----- | 2 |
eases in an unpredictable fashion. If these zero levels had been consistentlypresent over several days, I would have considered them of importance,but the finding of apparently normal complement activity on the precedingand following days makes me hesitate to interpret this as a significantobservation.
The finding of probable normal complement activity in most cases followingacute hemorrhage or trauma under the conditions of this study agrees withobservations of others, on the effect of hemorrhage on complement levelsin animals. The removal of 50 to 83 percent of circulating complement fromdogs by repeated plasmaphoresis has been reported to be followed by a returnof normal serum titer within 24 hours. In guinea pigs restoration of complementoccurred within 4 to 6 hours after removal by severe hemorrhage. It isprobable that complement continually enters the intravascular compartmentby 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 ofthe need for repeated observations, so the series was small. The figureshows the antibody response of two patients with severe injury. The responseof two normal controls is also recorded. The secondary immune responseto a specific antigen in normal adults may not appear for 6 days or perhapslonger; therefore, the response observed in the 2 nonoliguric casualtiesstudied cannot be said to be abnormal. One patient had not responded bythe seventh day, but he had been in severe shock so there may have beeneither a loss or a delay in the absorption of antigen, and so a delay inthe subsequent synthesis of antitoxin.
Figure 3 shows the antitoxin response of five patients with post-traumaticrenal insufficiency. It is quite clear from this figure that
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patients with acute renal failure may synthesize antibody in a comparablemanner to control subjects. One of these patients failed to produce anydetectable 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 thiswas abnormal.
The finding of normal antibody synthesis in severely wounded casualtiesis not surprising. In previous observations we showed that moribund patientsretained the capacity to synthesize specific antibody as well as or betterthan healthy subjects. Furthermore, observations on guinea pigs have shownthat a response to antigenic stimulation occurred after protracted exposureto cold, after the production of severe clostridial myositis, and afterattempts to block the reticuloendothelial system with large amounts ofIndia ink. The absence of a detectable increase in circulating antitoxinuntil about the sixth or seventh post-wound day in three of the patientsis of interest. There has been considerable discussion about the desirabilityof administering prophylactic tetanus antitoxin to previously immunizedcasualties instead of toxoid at the time of injury. This was the practiceof the British Army in World War II because of the possibility that theresponse to the booster dose of tetanus toxoid might not be sufficientlyrapid to protect in cases of tetanus with a short incubation period. Millerand Ryan have recently advised the injection in opposite extremities ofprophylactic antitoxin and toxoid to previously immunized patients whohave sustained shock or who have massively contaminated wounds. The datain this study lend some support to that proposal which might be particularlyimportant if the level of circulating antitoxin in a patient happened tobe low.
I would like now to present briefly two cases, one without post-traumaticrenal insufficiency and the other with it.
First, a Marine who sustained a land mine injury resulting ina bilateral traumatic amputation of the lower extremities and a compoundfracture of the right humerus. His wounds were dèbrided initiallybut at the evacuation hospital a re-amputation was required because ofmyositis in the stumps. His subsequent course was reasonably satisfactoryand he was evacuated to Japan and the wounds have since undergone successfulsecondary closure. Figure 4 shows some of the clinical data. The dailywhite counts and phagocytic activity showed no depression. Daily complementlevels, except for one, were within the normal range, and tetanus antitoxinrose from 0.35 unit per ml. to 1.23 units per ml. This patient representsan injured casualty who had extensive initial surgery, but developed myositisin the amputation stumps which was controlled by surgery. He did not haveany apparent defect in antibacterial defense.
The other was a patient who had sustained a mortar injury of the leftbuttock penetrating through to the pelvis. On examination at the evacuationhospital it was obvious that the wound had been inadequately dèbrided.The incision was small, large areas of muscle
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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 hada clostridial-like myositis of his left lower leg which required a supracondylaramputation. In addition, he had renal insufficiency. He developed a septicemiawhich we think was the final cause of death. We found no focus of infectionat autopsy other than the surface infection of the buttock. The followingfigure (fig. 5) presents data on the chemotherapy used in an attempt tocontrol the paracolon septicemia. White blood cell counts were elevated,and phagocytosis and complement levels were relatively normal. There wasa 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 similarto those from the previous patient. Yet, he developed septicemia and theother did not. One had a myositis in an extremity which we were able tore-amputate completely and so obtain a cure. The other had
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extensive pelvic injury which we were not able to dèbride toour satisfaction.
In conclusion, then, I found that neutrophils from a few severely woundedpatients show decreased activity. In addition, there may be a delay inthe appearance of tetanus antitoxin following the administration of a boosterdose of toxoid to such patients. Apart from that, I found no evidence thatseverely injured casualties with or without post-traumatic renal insufficiencywere more susceptible to infection because of some breakdown in antibacterialdefense mechanisms. On
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the other hand, the other evidence I have gathered suggests that thecombination of extensive trauma with bacterial contamination plus lessthan optimal surgical therapy will explain why infection developed in manyof the cases.
