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Wound Healing in Patients with Severe Battle Wounds and Renal Dysfunction

Medical Science Publication No. 4, Volume 1

WOUND HEALING IN PATIENTS WITH SEVERE
BATTLE WOUNDS AND RENAL DYSFUNCTION*

STANLEY M. LEVENSON, M. D.

I am going to restrict my remarks this morning to a discussion of some of the problems of wound healing encountered among a group of patients similar to those just described by Major Meroney-that is, patients with extensive wounds and serious renal dysfunction. When I arrived in Japan and Korea in January, 1953, it was generally considered by most of the Chiefs of Surgery and Surgical Consultants that delays in wound healing were infrequent among patients with battle injuries except among those who also had acute renal failure. The physicians at the Renal Center were also of the firm opinion that wound healing was impaired in these latter patients and that wound complications contributed significantly to their high mortality (50-60 percent). To obtain some specific data in this regard, all the clinical and autopsy records of the 70 patients admitted to the Renal Center from its opening in the spring of 1952 through the middle of February 1953 were reviewed in collaboration with Captain Paul Teschan.

The records of 21 of the patients were inadequate for analysis. Seven of the remaining 49 records were discarded because of very short survival times of the patients. Forty-two records, then, were deemed adequate for analysis. However, it should be mentioned that the progress notes were written by internists, that the records were not specifically directed towards problems of wound healing, that bacteriologic studies were inadequate and that only casual attention was paid to the wounds at autopsy.

Among the 42 patients whose records were analyzed, gross impairment of wound healing was noted in 31. The term "impairment" is used in a broad sense and is not meant to imply a specific or nonspecific defect in wound healing. Mortality among the patients with impaired wound healing was high; wound complications were among the more frequent and more important causes of death (table 1).

Two general types of wounds were present in these patients-wounds closed primarily, such as laparotomy incisions, and wounds left open after débridement. The time of secondary closure of the


*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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Table 1. Wound Healing in Patients with Renal Dysfunction

Group

Number of patients

Number of deaths

Average day of death

Patients with unimpaired wound healing

11

0

-----

Patients with impaired wound healing

31

16

15

latter wounds was delayed in patients with renal failure. In patients without renal dysfunction, such wounds were usually closed 5 to 10 days after injury. Patients with renal dysfunction were often at their sickest during this time and secondary closure was rarely carried out during this period. Consequently, the wounds of patients with renal dysfunction remained open for significantly longer periods of time than in patients without renal dysfunction. Similarly it should be pointed out that these patients were among the most seriously injured and usually were in severe shock in the early period after injury. Consequently, it is possible that under these circumstances débridement might have been inadequate in certain of these patients. There is also some question as to the quality of the later surgical care of these patients.

Among the 31 patients with gross impairment of wound healing, the open wounds were often described as indolent, with granulation tissue absent, or when present, soggy and edematous. In a number of these patients, progressive necrosis and suppuration of the wounds was described. I will not take time to show any pictures of such wounds, since you have already seen many illustrations of wounds just before and just after débridement and I am sure that the speakers this afternoon will present pictures of wounds in the later stages.

Among the 42 patients whose records were analyzed, there were 28 who had laparotomies (table 2). Six of these were in the group with unimpaired wound healing, and, as indicated by group classification, none of these wounds ruptured. Among the 31 patients with impaired wound healing, 22 had laparotomies. There were five abdominal wound dehiscences in this group. This is a high incidence of wound rupture and is apparently higher than occurred in patients with serious battle wounds but without renal dysfunction. However, this cannot

Table 2. Wound Healing in Patients with Renal Dysfunction

Group

Patients

Laparotomies

Dehiscences

Patients with unimpaired wound healing

11

6

0

Patients with impaired wound healing

31

22

5


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be stated with certainty at this time, since no overall systematic tabulation of wound healing among the battle casualties of the Korean conflict has been made. In this regard, there has been considerable difference of opinion among the surgical chiefs and consultants as to the incidence of postoperative hernias in laparotomized patients; opinions have varied from "very few" to "very many."

The actual incidence of impaired healing of laparotomy wounds among the patients with renal dysfunction may well be higher than indicated by the figures of wound ruptures. Once it appeared that these patients might be having difficulty in wound healing, sutures were left in for many weeks. Under this circumstance, the wounds of some patients were described as held together only by the retention sutures, with no apparent healing having occurred. Similarly, a number of patients whose laparotomy wounds looked good and appeared to be healing normally came to autopsy 7 or more days after injury. No special examination of the abdominal incision was made routinely, but in an occasional instance when the sutures were removed or an attempt was made to biopsy the wound, the wound fell apart.

Among the five patients with actual wound rupture, a possible local reason for the dehiscence was apparent in three (table 3). In one, dehiscence occurred on the ninth postoperative day and examination revealed an extensive hematoma in the wound; in another, dehiscence occurred on the tenth postoperative day-peritonitis and an infected abdominal wound were present; in the third, dehiscence occurred on the fourteenth day-severe peritonitis with ascites was present. No specific local reason for dehiscence was noted in the other two patients. In one of these two, dehiscence occurred on the eleventh day; in the other, on the sixteenth day. Disruption this late postoperatively is unusual and would suggest a definite delay in the healing process. At the time of the dehiscence, this last patient was emaciated. The abdominal wound was resutured and the patient lived for 9 more days. At autopsy, the resutured wound was described as follows: "There is a longitudinal mid-line abdominal surgical incision measuring approximately 12 cm. in length around which radiate multiple

Table 3. Wound Healing in Patients with Renal Dysfuntion, Dehiscences of Laparotomy Wounds

Number of patients with laparotomies

28.

Number of dehiscences

5.

Apparent "local cause" for dehiscence

3.

    Peritonitis  ascites

1; 14th day.

    Hematoma

1; 10th day.

    Wound infection

1; 9th day.

No apparent "local cause" for dehiscence

2; 11th and 16th days.


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superficial draining sinuses measuring 2 cm. in length. Granulation tissue lines the upper half of the surgical incision which presents an opening measuring 5 x 1 cm. The base of this sinus tract is lined by dense yellow-red granulation tissue. Wire sutures support the incision." Two more of the patients whose ruptured laparotomy wounds were resutured died, but the wounds were not specifically examined at autopsy.

Two of the five patients with dehiscences lived (table 4). The resutured wound apparently healed uneventfully in the patient whose dehiscence had presumably been secondary to the hematoma. The other patient who survived was the patient whose wound had ruptured 11 days postoperatively with no local cause for dehiscence being apparent. After resuturing, he developed peritonitis and intestinal obstruction. These complications were considered by those caring for the patient as subsequent to the dehiscence, rather than present before, and perhaps etiologically important for, the first dehiscence. A third laparotomy was performed on this patient through another incision 19 days after the resuturing of the first laparotomy wound. Localized intraperitoneal abscesses and obstructing adhesions were found. One week later, purulent material drained from the first and second abdominal incisions. Shortly thereafter, a fecal fistula appeared in the other abdominal incision. The patient had lost a considerable amount of weight (over 30 pounds) and was transferred to a general hospital in Japan for further therapy.

Table 4. Wound Healing in Patients with Renal Dysfunction.

Number of secondary sutures of dehisced laparotomy wounds

5

Number of patients surviving

2

    "Normal" healing of resutured wound

1

    "Abnormal" healing of resutured wound

1

Number of patients dying

3

    "Abnormal" healing of resutured wound

1

    Quality of wound healing unknown

2

A comparison between the two groups of patients (those patients with unimpaired wound healing versus those with impaired wound healing) was made to determine some of the factors which might have had some bearing on the observed differences in wound healing. It appears that those patients with impaired wound healing were in general the more seriously injured, the sicker, the more uremic, required more dialyses, had greater changes in water and electrolyte metabolism with associated edema and/or dehydration, lost more weight, had more severe infections, and showed a higher incidence of abnormal bleeding. The severity of anemia could not be adequately


301

estimated. In the majority of patients multiple factors were operative and presumably interrelated. Serious uremia, marked malnutrition and severe infection were the most frequent factors.

Severity of the Renal Dysfunction: Dialysis

Renal dysfunction was greater in the group with delayed wound healing. As you can see in table 5, the average time of diuresis among these latter patients was 12 days after injury as opposed to the average time of 5 days after injury of 10 of the 11 patients with unimpaired wound healing. In addition, 11 patients with impaired wound healing died 5 to 19 days after injury without ever diuresing. Similarly, whereas only 3 of the 11 patients with unimpaired wound healing had maximum levels of plasma nonprotein nitrogen over 275 mg. per 100 cc., two-thirds of the group with impaired healing had such high levels.

Table 5. Wound Healing in Patients with Renal Dysfunction.

 Group

Number of patients

Day of diuresis

Number of patients with maximum blood NPN over 275 mg. Percent

Patients with unimpaired wound healing

10
1

5
22

2
1

Patients with impaired wound healing

31

*12

21

*Includes 11 patients who died on the 5th to 19th days without ever diuresing.

Among the patients with apparently unimpaired wound healing, there was only one who required dialysis (table 6). This was a Korean soldier with wounds of the face and neck who developed a severe hemolytic reaction to a transfusion of 1,000 cc. of blood during his initial operative treatment. Following this, he developed oliguria and was transferred to the 11th Evacuation Hospital on the third post-injury day. During a prolonged period of oliguria (19 days) and uremia, three hemodialyses were performed. The neck and face

Table 6. Wound healing in Patients with Renal Dysfunction

Group

Number of patients

Number of patients dialyzed

Number of dialyses

Patients with unimpaired wound healing

10
1

0
1

0
3

Patients with impaired wound healing

31

24

56


302

wounds showed apparently normal and entirely satisfactory healing. These wounds were in well vascularized areas in which healing is usually favorable.

Among the 31 patients with apparently impaired wound healing, there were 24 who required dialyses. The average number of dialyses in these patients was about 2.3. At the moment, there is no specific evidence to implicate the dialysis procedure per se as an important factor in the pathogenesis of the impaired wound healing-e. g., there were a number of patients with impaired wound healing who did not have dialyses. The fact that many more patients in the impaired healing group were dialyzed than in the group with unimpaired healing may be simply indicative of the severity of the hyperkalemia and uremia of the former group. On the other hand, one cannot definitely rule out the dialysis procedure itself as an important factor-e. g., what is the washout of the water-soluble vitamins (specifically ascorbic acid) during dialysis?

Malnutrition. Weight loss is a constant feature of the patients with serious injuries and renal dysfunction. The average weight loss was greater among those patients with impaired wound healing. Weight losses of 20 to 25 pounds were common among the group with unimpaired healing, while among the group with impaired healing 30- to 40-pound weight loss was not uncommon (table 7). What the weight loss specifically represents in terms of body tissue, water, fat, etc., is not known. The first weights recorded are those on admission of the patient to the 11th Evacuation Hospital. At this time, many of the patients were presumably waterlogged. Insensible water loss must be an important factor in the weight loss of these patients, since prolonged hyperpnea is a common feature. However, examination of metabolic data available in a few patients reveals a large nitrogen "loss" (i. e., NPN accumulation in the body water, NPN lost by dialysis, and NPN excreted in the urine). In one patient, this amounted to about 45 gm. N per day, which represents the daily breakdown of about 2.5 pounds of body tissue (excluding fat).

Table 7. Wound Healing in Patients with Renal Dysfunction

Group

Number of patients

Weight loss (pounds)

Patients with unimpaired wound healing

11

20-30

Patients with impaired wound healing

31

30-45

Infection. Infection was one of the major complications among the severely injured patients with renal dysfunction. I am not going to


303

spend much time on this aspect of the problem because it is discussed in three other papers. However, I want to indicate some of the data which apply to this particular series of patients. Among the 31 patients with impaired wound healing, wound infection was almost universally present. Infection, either in the wound or elsewhere, is listed among the causes of death in all but 1 of the 16 patients in this group who died. Peritonitis is listed four times; intra-abdominal abscesses, six times; spreading infection of peripheral wounds, four times; severe bronchopneumonia, four times; septic infarcts (lung, kidney, etc.) twice, and empyema twice.

In view of certain observations of an increased migration of bacteria across the intestinal wall in uremic dogs, the autopsy records were examined to see whether there have been any instances of peritonitis in the absence of intra-abdominal injury. No instance of peritonitis in the absence of a previous laparotomy was found. There were one or two instances of mild peritoneal infection in patients with a "negative" laparotomy, but the possibility of undiscovered intra-abdominal injury cannot be ruled out.

It was evident from reviewing the records of these patients that wound healing was a very important complication among the patients with renal dysfunction. It would appear that in the majority of the patients multiple factors were operative and presumably interrelated. However, it was apparent that with the data at hand, no specific conclusion as to the relative importance, or interrelationship, of the various factors could be made. Studies to define the problem specifically and thereby lead to improved prophylaxis and therapy were indicated. A start in certain of these will be presented by other speakers later today.

Some of the problems which needed (and still need) solution are as follows:

1. What is the course of normal wound healing (open wounds, sutured wounds, etc.) in man?

There is a paucity of detailed correlated (clinical, histologic, bacteriologic, etc.) information regarding wound healing in man. There are very few controlled clinical studies and none specifically applicable to the problems at hand. Most of the specific data regarding wound healing have been obtained in animals. The difference in wound healing among various species makes it imperative that caution be used in directly relating the results of animal experiments to man.

2. What is the effect of the magnitude of injury on wound healing, and, if an effect is present, to what factors may it be attributed? What is the clinical significance of the "catabolic" reaction to injury?

Very few objective data concerning the physiological and clinical sequelae directly attributable to the early "catabolic" reaction to in-


304

jury are available. There are conflicting opinions as to the harm resulting from this period, and depending on the viewpoint taken, attempts are or are not made to reverse the process. Much of the conflict is due to the lack of objective indices of the benefits, or lack of benefits, of mitigating the early metabolic disturbances.

The injured man must heal his wounds for successful recovery; systematic observations of the healing of wounds, traumatic, operative and experimental, would provide objective evidence in one important area as to the significance of the "catabolic" period. For example, the seriously injured individual acts biochemically like a scorbutic in the first days and well after injury; does he also act like a scorbutic in regard to the healing of his wounds? Further, the intensity of the urinary nitrogen loss following injury may be decreased by the injection of testosterone propionate. Since the anabolic effects of testosterone are different for different tissues, what does the decrease in urinary nitrogen excretion mean in terms of wound healing?

It has been postulated by some that no attempt be made to reverse the "catabolic" reaction because it is a "defense mechanism" to supply metabolites to the injured area. There is no concrete evidence to support this. There is no reason, at the moment, to assume that the injured area is necessarily more proficient than other tissues in "utilizing" the circulating metabolites. We have recently studied the healing of experimental laparotomy wounds in normal and severely burned rats. Observations of the gross appearances, tensile strengths and histologic features of the incisions were made. The healing of laparotomy wounds in the burned rats was significantly different from that in the unburned controls. Epithelization was not affected, but there was a definite delay in the formation of granulation tissue in the incisional wounds of the burned animals with a lag in the appearance and maturation of the fibroblasts and the ground substance. The eventual number and amount of these two elements, however, did not appear to be affected, and abundant granulation formed in the wounds of the burned rats in time. In some of the burned rats the wound area appeared somewhat more edematous than that of the controls. The incidence of wound infection was also somewhat higher among the burned animals.

3. Is there a specific effect (direct or indirect) of renal dysfunction on wound healing? Or are the delays due to associated abnormalties in nutrition, water balance, ability to resist infection, etc.?

Various degrees of renal dysfunction will be produced experimentally in a number of different ways. Emphasis will be directed toward simulating the clinical problem of "lower nephron nephrosis." The course of wound healing in animals with renal dysfunction, untreated and treated in a variety of ways, including dialysis, will be studied.


305

Observations on local and systemic infection and various immune responses will be made. These data will be correlated with various nutritional and metabolic measurements.

4. What is the basis for the apparent high incidence of wound infection in the patients with renal dysfunction?

It is well recognized that infection, when present, is a detriment to wound healing. A careful study of wound infection is important, not only in the early post-injury period, but throughout the healing period. Why is wound infection so frequent, and so serious, in the severely wounded patient with renal dysfunction? Does the malnutrition predispose to wound infection, or does the wound infection accelerate the development of malnutrition? What is the ability of the seriously injured man in regard to antibacterial defense? Following simple starvation, lymphoid tissue is markedly depleted; chronically protein-depleted rats are unable to synthesize certain antibodies as well as normally nourished animals. What is the ability of the seriously wounded man who is on a totally inadequate diet to form antibodies? What is the efficiency of phagocytosis, etc., in such an individual? Further, most of these patients may be on various antibiotics, certain of which, when given orally, may lead to nutritional disturbances under certain circumstances.

5. What are the effects of plasma substitutes and/or anemia on wound healing?

It would appear that in many instances a combination of whole blood and dextran (or some other plasma substitute) may be satisfactory for early replacement therapy of shock. Under this circumstance, a certain degree of anemia will be present at the time the patient is evacuated further to the rear. Ordinarily, surgeons feel that anemia per se is detrimental to wound healing and will be inclined to transfuse such patients prior to secondary closure, etc. Is this a necessary or wise procedure (considering possible shortage of blood, transfusion reactions, etc.)? Is there a direct effect of anemia on wound healing or is there, perhaps, an indirect effect? Is hemoglobin a high-priority protein in the severely injured patient during the catabolic period and, if so, will protein be diverted from the healing wound to form hemoglobin if anemia is present? No conclusive data on the influence of anemia on wound healing in man are available; the data in animals are controversial.

What is the effect of plasma expanders per se on wound healing? Data in this regard are meager. Rhoads and his co-workers observed that whereas there was a delay in the healing of abdominal wounds in hypoproteinemic edematous dogs, there was no delay in hypoproteinemic dogs given acacia intravenously in amounts sufficient to eliminate the edema, but which, at the same time, accentuated the de-


306

crease in plasma protein concentration. Thorsen has reported no delay in the healing of incisional wounds in rabbits given dextran. We have observed no gross abnormalities in the healing of burns in patients who have received large amounts of dextran, but no special studies of the wounds were made.

6. What are the optimal prophylactic and therapeutic nutritional (dietary, hormonal, etc.) regimens for the wounded patient with or without renal dysfunction?

If the period of metabolic derangement persists, progressive nutritional deterioration with its consequent well known ill effects occurs. What is the optimal nutritional (dietary, hormonal, etc.) care of these individuals? I will discuss this in detail in another paper.

Proposed Studies

From the foregoing it is evident that a study of the individual and his wounds directed toward a comprehensive correlation and evaluation of systemic and local phenomena is needed. Such a study will entail the use of a variety of technics, clinical, metabolic, bacteriologic and pathologic. The clinical studies should be supplemented by animal studies in a variety of species.

Some Factors in Wound Healing Requiring Control

    A. Systemic Factors.

      1. Extent and sites of wounds.
      2. Associated injuries (and/or illnesses).
      3. Circulatory system (shock, sludging, etc.).
      4. Metabolic and nutritional state (including anemia, antibiotics, all nutrients, etc.).
      5. Plasma substitutes (primary and secondary effects).
      6. Infection (including "resistance" of individual, etc.).
      7. Blood clotting mechanism.

    B. Type of Wounds.

      1. Contaminated wounds, dérided and secondarily sutured (including time of secondary suture).
      2. Contaminated wounds débrided and primarily closed.
      3. Clean, incised wounds closed primarily (including type of closure, etc.).

    C. Local Factors.

      1. Extent and sites of wounds (including surrounding and supporting tissues; proximity to joints; direction of wound relative to lines of stress, etc.).
      2. Blood supply (arterial and venous).
      3. Infection (including antibiotics, etc.).
      4. Wound edema or dehydration (local or systemic basis).


307

    D. Medical and Surgical Care. The quality and types of medical and surgical care are, of course, of paramount importance, but will not be discussed in this paper.

In summary, this analysis of wound healing among patients with serious battle injuries and renal failure confirms the impressions of various physicans that wound complications were frequent and important in these patients. Further, the analysis has indicated the complexity of the problem, some possible interrelationships among various factors, and the need for concrete objective study, clinical and experimental.

Discussion

COLONEL HANSON. Stimulated by Dr. Levenson's visit to the Far East, a study of some of the problems of wound healing was undertaken by the research team in Korea in collaboration with the staff of the 406th Medical General Laboratory in Tokyo. Serial biopsy materials obtained from about 19 patients were examined and an attempt was made to evaluate certain histologic features such as the general state of healing as a whole, growth of capillaries, proliferation of fibroblasts, production of reticulum and collagen.

Some of the preliminary conclusions may be mentioned. I think that we can state that in the severely wounded casualty, the response to injury may be lessened in patients with marked renal failure, in cases where there is a diminished blood supply or local anemia, and in that group of cases where there has been a marked catabolic effect and severe weight loss. The wounds of such patients do not heal like those of the normal or less severely traumatized patients. However, we could not draw any conclusions as to mechanisms involved, but it is likely that many mechanisms, probably interrelated, are involved.

MAJOR BALCH. One thing Dr. Levenson did not bring out quite clearly enough in his presentation was the character of the surgical care of the patient whose records he reviewed. I was not at the Renal Center at the time those cases were studied, but I understand from others who were there that at the time the Renal Center was first set up, it was not properly realized that a full-time surgeon was needed in the care of these patients. Many of those patients were cared for surgically by the general surgical staff of the hospital. Now, those surgeons had other duties and responsibilities and they were frequently quite busy and could not come for many hours or, perhaps longer, to take care of the renal patients. So, evaluation of the complications that have been reported today, and I believe they are true complications, is complicated very much by the fact that it is likely that the surgical care was inadequate in those patients.


308

I would like to ask Colonel Hanson whether the factor of infection could be separated from delay in wound healing in the biopsy specimens?

COLONEL HANSON. In those cases where there was massive wound infection, the factor of infection could be separated from delays in wound healing, but in cases where there was just minor infection, it was questionable whether these factors could be separated.

DR. HOWARD. I wonder if one of the most important elements in the wound complications among these patients is their primary surgical care? We have by definition selected a group of patients who are critically injured, who are profoundly hypotensive and in whom the primary surgical care is quite likely to be compromised. I wonder if inadequate débridement or hasty closure of an abdominal wound, due to our efforts to salvage life at the moment, might not be reflecting itself in later wound complications?

DR. LEVENSON. That is probably true, Dr. Howard, and I mentioned that briefly in my presentation. However, at present, most records I have seen are not adequate to enable objective evaluation of the adequacy of débridement. I think we all would assume that in many instances débridement was inadequate, and in a few instances foreign material (clothing, etc.) was found in secondary débridements.

I am glad that Major Balch made his comment regarding the questionable quality of the later surgical care of these patients. I meant to mention it, but inadvertently did not. In this regard I would like to make one additional comment. Cross-infection was one of the factors possibly important in the high incidence of wound infection among this group of patients. These patients were kept on a single ward and it was not possible to carry out, either on the ward, in the dressing or operating rooms, procedures which have been advocated for the prevention of cross-infections.