Table 9. Wound Healing in Patients With Renal Dysfunction
 

*Includes 11 patients who died 5 to 19 days after injury without ever diuresing.

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protein 4.4 to 6.0 gm./100 ml. plasma), and low dietary intake, the neck and face wounds, as well as the cut-down 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 wash-out of the water soluble vitamins (specifically ascorbic acid) during dialysis?

Malnutrition

Weight loss is a constant feature of the patient 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. 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 fact 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). It is not possible at present to compare this figure with the nitrogen loss by patients with serious injury without associated renal dysfunction-the data are not available. Urinary nitrogen losses of 45 gm. of nitrogen per day (or greater) are not uncommon among young adult males with serious injuries without associated renal dysfunction, but these latter patients have not been on nutrient intakes as low as the patients studied at the 11th Evacuation Hospital. We know that the level of dietary intake makes a considerable difference in the amount of nitrogen excretion and net nitrogen loss after injury.

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Providing an adequate nutrient intake was a very difficult problem in these patients. Many were unable to take food orally over long periods of time. Parenteral alimentation was limited by the policy of rigid fluid restriction during the period of oliguria (which in some cases has persisted for 2 to 3 weeks). The problem was further complicated by the policy of no protein administration during this same period. (One wonders whether in the face of a very low caloric intake the nitrogen load is any less in those patients not receiving protein than in those receiving some protein.) Consequently, the nutrient intake of these patients was very low and grossly inadequate. The average daily caloric intake when the patient had been on only parenteral fluids was 500 to 1,000 calories per day-supplied as glucose. No data are available as to the utilization of carbohydrates by these patients (cf. the "intolerance" to carbohydrates by individuals with extensive injuries) but the rate of infusion has been generally slow. When fluid intake was restricted, the glucose was usually given as a 25 or 50 per cent solution by continuous drip through a polyethylene cannula inserted into the iliac vein via the femoral vein. No instance of pulmonary infarction was noted, but at autopsy in one patient a large thrombus with one end unattached was found in the iliac vein at the site of the infusion.

The only parenteral vitamin preparations which were available were vitamin C (in 500 mg. ampules), thiamine chloride (50 mg./cc.), and various vitamin K preparations. This resulted in a markedly imbalanced vitamin intake.

It was not possible to determine the oral dietary intake of these patients from the available records, but it would appear that the oral food intake was low until long in the convalescent period. A high-carbohydrate, high-fat liquid feeding supplying about 2,500 calories had been tried as a tube feeding (continuous drip) in one or two patients for short periods of time. Oral vitamin intake had usually been three of the standard Army multivitamin capsules per day.

Infection

Infection was one of the major complications among the severely injured patients with renal dysfunction. 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. Intra-abdominal abscesses are listed six times; peritonitis is listed four times; spreading infection of peripheral wounds, four times; severe bronchopneumonia, four times; septic infarcts (lung, kidney, etc.), twice; and empyema, twice. Inadequate bacteriologic data are available.

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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 had 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.

As mentioned, an important difference between the handling of wounds of the patients with renal dysfunction as compared with those without renal dysfunction was the time of secondary closure of open wounds. In patients without renal dysfunction, wounds were usually closed 5 to 10 days after injury. Patients with renal dysfunction were usually very sick 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.

Adequacy of débridement is one of the important factors in wound infection. The question may be raised whether inadequate débridement may not have been more frequent among these patients than indicated by the finding of retained non-metallic foreign bodies noted in a few patients (Table 4). Many of these patients were very severely injured and were in profound shock before and during the initial operative treatment. It is possible that inadequate débridement or hasty closure of an abdominal wound, due to efforts to salvage life, might have been carried out.

At the time the Renal Center was first set up, it was not realized that a surgeon was needed whose only responsibility was the care of these patients. The surgical care of these patients was in the hands of the general surgical staff of the hospital. These surgeons had other duties and responsibilities and they were not able to give undivided attention to these patients. Under these circumstances, it is likely that the surgical care was not optimal in some instances.

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 or in the dressing or operating rooms, many procedures which have been advocated for the prevention of cross-infections. There were no bacteriologic data available, however, to support or negate this opinion.

Bleeding Tendency

A number of the patients with renal dysfunction showed an abnormal bleeding tendency. During the second week in February 1953,

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two of the four patients in the ward at the time had clotting times greater than 2 hours. This persisted over a period of days with associated excessive blood loss. This was an unusual proportion of "bleeders" but the problem was seen often enough to make its incidence significant.

A study of the basic defect (or defects) in the clotting mechanism is reported elsewhere.¹

Wound healing is probably delayed in the presence of excessive bleeding into the wound, and perhaps indirectly by excessive bleeding elsewhere than in the wound.

Proposed Observations of Wound Healing

It is 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 is apparent that with the available data, no specific conclusion as to the relative importance, or interrelationship, of the various factors can be made. Studies to define the problem specifically and thereby lead to improved prophylaxis and therapy are indicated.

Some of the problems which 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 differences in wound healing among various species make it imperative that caution be used in directly relating the results of animal experiments to man.

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

Very few objective data of the physiological and clinical sequelae indirectly attributable to the early "catabolic" reaction to injury 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

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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 for sometime 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 testoterone 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.² Observations of the gross appearance, 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 abnormalities innutrition, water balance, ability to resist infection, etc.?

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

Various degrees of renal dysfunction should be produced experimentally in a number of different ways. Emphasis should be directed towards 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, should be studied. Observations on local and systemic infection and various immune responses should be made. These data may be correlated with various nutritional and metabolic measurements.

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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? (A preliminary study on some aspects of these latter two problems is reported elsewhere by Balch.³) What is the effect of extracorporeal dialysis on resistance to infection? For example, in vitamin C deficiency, susceptibility to infection is increased; it is possible that there is a considerable "washout" of ascorbic acid during dialysis. 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 very 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 hypopro-

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teinemic dogs given acacia intravenously in amounts sufficient to eliminate the edema, but which, at the same time, accentuated the decrease in plasma protein concentration.⁴ Thorsen has reported no delay in the healing of incisional wounds in rabbits given dextran.⁵ 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 optional nutritional (dietary, hormonal, etc.) care of these individuals?

What Is Needed

A study of the individual and his wounds directed toward a comprehensive correlation and evaluation of systemic and local phenomena is indicated. 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, débrided and secondary 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.).

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2. Blood supply (arterial and venous).

3. Infection (including antibiotics, etc.).

4 . Wound edema or dehydration (local or systemic basis).

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.

Conclusion. This analysis of wound healing among patients with serious battle injuries and renal failure confirmed the impressions of various physicians, 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.

1. 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. Forty-two records were deemed adequate for analysis. However, the progress notes were written by internists, the records were not specifically directed towards problems of wound healing, bacteriologic studies were inadequate and only casual attention was paid to the wounds at autopsy. No histologic studies of the wounds were done.

2. 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 defect in wound healing. Mortality among the patients with impaired wound healing was high; wound complications were among the more frequent and important causes of death.

3. It would appear that "impairment" of wound healing among these patients was greater than occurred in patients with serious battle wounds but without renal dysfunction. However, this cannot be stated with certainty, since no over-all systematic tabulation of wound healing among the battle casualties of the Korean conflict was made.

4. Among the patients with battle wounds and renal dysfunction, a comparison was made between those patients with unimpaired wound healing and those with impaired wound healing 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, sicker, more uremic, required more dialyses, had greater changes in water and electrolyte metabolism, lost more weight, had more severe infections, and showed a higher incidence of abnormal

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bleeding. The severity of the anemia could not be adequately estimated.

5. It would appear that in the majority of these patients multiple factors were leading to wound healing difficulties. These factors were presumably interrelated in the apparent serious uremia, serious infection and serious malnutrition. Some aspects of the pathogenesis and significance of these factors are discussed.

6. With the data at hand, no specific conclusion can be made covering the relative importance, or interrelationship, of the various factors. Studies are needed to define the problem specifically and thereby lead to improved prophylaxis and therapy. Such studies will require various clinical, metabolic, bacteriologic and pathologic technics. Some of the problems which need solution are as follows:

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

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

c. Is there a specific effect (direct or indirect) of renal dysfunction on wound healing? Or are the delays due to associated abnormalities innutrition, water balance, ability to resist infection, etc.? What is the basis for the apparent high incidence of wound infection in the patients with renal dysfunction?

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

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

7. Some factors requiring control in wound healing studies are discussed.

1. Crosby, W. H., and Stefanini, M.: J. Lab. & Clin. Med. 40: 374, 1952.

2. Levenson, S. M.: Surg., Gynec. & Obst. 99: 74, 1954.

3. Balch, H. H., Jr.: To be published.

4. Rhoads, J. E., Fliegelman, M. T., and Panzer, L. M.: J. A. M. A. 118: 21, 1942.

5. Thorsen, G.: Acta. Chir. Scandinav. 100: 422, 1950.