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Healing of the surgical wound
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Healing of the surgical wound H. Factors influencing repair and regeneration David R. Harris, M.D. Palo Alto, CA In Part II, various factors affecting the healing wound are considered. These include the environment, nutrition, bacterial infection, and mechanical influences. Relating the healing process to these considerations can aid in developing better surgical judgment, minimizing complications, and improving the technical result of excision and repair. (J AM ACAD DERMATOL1:208-215, 1979.)
Surgical wounds heal, in part by regeneration, or reconstitution of normal tissue integrity with no significant architectural distortion. An example is epithelialization of a superficial erosion, a denuded blister, or the apposed edges of an incision. In addition, disruptions of deeper dermal portions of the epithelium heaI by repair, or restoration with varying degrees of permanent architectural change. This change is, in short, scar formation. 1 These basic processes of wound healing were explored in part I of this communication. In this second part, we will appraise various factors influencing regeneration and repair and their importance in relation to the surgical result. Each factor, outlined in Table I, will be considered in turn. ENVIRONMENT, LOCAL CLIMATE, AND WOUND DRESSINGS Regeneration of epithelium is influenced both by local environment (the temperature and humidity immediately surrounding the wound surface beneath a dressing) and the larger environment, the climate of the geographical area in which the patient resides. 2-4 In part I of this review, we learned that migration of epidermal cells, the sinFrom the Department of Dermatology, Stanford University School of Medicine, Address for reprints: 700 West Parr Ave., Suite M, Los Gatos, CA 95030.
208
gle most important factor in restoration of epidermis, occurs within 48 to 72 hours. However, air exposure or a nonocclusive dressing allows dehydration of denuded dermis at the edge and base of wounds with subsequent incorporation in the crust. Crust represents a mechanical barrier to epidermal migration, since cells must move by cleaving a plane between the viable wound bed and overlying dead, dry material (Fig. 1, part I). This is accomplished at great metabolic expenditure by enzymatic action and phagocytic activity. The result is a new epidermal surface in the form of a linear groove in apposed edges, a dell or depression in excision defects. 4' 5 Maintenance of hydration will alter the course of both epidermal migration and kinetic response to incisions. 6 It has been shown that various topical agents and occlusive inert dressings, which limit tissue death and maintain hydration, enhance epithelialization. 7-9 Investigations reveal that application of an occlusive plastic film to superficial and deep incision wounds will hasten regeneration time as much as twofold over air-exposed sites. When exudate remains serous, granulation tissue quickly forms a solid base across which epidermis migrates unimpeded by dried crust and tissue debris 1~ (Fig. 1). Moreover, the inflammatory response is lessened by occlusive dressings. Unfortunately, whereas a totally occlusive 0190-9622/79/030208 +08500.80/0 9 1979 Am Acad Dermatol
Volume 1 Number 3 September, 1979
Healing
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Fig. 1. Comparison of the mode of epidermal regeneration in shallow skin wounds under exposed (no dressing) and occlusive conditions. (From Winter GD: Epidermal regeneration studied in the domestic pig, in Maibach HI, Royce DT, editors: Epidermal wound healing. Copyright 9 1972 by Year Book Medical Publishers, Inc., Chicago. Used by permission.) membrane maintains good hydration, it also traps exudate. Retained exudate is a culture media for bacteria. Better would be a semipermeable dressing that provides a moist surface for epidermal migration while allowing for sufficient drainage or absorption of tissue fluid, s' 13, t4 This ideal dressing is not yet developed. NUTRITIONAL CONSIDERATIONS
Repair of tissue requires more amino acids, carbohydrates, lipids, minerals, water, vitamins, trace elements, and oxygen than does normal metabolism of epidermis and connective tissue.
Table I. Factors influencing healing of wounds
A. B.
C. D.
Environment--local climate and wound dressings Nutritional consideration 1. Proteins and carbohydrates 2. Vitamins, especially A and C 3. Trace elements, especially zinc 4. Oxygen tension Bacteria! infection Mechanical influences 1. Foreign bodies (including crust, devitalized tissue, debris, and suture material) 2. Hematoma formation 3. Tension at wound edges
Proteins and carbohydrates
One of the more important nutritional considerations, especially in the aged, is adequate protein intake. A high-protein diet will promote tensile strength during the fibroblastic phase of repair. Conversely, protein deficiency prolongs the lag phase, depresses synthesis of collagen by fibroblasts, and increases risk of wound disruption. x~ Glucose, too, is an essential building block. Without a sufficient quantity of glucose, oxidative metabolism is compromised, and incorporation of proline into collagen, mucopolysaccharide formation, and oxygen uptake and consumption are impaired. 16-19 Vitamins, especially A and C
Numerous studies have shown that the addition of vitamin A (the alcohol) and its acid, both topically and systemically, can have a profound effect on keratinization and wound healing. The mitotic
rate, mucopolysaccharide synthesis in granulation tissue, and epidermal migration are increased. 2~ However, excessive a~ounts of this vitamin may also inhibit normal growth .26, z7 Probably the first biochemical observation of wound healing was the relation of vitamin C and scurvy to the healing process. Deficiency of ascorbic acid leads to failure of fibroblasts to produce collagen. It appears that while normal collagen synthesis or tumover may not require this vitamin, the rapid metabolism of wound repair requires at least normal quantities of ascorbic acid. 2s-3~ Compounds that stimulate lysosomal activity, such as vitamin A, digitoxin, and testosterone, also stimulate collagen synthesis. al,a2 Conversely, lysosomal stabilizers, such as glucocorticoids and aspirin, depress repair (presumably by depressing collagen synthesis), ea Vitamin E (the tocopherols) is a lysosomal stabilizer and fits within this latter group. The only
210
Journal of the American Academy of Dermatology
Harris
OCCI.US!OH
AIR EXPOSURE
of zinc by mouth reverse the deficiency and accelerate healing, apparently by incorporation into amino acid metabolism and synthesis of collagen substrate.'m Polies and Strain showed that in otherwise healthy young patients, surgically unopposed defects heal at twice the rate of controls when 220-rag zinc sulfate supplements are added to each of three daily meals .44 In addition to zinc deficiency, healing may be adversely affected by either deficiency or toxic excesses of cadmium, cobalt, copper, iodine, manganese, molybdenum, and selenium. OXYGEN TENSION
Fig. 2. Diagrammatic summary of epithelialization of air-exposed and occluded incisions. Note differences in plane of epidermal migration between incisions at 72 hours. (From Rovee DT, et al: Effect of local wound environment on epidermal healing, in Maibach HI, Rovee DT, editors: Epidermal wound healing. Copyright 9 1972 by Year Book Medical Publishers, Inc., Chicago. Used by permission.) controlled study to date measuring the effect of vitamin E on collagen synthesis and tensile strength suggests that this vitamin may significantly retard wound repair and that vitamin A counteracts this inhibitory effect. ~4 Vitamin E, in fact, may have more clinical value in modifying scar :formation than in promoting healing. TRACE ELEMENTS, ESPECIALLY ZINC In the past decade, studies in animals and clinical trials in humans have shown that zinc is an important factor in wound healing.~'35-a8 Zinc insufficiency is probably as common as iron or vitamin C deficiency, especially in the hospitalized, in the burned patient, and in many chronic disease states, a'~'4~ Compared to controls, low serum zinc levels are associated with delayed formation of granulation tissue, prolonged epithelial defects, and decreased tensile strength. 4~'4'2 Supplements
in healing wounds, oxygen appears to be essential to the synthesis of collagen and epithelialization. The supply of oxygen depends on difti~sion. With vascular disruption and edema, injured tissue suffers from low oxygen tension. 4'~'4~ Sound healing can be accelerated in an atmosphere of hyperbaric oxygen. 47 Moreover, migration rate of epidermis under occlusive films is correlated with oxygen permeability of the membrane. The more permeable the membrane by oxygen, the faster the reestablishment of epithelial continuity. 4~ BACTERIAL INFECTION Wounded skin and dressings Since most wounds become contaminated with microorganisms to some degree, the mere presence of bacteria in a wound does not in itself make infection a certainty. Tissue damage, injury to wound edges, presence of devitalized tissue, foreign bodies, and suture material are generally more important factors favoring infection than concentration or type of bacterial organism. 49'5~ Trauma to tissue caused by poor surgical technique cannot be overemphasized as a factor. At the cellular level, crush injury compromises blood supply and increases cell death with loss of nutrients. All of these events enhance growth of microorganisms. 5t With respect to wound dressings, occlusive membranes overlying normal skin for 72 hours will promote lush growth of Staphylococcus attreus and production of toxins. Moreover, stripping the stratum corneum by adhesive tape before occlusion allows invasion and the establishment of
Volume 1 Number 3 September, 1979
Healing of surgical wound
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Fig. 3. Surgical dressing sequence. A, Tenacious nonirritating spray adhesive is applied around sutured incision wound. B, One-inch wide strip of semipermeable woven tape is affixed to adhesive, covering the incision. C, Coarse mesh gauze is placed over the tape. D, Gauze held firmly by paper tape affixed to skin with more adhesive spray. This dressing will remain in place unfailingly for at least the first 48 hours. After this, only the semipermeable woven tape need remain in place directly over the incision. infection in as little as 24 hours. Trapping of tissue fluid and nutrients influences bacterial ga'owth. '~2 Still other factors effecting an increase in bacterial contamination are the host, underlying disease, immunosuppressive therapy, and inadequate attention to asepsis) a In spite of these influences, prophylactic antibiotics generally are not recommended for excisions and primary closure of clean wounds. 54'5'~ However, given reasonable indication for antibiotic therapy, appropriate antibiotics 1 to 2 days before, or within 4 hours after surgery, are recommended by some. Postoperatively, a short, 3-4-day course of such therapy would appear to be sufficient. 56-59 MECHANICAL INFLUENCES Foreign bodies The influence of a crust on migration of epithelium has been discussed. In addition, we have
explored the role played by debris, devitalized tissue, and toreign bodies like suture material in wound infection. Hematoma formation
Hematoma formation is another adverse mechanical influence, creating a space-occupying substance. Hematomas compromise repair and tensile strength. Dehiscence and infection are common sequelae. Proper hemostasis before closure and adequate approximation of the tissue defect will prevent the complication. Tension at wound edges
Tension at wound edges is an important factor in wound repair. Tension reduces the rate of repair, compromises wound strength, decreases contraction, and :increases the width of the final scar.
212
Journal of the American Academy of Dermatology
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that tensile strength increments plateau at the second month. (From Levenson SM, Geever EG, Crawley LV, et al: Ann Surg 161: 293, 1965.) SOME PRACTICAL SUGGESTIONS Wound dressings
We have stated that totally occlusive dressings trap bacteria and can promote infection. This is particularly true for traumatized wounds, open wounds, poorly vascularized or devitalized tissue, and wounds with foreign matter. Nevertheless, for wounds properly handled and neatly apposed at edges, a modified occlusive dressing can be applied that will favor unhindered epithelialization of wound edges with little loss of tissue and no infection. A closed excision so occluded generates across the defect within 18 to 24 hours, without inflammation or crust. An air-exposed wound of the same sort takes at least triple the time to close and leaves a groove or depression that represents the plane of migrating epithelium extending beneath a thick crust (Fig. 2). Fig. 3 illustrates an effective, partially occlusive dressing that I use for sutured wounds. First, the edges of the surgical wound are painted or sprayed with an extremely tenacious, nonallergic, pressure-sensitive silicone adhesive (Hollister medical adhesive; Hollister, Inc., Chicago, IL). Next, a 1-inch strip of semipermeable woven tape is applied over the incision (Dermicel; Johnson & Johnson, New Brunswick, N J). The adhesive holds the material firmly in place for at least 3 to 7 or 8 days. Layers of coarse mesh gauze are placed over the cloth tape, the thickness varying accord-
ing to the pressure required, the surgical site, and the type of repair. The gauze is, in turn, held with a 2- to 3-inch paper tape (Micropore; 3M Co., St. Paul, MN). This final cover is affixed to the skin with the Hollister adhesive and holds unfailingly for the first 48 hours. After 2 days the gauze is removed, but the Dermicel tape is allowed to remain. If it comes off during bathing, or simply loosens, our patients are provided a small amount of Dermicel (wrapped on a tongue blade) for reapplication. Nutrition
In addition to a well-balanced diet, supplements of zinc would appear of benefit, especially to the debilitated or elderly patient. Zinc sulfate hyptahydrate (USP), in a dosage of 220 mg three times daily for adults and half that for children, is adequate. The medication causes gastric irritation in some and should be taken after meals with m i l k . 44 Multivitamins containing zinc are less irritating, convenient, but expensive alternatives. Mechanical influences
Careful handling of wound edges, meticulous debridement, and reduction of tension throughout the depth of the wound are most helpful to the healing. Inadequate consideration of any of these factors can lead to delayed healing, devitalized tissue, infection, and increased scar formation. First, incisions should be made parallel to the natural lines of tension, the wrinkle or creases and folds of the skin, especially on the face. In suturing a defect, layered closure is best. In addition to relieving tension, approximation of wound edges through the entire depth of a wound serves both to obliterate dead space and to minimize the possibility of hematoma formation. G~ It is well to remember that the first week after surgery is a lag period preceding fibrogenesis, and wound strength is feeble. Wound dihiscence is most likely to occur between the time skin sutures are removed and tensile strength plateaus--from the first or second week to the second or third month (Fig. 4). Wounds gain only 3% to 5% of their final strength by the time nonabsorbable sutures are usually removed at 2 weeks. In fact, surgical closures have but 50% of original tissue strength by the end of
Volume l Number 3 September, 1979
Healing of surgical wound
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Fig. 5. A, The placement of subcuticular (buried) sutures to eliminate dead space and relieve tension on the wound edge. B, Subcuticular, slowly absorbed sutures in place. Note the reduction in width of wound without penetrating epidermis. C, A subepidermal running suture is utilized to appose the wound edges, leaving only two puncture wounds above and below the incision. Skin sutures can be placed sparingly to more precisely adjust apposition. These skin sutures can be removed in the first 2 to 4 days, leaving the subepidermal suture in place as long as wound support is necessary. D, Skin tapes should be utilized frequently to hold apposed edges of skin wounds in areas where body motion increases tension, especially after removal of skin sutures.
the first month. Thus, the practical importance of placing slowly absorbable or permanent, buried sutures in a layered closure is obvious. In addition, skin or adhesive tapes of the "Steri-Strip" type should be applied for the first month after removal of skin sutures (Fig. 5). Finally, skin sutures should be few and placed only for final apposition of the edges, never to approximate firmly or to take up loss of substance. Moreover, skin sutures should be removed early, in order to minimize puncture scars ("railroad tracks") and " a b s c e s s e s " caused by epithelial disruption at puncture wound sites (Fig. 5, C).
In conclusion, strict adherence to the principles of wound healing is synonymous with good surgical technique and allows for consistently pleasing surgical results. REFERENCES
1. Miller W, et al: Effect of zinc deficiency and restricted feeding on wound healing in the bovine. Proc Soc Exp Biol Med 118:427-430, 1965. 2. Bothwell J, et al: The effect of climate on the repair of cutaneous wounds in humans, in Maibach HI, Rovee, DT, editors: Epidermal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. 3, Gimbel N, et al: A study of epithelialization on blistered burns. Arch Surg 74:800-803, 1956.
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4. Krowczyk W: A pattern of epidermal cell migration during wound healing. J Cell Biol 49:247-263, 1971. 5. Gillman T, Penn J: Studies on repair of cutaneous wounds. II, The healing of wounds involving loss of superficial portions of the skin. Med Proc. 2:150, 1956. 6. Rovee DT, et al: Effect of local wound environment on epidermal healing, in Maibach HI, Royce DT, editors: Epidermal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. 7. Bothwell J, Rovee DT: The effect of dressings on the repair of cutaneous wounds in humans, in Harkness K, editor: Surgical dressings and wound healing. London, 1971, Bradford University Press. 8. Harris DR, Keefe RL: A histologic study of gold leaf treated experimental wounds. J Invest Dermatol 52: 487-494, 1969. 9. Harris D, Yonkey J: Evaluating the effects of hemostatic agents on the healing of superficial wounds, in Maibach HI, Royce DT, editors: Epidermal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. 10. Hinman C, Maibach H: Effect of air exposure and occlusion on experimental human skin wounds. Nature (Lond) 200:377-378, 1963. 1.1. Winter G: Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig. Nature 193: 293- 294, 1962. 1Z Winter G: The movement of epidermal cells over the wound surface, in Montagna W , Billingham R, editors: Advances in the biology of the skin, New York, 1964, Pergamon Press, vol. 5. 13. Harris DR, Filarski SA Jr, Hector RE: The effect of silastic sheet dressings on the healing of split-skin graft donor sites. Plast Reconstr Surg 52:189-190, 1973. 14. Scales JT: Wound healing and the dressing. Br J Indust Med 70:82-94, 1963. 15. Van Winkle W Jr: The tensile strength of wounds and factors that influence it. Surg Gynecol Obstet 129:819842, 1969. 16. Carney SA, Lawrence JC, Ricketts CR: The incorporation of [ 14C] proline by mammalian skin in tissue culture, Biochim Biophys Acta 111:154-158, 1965. 17. Cassel J: Aggregation phenomena of collagen, in Elden H, editor: Biophysical properties of the skin. New York, 1972, John Wiley & Sons, Inc., vol. 1. 18. Cmiekshank CN, Hershey FB: The effect of heat on the metabolism of guinea pig's ear skin. Ann Surg 151: 419-430, 1960. 19. Lawrence J, Ricketts C: The metabolic uptake of sulfate ions by skin. Exp Cell Res 12:633-638~ I957. 20. Hunt TK, Ehrlich HP, Garcia JA, et al: Effect of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animals and man. Ann Surg 170:633-641, 1969. 21. Hunter R, Pinkus H: The effect of oral vitamin A on the number of keratin cells of human epidermis. J Invest Dermatol 37:459-460, 1961. 22. Lee KH: Studies on the mechanism of action of salicylates. III. Effect of vitamin A on the wound healing retardation action of aspirin. J Pharm Sci 57: 1238- 1240, 1968. 23. Prutkin L: Wound healing and vitamin A acid. Acta Derm Venereol (Stockh) 52:489-492, 1972.
Journal of the American Academy of Dermatology
24. Sherman BS: The effect of vitamin A on epithelial mitosis in vitro and in vivo. J Invest Dermatol 37:469480, 1961. 25. Wolf G, Johnson BC: Vitamin A and mucopolysaccharide biosynthesis. Vitam Horm 18:439-455, 1960. 26. Fall H, Mellaney E: Metaplasia produced in cultures of chick ectoderm by high vitamin A. J Physiol (Lond) 119:470-488, 1953. 27. Lawrence DJ, Bern HA, Steadman MG: Vitamin A and keratinization. Studies on the hamster cbeekpouch. Ann Otol 69:645-660, 1960. 28. Levenson SM, Geever EG, Crowley LV, et al: The healing of rat skin wounds. Ann Surg 161:293-308, 1965. 29. Priest RE, Bublitz C: The influence of ascorbic acid and tetrahydropteridine on the synthesis of hydroxyproline by cultured cells. Lab Invest 17:371-379, 1967. 30. Ross R: Wound healing. Sci Am 220:40-50, 1969. 31. Herrman J, Woodward S: Stimulation of fibroplasia by vitamin A. Surg Forum 20:500-505, 1909, 32, Manning JP, Dipasquale G: The effect of vitamin A and hydrocortisone on the normal alkaline phosphate response to skin wounding in rats. J Invest Dermatol 49:225-229, 1967. 33. Erhlich HP, Hunt TK: The effects of cortisone and anabolic steroids on the tensile strength of healing wounds. Ann Surg 170:203-206, 1969. 34. Erhlich HP, Tarver H, Hunt TK: Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann Surg 175:235-240, 1972. 35. Pories WJ, Henzel JH, Rob CG, et al: Acceleration of Wound healing in man with zinc sulfate given by mouth. Lancet 1: 121-124, 1967. 36. Pories WJ, Henzel JH, Rob CG, et al: Acceleration of healing with zinc sulfate. Ann Surg 165:432-436, 1967. 37. Sanstead H, Shepard G: The effect of zinc deficiency on the tensile strength of healing surgical incisions in the integument of the rat. Proc Soc Exp Biol Med 128:687689, 1968. 38. Shelar M, et al: The hypertrophic scar: Hexosamine containing components of burn scars. Proc Soc Exp Biol Med 139:544-547, 1972. 39. Pories W, et al: Zinc deficiency as a cause for delayed wound healing. Curr Top Surg Res 1:315-323, 1969. 40. Prasad A, Oberleas D: Zinc: Human nutrition and metabolic effects. Ann Intern Med 73:631-636, 1970. 41. Hallbook T, Lanner E: Serum-zinc and healing of venous leg ulcers. Lancet 2:780-782, 1972. 42. Pullen FW, Pories WJ, Strain WH: Delayed healing: The rationale for zinc therapy. Laryngoscope 81:1638-1649, t971. 43. Hisu J, Anthony W: Zinc deficiency and urinary excretion of taurine-aSS and inorganic sulfate-aSS following cystine-aSS injection in rats. J Nutr 100:1189-1195, 1970. 44. Pories W, Strain W: Zinc sulfate therapy in surgical patients, in Pories W, et al, editors: Clinical applications of zinc metabolism. Springfield, IL, 1974, Charles C Thomas, Publisher. 45. Zederfeldt B: Studies on wound healing and trauma with special reference in intravascular aggregation of erythrocytes. Acta Chir Scand, Suppl 224, 1957. 46. Hunt T, Zederfeldt B: Nutritional and environmental aspects of wound healing, in Dunphy J, VanWinkle W,
Volume 1 Number 3 September, 1979
47. 48. 49. 50. 51. 52.
53.
editors: Repair and regeneration. New York, 1968, McGraw-Hill Book Co. Barr PO, Enfors W, Eriksson G: Hyperbaric oxygen therapy in dermatology. Br J Dermatol 86:631-635, 1972. Silver I: Oxygen tension and epithelization, in Maibach HI, Rovee DT, editors: Epidet'mal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. Altemeier WA: Control of wound infection. J R Coll Surg Edinb 11:27 1-282, 1966. Altemeier W: The significance of infection in trauma. Bull Am Coil Surg 57:7-14, March, 1972. Altemeier W, Sanford J: Conversation on wound healing, in Dunphy J, editor: Wound healing. New York, 1974, Medcom Press. Marples R, Kligman A: Bacterial infection of superficial wounds: A human model for Staphylococcus aureus, in Maibach HI, Rovee DT, editors: Epidermal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. McGowan JE Jr, Finland M: Infection and antibiotic usage at Boston City Hospital: Changes in prevalence
Healing of surgical wound
54. 55. 56. 57. 58. 59. 60.
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during the decade 1964-1973. J Infect Dis 129:421-428, 1974. Roberts W, Visconti J: The rational and irrational use of systemic antimicrobial drugs. Am J Hosp Pharm 29: 828-834, 1972. Simmons HE, Stolley PD: This is medical progress? Trends and consequences of antibiotic use in the United States. JAMA 227: 1023- 1028, 1974. Barnes BA: Prophylactic use of antibiotics. Surgery 67:36%370, 1970. Miles A, et al: The value and duration of defense reactions of the skin to the primary lodgement of bacteria. Br J Exp Pathol 38:79-96, 1957. Polk HC Jr, Lopez-Mayor JF: Postoperative wound infection: A prospective study of determinant factors and prevention. Surgery 66:97-103, 1969. Pollack A, Tindal D: The effect of a single dose parenteral antibiotic in the prevention of wound infection: A controlled trial. Br J Surg 59:98-99, 1972. Grabb W, Smith J: Plastic surgery: A concise guide to clinical practice. Boston, 1973, Little, Brown & Co.
i
ii il
I II IIIII II
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Healing of the surgical wound H. Factors influencing repair and regeneration David R. Harris, M.D. Palo Alto, CA In Part II, various factors affecting the healing wound are considered. These include the environment, nutrition, bacterial infection, and mechanical influences. Relating the healing process to these considerations can aid in developing better surgical judgment, minimizing complications, and improving the technical result of excision and repair. (J AM ACAD DERMATOL1:208-215, 1979.)
Surgical wounds heal, in part by regeneration, or reconstitution of normal tissue integrity with no significant architectural distortion. An example is epithelialization of a superficial erosion, a denuded blister, or the apposed edges of an incision. In addition, disruptions of deeper dermal portions of the epithelium heaI by repair, or restoration with varying degrees of permanent architectural change. This change is, in short, scar formation. 1 These basic processes of wound healing were explored in part I of this communication. In this second part, we will appraise various factors influencing regeneration and repair and their importance in relation to the surgical result. Each factor, outlined in Table I, will be considered in turn. ENVIRONMENT, LOCAL CLIMATE, AND WOUND DRESSINGS Regeneration of epithelium is influenced both by local environment (the temperature and humidity immediately surrounding the wound surface beneath a dressing) and the larger environment, the climate of the geographical area in which the patient resides. 2-4 In part I of this review, we learned that migration of epidermal cells, the sinFrom the Department of Dermatology, Stanford University School of Medicine, Address for reprints: 700 West Parr Ave., Suite M, Los Gatos, CA 95030.
208
gle most important factor in restoration of epidermis, occurs within 48 to 72 hours. However, air exposure or a nonocclusive dressing allows dehydration of denuded dermis at the edge and base of wounds with subsequent incorporation in the crust. Crust represents a mechanical barrier to epidermal migration, since cells must move by cleaving a plane between the viable wound bed and overlying dead, dry material (Fig. 1, part I). This is accomplished at great metabolic expenditure by enzymatic action and phagocytic activity. The result is a new epidermal surface in the form of a linear groove in apposed edges, a dell or depression in excision defects. 4' 5 Maintenance of hydration will alter the course of both epidermal migration and kinetic response to incisions. 6 It has been shown that various topical agents and occlusive inert dressings, which limit tissue death and maintain hydration, enhance epithelialization. 7-9 Investigations reveal that application of an occlusive plastic film to superficial and deep incision wounds will hasten regeneration time as much as twofold over air-exposed sites. When exudate remains serous, granulation tissue quickly forms a solid base across which epidermis migrates unimpeded by dried crust and tissue debris 1~ (Fig. 1). Moreover, the inflammatory response is lessened by occlusive dressings. Unfortunately, whereas a totally occlusive 0190-9622/79/030208 +08500.80/0 9 1979 Am Acad Dermatol
Volume 1 Number 3 September, 1979
Healing
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.
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Fig. 1. Comparison of the mode of epidermal regeneration in shallow skin wounds under exposed (no dressing) and occlusive conditions. (From Winter GD: Epidermal regeneration studied in the domestic pig, in Maibach HI, Royce DT, editors: Epidermal wound healing. Copyright 9 1972 by Year Book Medical Publishers, Inc., Chicago. Used by permission.) membrane maintains good hydration, it also traps exudate. Retained exudate is a culture media for bacteria. Better would be a semipermeable dressing that provides a moist surface for epidermal migration while allowing for sufficient drainage or absorption of tissue fluid, s' 13, t4 This ideal dressing is not yet developed. NUTRITIONAL CONSIDERATIONS
Repair of tissue requires more amino acids, carbohydrates, lipids, minerals, water, vitamins, trace elements, and oxygen than does normal metabolism of epidermis and connective tissue.
Table I. Factors influencing healing of wounds
A. B.
C. D.
Environment--local climate and wound dressings Nutritional consideration 1. Proteins and carbohydrates 2. Vitamins, especially A and C 3. Trace elements, especially zinc 4. Oxygen tension Bacteria! infection Mechanical influences 1. Foreign bodies (including crust, devitalized tissue, debris, and suture material) 2. Hematoma formation 3. Tension at wound edges
Proteins and carbohydrates
One of the more important nutritional considerations, especially in the aged, is adequate protein intake. A high-protein diet will promote tensile strength during the fibroblastic phase of repair. Conversely, protein deficiency prolongs the lag phase, depresses synthesis of collagen by fibroblasts, and increases risk of wound disruption. x~ Glucose, too, is an essential building block. Without a sufficient quantity of glucose, oxidative metabolism is compromised, and incorporation of proline into collagen, mucopolysaccharide formation, and oxygen uptake and consumption are impaired. 16-19 Vitamins, especially A and C
Numerous studies have shown that the addition of vitamin A (the alcohol) and its acid, both topically and systemically, can have a profound effect on keratinization and wound healing. The mitotic
rate, mucopolysaccharide synthesis in granulation tissue, and epidermal migration are increased. 2~ However, excessive a~ounts of this vitamin may also inhibit normal growth .26, z7 Probably the first biochemical observation of wound healing was the relation of vitamin C and scurvy to the healing process. Deficiency of ascorbic acid leads to failure of fibroblasts to produce collagen. It appears that while normal collagen synthesis or tumover may not require this vitamin, the rapid metabolism of wound repair requires at least normal quantities of ascorbic acid. 2s-3~ Compounds that stimulate lysosomal activity, such as vitamin A, digitoxin, and testosterone, also stimulate collagen synthesis. al,a2 Conversely, lysosomal stabilizers, such as glucocorticoids and aspirin, depress repair (presumably by depressing collagen synthesis), ea Vitamin E (the tocopherols) is a lysosomal stabilizer and fits within this latter group. The only
210
Journal of the American Academy of Dermatology
Harris
OCCI.US!OH
AIR EXPOSURE
of zinc by mouth reverse the deficiency and accelerate healing, apparently by incorporation into amino acid metabolism and synthesis of collagen substrate.'m Polies and Strain showed that in otherwise healthy young patients, surgically unopposed defects heal at twice the rate of controls when 220-rag zinc sulfate supplements are added to each of three daily meals .44 In addition to zinc deficiency, healing may be adversely affected by either deficiency or toxic excesses of cadmium, cobalt, copper, iodine, manganese, molybdenum, and selenium. OXYGEN TENSION
Fig. 2. Diagrammatic summary of epithelialization of air-exposed and occluded incisions. Note differences in plane of epidermal migration between incisions at 72 hours. (From Rovee DT, et al: Effect of local wound environment on epidermal healing, in Maibach HI, Rovee DT, editors: Epidermal wound healing. Copyright 9 1972 by Year Book Medical Publishers, Inc., Chicago. Used by permission.) controlled study to date measuring the effect of vitamin E on collagen synthesis and tensile strength suggests that this vitamin may significantly retard wound repair and that vitamin A counteracts this inhibitory effect. ~4 Vitamin E, in fact, may have more clinical value in modifying scar :formation than in promoting healing. TRACE ELEMENTS, ESPECIALLY ZINC In the past decade, studies in animals and clinical trials in humans have shown that zinc is an important factor in wound healing.~'35-a8 Zinc insufficiency is probably as common as iron or vitamin C deficiency, especially in the hospitalized, in the burned patient, and in many chronic disease states, a'~'4~ Compared to controls, low serum zinc levels are associated with delayed formation of granulation tissue, prolonged epithelial defects, and decreased tensile strength. 4~'4'2 Supplements
in healing wounds, oxygen appears to be essential to the synthesis of collagen and epithelialization. The supply of oxygen depends on difti~sion. With vascular disruption and edema, injured tissue suffers from low oxygen tension. 4'~'4~ Sound healing can be accelerated in an atmosphere of hyperbaric oxygen. 47 Moreover, migration rate of epidermis under occlusive films is correlated with oxygen permeability of the membrane. The more permeable the membrane by oxygen, the faster the reestablishment of epithelial continuity. 4~ BACTERIAL INFECTION Wounded skin and dressings Since most wounds become contaminated with microorganisms to some degree, the mere presence of bacteria in a wound does not in itself make infection a certainty. Tissue damage, injury to wound edges, presence of devitalized tissue, foreign bodies, and suture material are generally more important factors favoring infection than concentration or type of bacterial organism. 49'5~ Trauma to tissue caused by poor surgical technique cannot be overemphasized as a factor. At the cellular level, crush injury compromises blood supply and increases cell death with loss of nutrients. All of these events enhance growth of microorganisms. 5t With respect to wound dressings, occlusive membranes overlying normal skin for 72 hours will promote lush growth of Staphylococcus attreus and production of toxins. Moreover, stripping the stratum corneum by adhesive tape before occlusion allows invasion and the establishment of
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Fig. 3. Surgical dressing sequence. A, Tenacious nonirritating spray adhesive is applied around sutured incision wound. B, One-inch wide strip of semipermeable woven tape is affixed to adhesive, covering the incision. C, Coarse mesh gauze is placed over the tape. D, Gauze held firmly by paper tape affixed to skin with more adhesive spray. This dressing will remain in place unfailingly for at least the first 48 hours. After this, only the semipermeable woven tape need remain in place directly over the incision. infection in as little as 24 hours. Trapping of tissue fluid and nutrients influences bacterial ga'owth. '~2 Still other factors effecting an increase in bacterial contamination are the host, underlying disease, immunosuppressive therapy, and inadequate attention to asepsis) a In spite of these influences, prophylactic antibiotics generally are not recommended for excisions and primary closure of clean wounds. 54'5'~ However, given reasonable indication for antibiotic therapy, appropriate antibiotics 1 to 2 days before, or within 4 hours after surgery, are recommended by some. Postoperatively, a short, 3-4-day course of such therapy would appear to be sufficient. 56-59 MECHANICAL INFLUENCES Foreign bodies The influence of a crust on migration of epithelium has been discussed. In addition, we have
explored the role played by debris, devitalized tissue, and toreign bodies like suture material in wound infection. Hematoma formation
Hematoma formation is another adverse mechanical influence, creating a space-occupying substance. Hematomas compromise repair and tensile strength. Dehiscence and infection are common sequelae. Proper hemostasis before closure and adequate approximation of the tissue defect will prevent the complication. Tension at wound edges
Tension at wound edges is an important factor in wound repair. Tension reduces the rate of repair, compromises wound strength, decreases contraction, and :increases the width of the final scar.
212
Journal of the American Academy of Dermatology
Harris
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that tensile strength increments plateau at the second month. (From Levenson SM, Geever EG, Crawley LV, et al: Ann Surg 161: 293, 1965.) SOME PRACTICAL SUGGESTIONS Wound dressings
We have stated that totally occlusive dressings trap bacteria and can promote infection. This is particularly true for traumatized wounds, open wounds, poorly vascularized or devitalized tissue, and wounds with foreign matter. Nevertheless, for wounds properly handled and neatly apposed at edges, a modified occlusive dressing can be applied that will favor unhindered epithelialization of wound edges with little loss of tissue and no infection. A closed excision so occluded generates across the defect within 18 to 24 hours, without inflammation or crust. An air-exposed wound of the same sort takes at least triple the time to close and leaves a groove or depression that represents the plane of migrating epithelium extending beneath a thick crust (Fig. 2). Fig. 3 illustrates an effective, partially occlusive dressing that I use for sutured wounds. First, the edges of the surgical wound are painted or sprayed with an extremely tenacious, nonallergic, pressure-sensitive silicone adhesive (Hollister medical adhesive; Hollister, Inc., Chicago, IL). Next, a 1-inch strip of semipermeable woven tape is applied over the incision (Dermicel; Johnson & Johnson, New Brunswick, N J). The adhesive holds the material firmly in place for at least 3 to 7 or 8 days. Layers of coarse mesh gauze are placed over the cloth tape, the thickness varying accord-
ing to the pressure required, the surgical site, and the type of repair. The gauze is, in turn, held with a 2- to 3-inch paper tape (Micropore; 3M Co., St. Paul, MN). This final cover is affixed to the skin with the Hollister adhesive and holds unfailingly for the first 48 hours. After 2 days the gauze is removed, but the Dermicel tape is allowed to remain. If it comes off during bathing, or simply loosens, our patients are provided a small amount of Dermicel (wrapped on a tongue blade) for reapplication. Nutrition
In addition to a well-balanced diet, supplements of zinc would appear of benefit, especially to the debilitated or elderly patient. Zinc sulfate hyptahydrate (USP), in a dosage of 220 mg three times daily for adults and half that for children, is adequate. The medication causes gastric irritation in some and should be taken after meals with m i l k . 44 Multivitamins containing zinc are less irritating, convenient, but expensive alternatives. Mechanical influences
Careful handling of wound edges, meticulous debridement, and reduction of tension throughout the depth of the wound are most helpful to the healing. Inadequate consideration of any of these factors can lead to delayed healing, devitalized tissue, infection, and increased scar formation. First, incisions should be made parallel to the natural lines of tension, the wrinkle or creases and folds of the skin, especially on the face. In suturing a defect, layered closure is best. In addition to relieving tension, approximation of wound edges through the entire depth of a wound serves both to obliterate dead space and to minimize the possibility of hematoma formation. G~ It is well to remember that the first week after surgery is a lag period preceding fibrogenesis, and wound strength is feeble. Wound dihiscence is most likely to occur between the time skin sutures are removed and tensile strength plateaus--from the first or second week to the second or third month (Fig. 4). Wounds gain only 3% to 5% of their final strength by the time nonabsorbable sutures are usually removed at 2 weeks. In fact, surgical closures have but 50% of original tissue strength by the end of
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Healing of surgical wound
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Fig. 5. A, The placement of subcuticular (buried) sutures to eliminate dead space and relieve tension on the wound edge. B, Subcuticular, slowly absorbed sutures in place. Note the reduction in width of wound without penetrating epidermis. C, A subepidermal running suture is utilized to appose the wound edges, leaving only two puncture wounds above and below the incision. Skin sutures can be placed sparingly to more precisely adjust apposition. These skin sutures can be removed in the first 2 to 4 days, leaving the subepidermal suture in place as long as wound support is necessary. D, Skin tapes should be utilized frequently to hold apposed edges of skin wounds in areas where body motion increases tension, especially after removal of skin sutures.
the first month. Thus, the practical importance of placing slowly absorbable or permanent, buried sutures in a layered closure is obvious. In addition, skin or adhesive tapes of the "Steri-Strip" type should be applied for the first month after removal of skin sutures (Fig. 5). Finally, skin sutures should be few and placed only for final apposition of the edges, never to approximate firmly or to take up loss of substance. Moreover, skin sutures should be removed early, in order to minimize puncture scars ("railroad tracks") and " a b s c e s s e s " caused by epithelial disruption at puncture wound sites (Fig. 5, C).
In conclusion, strict adherence to the principles of wound healing is synonymous with good surgical technique and allows for consistently pleasing surgical results. REFERENCES
1. Miller W, et al: Effect of zinc deficiency and restricted feeding on wound healing in the bovine. Proc Soc Exp Biol Med 118:427-430, 1965. 2. Bothwell J, et al: The effect of climate on the repair of cutaneous wounds in humans, in Maibach HI, Rovee, DT, editors: Epidermal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. 3, Gimbel N, et al: A study of epithelialization on blistered burns. Arch Surg 74:800-803, 1956.
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4. Krowczyk W: A pattern of epidermal cell migration during wound healing. J Cell Biol 49:247-263, 1971. 5. Gillman T, Penn J: Studies on repair of cutaneous wounds. II, The healing of wounds involving loss of superficial portions of the skin. Med Proc. 2:150, 1956. 6. Rovee DT, et al: Effect of local wound environment on epidermal healing, in Maibach HI, Royce DT, editors: Epidermal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. 7. Bothwell J, Rovee DT: The effect of dressings on the repair of cutaneous wounds in humans, in Harkness K, editor: Surgical dressings and wound healing. London, 1971, Bradford University Press. 8. Harris DR, Keefe RL: A histologic study of gold leaf treated experimental wounds. J Invest Dermatol 52: 487-494, 1969. 9. Harris D, Yonkey J: Evaluating the effects of hemostatic agents on the healing of superficial wounds, in Maibach HI, Royce DT, editors: Epidermal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. 10. Hinman C, Maibach H: Effect of air exposure and occlusion on experimental human skin wounds. Nature (Lond) 200:377-378, 1963. 1.1. Winter G: Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig. Nature 193: 293- 294, 1962. 1Z Winter G: The movement of epidermal cells over the wound surface, in Montagna W , Billingham R, editors: Advances in the biology of the skin, New York, 1964, Pergamon Press, vol. 5. 13. Harris DR, Filarski SA Jr, Hector RE: The effect of silastic sheet dressings on the healing of split-skin graft donor sites. Plast Reconstr Surg 52:189-190, 1973. 14. Scales JT: Wound healing and the dressing. Br J Indust Med 70:82-94, 1963. 15. Van Winkle W Jr: The tensile strength of wounds and factors that influence it. Surg Gynecol Obstet 129:819842, 1969. 16. Carney SA, Lawrence JC, Ricketts CR: The incorporation of [ 14C] proline by mammalian skin in tissue culture, Biochim Biophys Acta 111:154-158, 1965. 17. Cassel J: Aggregation phenomena of collagen, in Elden H, editor: Biophysical properties of the skin. New York, 1972, John Wiley & Sons, Inc., vol. 1. 18. Cmiekshank CN, Hershey FB: The effect of heat on the metabolism of guinea pig's ear skin. Ann Surg 151: 419-430, 1960. 19. Lawrence J, Ricketts C: The metabolic uptake of sulfate ions by skin. Exp Cell Res 12:633-638~ I957. 20. Hunt TK, Ehrlich HP, Garcia JA, et al: Effect of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animals and man. Ann Surg 170:633-641, 1969. 21. Hunter R, Pinkus H: The effect of oral vitamin A on the number of keratin cells of human epidermis. J Invest Dermatol 37:459-460, 1961. 22. Lee KH: Studies on the mechanism of action of salicylates. III. Effect of vitamin A on the wound healing retardation action of aspirin. J Pharm Sci 57: 1238- 1240, 1968. 23. Prutkin L: Wound healing and vitamin A acid. Acta Derm Venereol (Stockh) 52:489-492, 1972.
Journal of the American Academy of Dermatology
24. Sherman BS: The effect of vitamin A on epithelial mitosis in vitro and in vivo. J Invest Dermatol 37:469480, 1961. 25. Wolf G, Johnson BC: Vitamin A and mucopolysaccharide biosynthesis. Vitam Horm 18:439-455, 1960. 26. Fall H, Mellaney E: Metaplasia produced in cultures of chick ectoderm by high vitamin A. J Physiol (Lond) 119:470-488, 1953. 27. Lawrence DJ, Bern HA, Steadman MG: Vitamin A and keratinization. Studies on the hamster cbeekpouch. Ann Otol 69:645-660, 1960. 28. Levenson SM, Geever EG, Crowley LV, et al: The healing of rat skin wounds. Ann Surg 161:293-308, 1965. 29. Priest RE, Bublitz C: The influence of ascorbic acid and tetrahydropteridine on the synthesis of hydroxyproline by cultured cells. Lab Invest 17:371-379, 1967. 30. Ross R: Wound healing. Sci Am 220:40-50, 1969. 31. Herrman J, Woodward S: Stimulation of fibroplasia by vitamin A. Surg Forum 20:500-505, 1909, 32, Manning JP, Dipasquale G: The effect of vitamin A and hydrocortisone on the normal alkaline phosphate response to skin wounding in rats. J Invest Dermatol 49:225-229, 1967. 33. Erhlich HP, Hunt TK: The effects of cortisone and anabolic steroids on the tensile strength of healing wounds. Ann Surg 170:203-206, 1969. 34. Erhlich HP, Tarver H, Hunt TK: Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann Surg 175:235-240, 1972. 35. Pories WJ, Henzel JH, Rob CG, et al: Acceleration of Wound healing in man with zinc sulfate given by mouth. Lancet 1: 121-124, 1967. 36. Pories WJ, Henzel JH, Rob CG, et al: Acceleration of healing with zinc sulfate. Ann Surg 165:432-436, 1967. 37. Sanstead H, Shepard G: The effect of zinc deficiency on the tensile strength of healing surgical incisions in the integument of the rat. Proc Soc Exp Biol Med 128:687689, 1968. 38. Shelar M, et al: The hypertrophic scar: Hexosamine containing components of burn scars. Proc Soc Exp Biol Med 139:544-547, 1972. 39. Pories W, et al: Zinc deficiency as a cause for delayed wound healing. Curr Top Surg Res 1:315-323, 1969. 40. Prasad A, Oberleas D: Zinc: Human nutrition and metabolic effects. Ann Intern Med 73:631-636, 1970. 41. Hallbook T, Lanner E: Serum-zinc and healing of venous leg ulcers. Lancet 2:780-782, 1972. 42. Pullen FW, Pories WJ, Strain WH: Delayed healing: The rationale for zinc therapy. Laryngoscope 81:1638-1649, t971. 43. Hisu J, Anthony W: Zinc deficiency and urinary excretion of taurine-aSS and inorganic sulfate-aSS following cystine-aSS injection in rats. J Nutr 100:1189-1195, 1970. 44. Pories W, Strain W: Zinc sulfate therapy in surgical patients, in Pories W, et al, editors: Clinical applications of zinc metabolism. Springfield, IL, 1974, Charles C Thomas, Publisher. 45. Zederfeldt B: Studies on wound healing and trauma with special reference in intravascular aggregation of erythrocytes. Acta Chir Scand, Suppl 224, 1957. 46. Hunt T, Zederfeldt B: Nutritional and environmental aspects of wound healing, in Dunphy J, VanWinkle W,
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editors: Repair and regeneration. New York, 1968, McGraw-Hill Book Co. Barr PO, Enfors W, Eriksson G: Hyperbaric oxygen therapy in dermatology. Br J Dermatol 86:631-635, 1972. Silver I: Oxygen tension and epithelization, in Maibach HI, Rovee DT, editors: Epidet'mal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. Altemeier WA: Control of wound infection. J R Coll Surg Edinb 11:27 1-282, 1966. Altemeier W: The significance of infection in trauma. Bull Am Coil Surg 57:7-14, March, 1972. Altemeier W, Sanford J: Conversation on wound healing, in Dunphy J, editor: Wound healing. New York, 1974, Medcom Press. Marples R, Kligman A: Bacterial infection of superficial wounds: A human model for Staphylococcus aureus, in Maibach HI, Rovee DT, editors: Epidermal wound healing. Chicago, 1972, Year Book Medical Publishers, Inc. McGowan JE Jr, Finland M: Infection and antibiotic usage at Boston City Hospital: Changes in prevalence
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during the decade 1964-1973. J Infect Dis 129:421-428, 1974. Roberts W, Visconti J: The rational and irrational use of systemic antimicrobial drugs. Am J Hosp Pharm 29: 828-834, 1972. Simmons HE, Stolley PD: This is medical progress? Trends and consequences of antibiotic use in the United States. JAMA 227: 1023- 1028, 1974. Barnes BA: Prophylactic use of antibiotics. Surgery 67:36%370, 1970. Miles A, et al: The value and duration of defense reactions of the skin to the primary lodgement of bacteria. Br J Exp Pathol 38:79-96, 1957. Polk HC Jr, Lopez-Mayor JF: Postoperative wound infection: A prospective study of determinant factors and prevention. Surgery 66:97-103, 1969. Pollack A, Tindal D: The effect of a single dose parenteral antibiotic in the prevention of wound infection: A controlled trial. Br J Surg 59:98-99, 1972. Grabb W, Smith J: Plastic surgery: A concise guide to clinical practice. Boston, 1973, Little, Brown & Co.