Smoking and Wound Healing PAULSILVERSTEIN,


Oklahoma City, Oklahoma

The association between cigarette smoking and delayed wound healing is well recognized in clinical practice, although extensive controlled studies have yet to be performed. The documented effects of the toxic constituents of cigarette smoke-particularly nicotine, carbon monoxide, and hydrogen cyanide-suggest potential mechanisms by which smoking may undermine expeditious wound repair. Nicotine is a vasoconstrictor that reduces nutritional blood flow to the skin, resulting in tissue ischemia and impaired healing of injured tissue. Nicotine also increases platelet adhesiveness, raising the risk of thrombotic microvascular occlusion and tissue ischemia. In addition, proliferation of red blood cells, fibroblasts, and macrophages is reduced by nicotine. Carbon monoxide diminishes oxygen transport and metabolism, whereas hydrogen cyanide inhibits the enzyme systems necessary for oxidative metabolism and oxygen transport at the cellular level. Slower healing has been observed clinically in smokers with wounds resulting from trauma, disease, or surgical procedures. The reduced capacity for wound repair is a particular concern in patients undergoing plastic or reconstructive surgery. Compared with nonsmokers, smokers have a higher incidence of unsatisfactory healing after face-lift surgery, as well as a greater degree of complications following breast surgery. Smokers should be advised to stop smoking prior to elective surgery or when recovering from wounds resulting from trauma, disease, or emergent surgery.

From the University of Oklahoma Health Science Center, Oklahoma City, Oklahoma. Requests for reprints should be addressed to Paul Silverstein, M.D., 3301 N.W. 63rd Street, Oklahoma City, Oklahoma 73116.


July 15, 1992

The American Journal of Medicine


he detrimental effects of smoking on wound healing were first reported in 197’7 by Mosely and Finseth [ll, who observed impaired healing of a hand wound in a smoker with arteriosclerosis. Even though these findings appeared in the literature more than a decade ago, the relationship between smoking and delayed wound healing has yet to be studied extensively. To date, most published reports have been based on retrospective clinical analyses; few prospective, controlled studies have been conducted, and only a small amount of controlled laboratory data is available. Nonetheless, the tendency toward slower wound repair in smokers has been well recognized on a clinical level for many years. Cigarette smoke contains >4,000 toxic constituents in either the gaseous or particulate phase (Table I) [Z]. The documented effects of some of these toxins may yield clues as to the mechanisms underlying delayed wound healing. The toxins of greatest interest are nicotine and the two most common gases in cigarette smoke-carbon monoxide and hydrogen cyanide.

POTENTIALMECHANISMSOF DELAYEDHEALING When cigarette smoke is inhaled into the lungs, many of its toxic constituents, including nicotine, are of a particulate size that can either directly poison the cilia or pass the cilia1 barrier, undergo tissue absorption, enter the bloodstream, and gain access to other parts of the body. Other toxins, such as carbon monoxide and hydrogen cyanide, are inhaled in the gaseous phase. With each cigarette smoked, approximately 2-3 mg of nicotine and 2030 mL of carbon monoxide are inhaled [3]. Nicotine exerts several specific effects that can influence wound healing. First, proliferation of red blood cells, fibroblasts, and macrophages is diminished [3]. Fibroblasts and macrophages are responsible for transporting healing substances to the wound area and producing scarring. Fibroblasts must be present to lay down collagen, and the collagen must be hydroxylated so it can form strands and weave a healthy scar. Second, nicotine has been associated with inwhich causes creased platelet adhesiveness, microclots and decreases microperfusion [l]. Diminished microperfusion leads to an increase in

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thrombotic microvascular occlusion and, eventually, tissue ischemia. Third, even while the tissue is becoming deprived of oxygen and blood flow, nicotine produces cutaneous vasoconstriction. This vasoconstriction results from the release of adrenal and peripheral catecholamines, which also increase heart rate, blood pressure, and oxygen demand [4]. Moreover, studies have shown that catecholamines released in this fashion stimulate formation of chaloneshormones that undermine wound healing by retarding and decreasing the rate of epithelialization [5]. The affinity of carbon monoxide for hemoglobin binding is 200 times that of oxygen. Consequently, carbon monoxide competitively inhibits the binding of oxygen, decreasing the oxygen-carrying capacity of hemoglobin and reducing the amount of oxygen reaching the periphery [3]. In addition, as carboxyhemoglobin levels rise in the bloodstream, the oxygen dissociation curve shifts to the left [4,6]. In other words, oxygen is less able to dissociate from red blood cells and diffuse into the tissues. The decrease in the levels of oxygen available for tissue perfusion leads to cellular hypoxia and diminished wound healing. Wound healing also requires enzyme formation. The primary effect of hydrogen cyanide is inhibition of the enzyme systems necessary for oxidative metabolism and oxygen transport at the cellular level

Ul. Taken together, the effects of these toxic substances clearly have the potential to undermine the conditions required for expeditious wound repair and healthy scar formation. The vasoconstriction caused by nicotine reduces nutritional blood flow to peripheral areas in the extremities and skin, resulting in a degree of tissue ischemia that impairs the healing of injured tissue. The impaired oxygen transport and metabolism caused by carbon monoxide, as well as enzyme poisoning by hydrogen cyanide, further reduces the oxidative metabolism needed for cellular repair. The direct damage to macrophages and fibroblasts, coupled with inhibition of epithelialization, completes the damage of the medium required for timely wound healing.

CLINICALIMPLICATIONS Both clinical observations and a limited number of controlled studies seem to confirm a relationship between the known effects of the toxic constituents of cigarettes at the vascular and cellular levels and delayed wound healing in smokers. Slower healing has been noted in smokers with wounds resulting from trauma or disease, as well as those recovering from surgical procedures.



TABLE I Toxic Constituents of Cigarette Smoke GasPhase


Carbon dioxide Carbon monoxide

Particulate matter Nicotine

Hydrogen cyanide Nitrogen oxides

Catechol Phenol

Acetone Formaldehyde

N’-nitrosonornicotine Quinoline

Acrolein Ammonia

Aniline 2-Toluidlne

Pyridine 34inylpyridine

Nlckel N-nitrosodiethanolamine

N-nitrosodimethylamine N-nitrosopyrrolidine

Benzojafpyrene Benzathracene Z-Naphthylamine

idapted with permission from 121.

The medical literature contains extensive reports documenting slower healing of duodenal ulcers in smokers [7], and dental professionals have long been familiar with the delayed healing of oral wounds in smokers. One of the few controlled studies on surgical wound healing focused on 120 women who had undergone laparotomy sterilization [8]. Using a scoring system, the investigators determined that cosmetic scar results were significantly poorer in 69 smokers than in 51 nonsmokers. Scarring was unsatisfactory in 25% of the smokers, compared with none of the nonsmokers. Compromised wound healing is a particular concern in smokers undergoing plastic or reconstructive surgery. The survival of skin flaps and skin grafts depends on adequate blood supply and oxygenation. When a flap is moved from one part of the body to another, microvascular anastomoses are constructed to reestablish the blood supply and keep the flap viable. Because flaps and grafts have been detached from their donor sites, a large amount of oxygen is required for skin survival. A thin skin graft can survive for approximately 48 hours simply on the basis of diffusion of oxygen from the wound surface up through the liquid interface with the graft. Within 12 hours, one can observe evidence of inosculation-that is, random connections between the capillaries in the graft and capillaries in the wound bed. Within 24 hours, the flow of red blood cells through the graft can be seen under a microscope. Within 48 hours, the graft dermis is invaded by blood vessels growing from the wound bed into the graft. In part, this latter process is stimulated by hypoxia and an anaerobic metabolic environment that promotes capillary budding and proliferation. Notably, however, if oxygen is not transported by the red blood cells into the graft, the graft will not survive past 48 hours. Thin-

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The American Journal of Medicine

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TABLE II Risk of Skin Slough in Smokers Versus Nonsmokers Following Face Lift Surgery ‘*’ lpatients with skin ‘lough) = 10.2%(overall chance of having skin slough) 1,186 (total patients surveyed) 74%of 10.2%= 7.5%(chance that a smoking patient will develop skin slough) 26% of 10.2%= 2.7%(chance that a nonsmoking patient will develop skin slough) sprinted with permission from [9].

ner grafts are more apt to survive than are thicker grafts. Composite grafts-such as eyebrow reconstruction, which involves the grafting of skin, hair follicles, dermis, and some subcutaneous fat-are highly unlikely to survive in the absence of adequate blood supply. Consequently, factors such as vasospasm and vasoconstriction can severely compromise the likelihood of keeping grafts and flaps alive. Even in the presence of adequate blood supply, a graft or flap can be destroyed by oxygen deprivation. When a face lift is performed, an incision is made in the hairline, above the ears, around the front of the ears, under the earlobes, behind the ears, and back into the hairline. The skin is then carefully dissected and undermined from the ears to the corners of the eyes, corners of the mouth, and down into the neck. The skin of the face is thus detached from the subcutaneous tissue and all blood supply except for that entering from the medial part of the face and neck. In a retrospective review of 1,186 face-lift procedures, investigators concluded that skin slough was significantly more likely to occur in smokers than in nonsmokers [9]. The results showed that 74% of skin sloughs were due to smoking, independent of those associated with hematoma. The risk of skin slough was calculated as being 7.5% in smokers versus 2.7% in nonsmokers (Table II). A subsequent prospective study likewise found a significantly greater incidence of skin sloughs after face and neck lifts in 31 smokers, compared with 12 exsmokers and 40 nonsmokers [lo]. From a medicallegal standpoint, then, one must question whether a face lift or any other type of elective cosmetic surgery should be undertaken in a smoker. Similar issues arise with regard to breast reductions and mastectomies. In these procedures, the incision is made below the breast and up through the middle of the breast, with subsequent dissection of all the tissue beneath the skin down to the fascia, over the pectoralis major muscle. The result is a skin flap of the chest wall that is not normally as lA-24s

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The American Journal of Medicine

well vascularized as is facial skin. The blood supply for the breast skin is derived from the periphery through the intercostal perforating vessels, entering laterally through the serratus anterior muscle and medially from branches of the internal mammary artery. This supply may be inadequate in smokers. Consequently, the incidence of woundhealing complications is 30-50% higher in smokers than in nonsmokers undergoing breast surgery. Although the surgeon may refuse to perform cosmetic breast surgery on a smoker, the need for mastectomy in a patient with premalignant or malignant disease presents a more complex situation. At a minimum, the patient should be instructed to stop smoking prior to the procedure. To maximize the likelihood of successful smoking cessation, the use of nicotine polacrilex should be combined with an effective behavioral modification program.

CONCLUSION The particulate and gaseous components of cigarette smoke clearly have an inhibitory effect on wound healing. The effects of nicotine, carbon monoxide, and hydrogen cyanide combine to cause tissue anoxia, cellular hypoxia, prevention of the proliferation of epithelial cells, vasoconstriction, a decrease in the oxygen-carrying capacity of blood cells, and poisoning of the enzyme systems required for wound healing. All clinicians must be ‘aware of these liabilities when earing for patients who have suffered wounds as the result of trauma or disease or who are about to schedule elective surgery. Surgeons should take these complicating factors into account when advising patients of their prognoses and obtaining informed consent.

REFERENCES 1. Mosely LH, Finseth F. Cigarette smoking: impairment of digital blood flow and wound healing in the hand. Hand 19n; 9: 97-101. 2. The health consequences of smoking: cardiovascular disease. A report of the surgeon general. Rockville, Maryland: U.S. Department of Health and Human Services, 1983. 3. Sherwin MA, Gastwirth CM. Detrimental effects of cigarette smoking on lower extremity wound healing. J Foot Surg 1990; 29: 84-7. 4. Nolan J, Jenkins RA, Kurihara K, Schultz RC. The acute effects of cigarette smoke exposure on experimental skin flaps. Plast Reconstr Surg 1985; 75: 544-9. 5. Mosely LH, Finseth F, Goody M. Nicotine and its effect on wound healing. Plast Reconstr Surg 1978; 61: 570-5. 6. Rees TD. The acute effects of cigarette smoke exposure on experimental skin flaps: a discussion. Plast Reconstr Surg 1985; 75: 550-l. 7. Piper DW, McIntosh JH, Hudson HM. Factors relevant to the prognosis of chronic duodenal ulcer. Digestion 1985; 31: 9-16. 8. Siana JE, Rex S, Gottrup F. The effect of cigarette smoking on wound healing. Stand J Plast Reconstr Surg 1989; 23: 207-9. 9. Rees TD, Liverett DM, Guy CL. The effect of cigarette smoking on skin-flap survival in the face lift patient. Plast Reconstr Surg 1984; 73: 911-5. 10. Riefkohl R, Wolfe JA, Cox EB, McCarty KS Jr. Association between cutaneous occlusive vascular disease, cigarette smoking, and skin slough after rhytidectomy. Plast Reconstr Surg 1986; n: 592-5.

Volume 93 (suppl 1A)

Smoking and wound healing.

The association between cigarette smoking and delayed wound healing is well recognized in clinical practice, although extensive controlled studies hav...
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