Zinc and the Healing of Chronic Leg Ulcers

M, BERT MYERS, MD, New Orleans; Louisiana GEORGE CHERRY, New Orleans, Louisiana

ISffectivc treatment ~f chronic stasis ulcers of the leg consists of good wound care. external support (boots, elastic bandages, casts, and the like), and bed rest. Such a regimen must often be followed for months before even s~r, all ulcers heal. The search for a drug which would accelerate the process has so far been fruitless, but constant testing is warranted since short- cnir, g the healing period would save much morbidity.

In the past few years, evidence has been accumn- l~ttil~g that zinc is important in wound healing. In 1960, Strain, Porics. attd Hinshaw [1] reported that in rats k'd zinc and mcthionine full thickness wounds healed more rapidly than in control animals. Prasad and others I21 in I963 recognized zinc deficiency in man. and found that patients lacking in the metal had poor heal- ing, a defect corrcctible by adding zinc to their diet. In 1966, Porics and Strain 13], believing that many postoperative patients might be zinc-deficient, reported accelerated healing of open pilonidal wounds by the :~ddition of zinc sulfate to the diet of otherwise healthy servicemen. It was thus thought that perhaps some of the patients with slow-hca!ing leg ulcers might be zinc- deficient, and that the addition of this iota to their d:,et might benefit the healing rate.

Material and Methods Forty ambulatory patients were followed up for a

sufficient period of time Io evah~at0 the healing rate of their ulcers. The patients had ie:;ions which had heen continuously present for from three m~,nth ~, [~" twenly-five years (mean 4.7 years). Six pa¢ienls had ulcers on both legs. All patients were seen twice ti week in a special clinic. At each visit the wound w'.ts cleaned wida hydro- gcn peroxide and tl~en covered with a nonadherenl dress- ing, sterile gauze, and an el'as(it bandage, so arranged that pressure was applied over the tilter. The patients were instructed to spend as much time as po'.;s~blc in bed. ()nce a week, each ulcer was photographed on color film, using a fixed light source :rod dist;mce, Included in the picture was a cenlimeler ruler, carefully placed in the plane of the ulcer. (Figure 1). The developed trans- parencies were projected onto a large shcel of drawing paper, adjusting the distance of projector to paper until the image of tlle centimeter scale exactly coincided with

r-tom the Department of Surgery, Louisiana State University School of Medicine. and Touro Research Institute. New Orleans. Lotlfsian~, This work was in part supported by a grant from the John A. Hart, for(~ Foundation,

the ruler used in the original photograph, The image size v~'as lhu~ 1:1 with that of the lesion, The borders were then traced, and the areas of the ulcers measured with a compensating planimeter. (Figure 2.) The resulting values were plotted against time, using both arithmetic and semitog graph paper, (Figures 3 and 4.) For any given segment of time (control or treatment), the healing rate in square centimeters per week was determined by subtracting the area at the end of the period from that at the beginning, and dividing the restllt, anl figure by the number of weeks. Healing ulcers thus received minus numbers; entart.,ing ulcers, plus numbers.

Serum zinc levels were determined on eighty.six blood samples obtained from twenty-eight of the patients at various lirnes during their treatment. The tests were run on an atomic absorption spectrophotometer.

Sixteen of the patients were ~ivcn oral zinc as die',-a, ry supplements, Gelatin capsules were filled with 220 mg of analytical grade zinc sulfate (ZnSO,:TH=O) by the hos- pital pharmacy. The patients were instructed to take one capsule three time.~ a day, immediately after each meal. The patients ~,ho received supplemental zinc had been followed tip for from four to seventeen weeks (mean 5.6 weeks) before the drug was added to their regimen.

~e~ults Pk;:~imet.er measureme, t s of lhe forty patients re-

vealed tl'ffit the ulcer size at the time of t|.~e firs~ visit to the clinic ranged from 0.97 to 112 em ~ (mean 26.0 cm'-'). Analysis of the graphs showed that most of the ulcers healed at a progressive rate= generally more rapidly during the first few weeks of trealmcnt. The healing rate curves tended to be asymptotic, anti whoa pleaded on semilog paper often came close to being straight lines. (Figure 3.) In nine patients, however, at some time during the period of observation, the ulcers inexplicably enlarged, but after a varying time, began to heal again. The hoped-for c~;rrelation be- tween the serum zinc level attd the healing rate was not found. Zinc levels were obtained in twenty-four patients followed up long enough to establish a healing rate (at least four weeks). Ten patients were con- sidercd to have rapidly healing ulcers (mean healing rate of - 1 . 4 8 cm :~ per week) . This group had an average serum zinc level of 111 ttg per cent. Fourteen other patients were considered to have poor healing (mean rate of - 0 . 2 4 cm: per week) . In this latter group, the average scrim( zinc level was 114 pg per

Vol. 120, Jury 1970 77

Figure I. Photograph o f ulcer showing placement of cent imeter ruler in the plane of the lesion.

Figure 2. Planimeter resfting on a worksheet w i t h 1:1 drawing of one pat ient 's ulcer, The progressive decrease in ulcer size is obvious.

E %

Z00

t50

tOO

50

% z

o IJ

I00

5 0 4 0

3 0

2 0

IO

~e~'HM(~'IC SCAL[ RD 50 C F

ZINC LEV£L

142 ~37 2 8 ~ 15~ • o • •

0 5 I0 15 20

ST~tLOG SCAL£

""~'-t .

1 " ~ I . 4 r .

0 5 10 15 2O

wE.E~s

Figure 3. Graph of ulcer areas p l o t t e d against t ime. In the upper port ion the ordinate is ar i thmetic, whereas in the t o w e r i t is logari thmic, The serum zinc levels in p g p e r cent a r e placed at the t ime the blood samples were drawn. This pat ient had had her ulcer f o r more than three years. Oral zinc therapy was begun a f t e r a n eigt~t week contro l period.

Figure 4. G r a p h of another pat ient who had a very long contro l period as well as extended zinc therapy. Note rise in serum zinc level. The curve shows progressive healing, but there was no increase in rate after oral zinc w a s added to the regimen. This pat ient 's ulcer w a s present for seven y e a r s before s h e c a m e to t h e c l i n i c .

ARt THt~IE TIC SCALE

% u z

CP 50 CE"

CONTWOL , ,

ZINC ~ . _ _

4 0 0 1S[RUM ZINC LEVEL

52 89 96 ;~40 206 • t o • •

3O0

ZOO . ' .

0 5 ~0 15 20 25 30

WEEKS 4

78 The Amer ican Journa l o f Surgery

Zinc and Chronic Leg Ulcers

TABLE I Comparison of Serum Zinc Level and Healing Rate

Ulcer Size on Healing Rate Serum Zinc Age (yr) Sex First Visit (cm~/wk) (#g per cent)

Mean Range Patients Number Mean Range Male Female (cm =) (cm 2) Mean Range Mean Range

With good heal ing 10 52 36-69 2 8 33,1 12.0-72.2 --1.48 --4,26 to -- .64 111 39-176

With poor ilealing 14 52 41-70 2 12 26.4 2.6-111.6 ~.24 ~.39 to -I-.19 114 63-219

cent, essentially the same as in the patients with good healing. (Table I.) The normal serum zinc levcl is 95 to 135 Hg per cent. Patients with values above and below the normal range were found in botll groups.

Sixtecn patients (two males and fourteen females) rcceivcd supplemental oral zinc. All had significant increases in their serum zinc level, verifying that they were indeed taking the drug. The serum level in this group rangcd from 102 to 467 with a mean of 213 ~g per cent. The therapy, however, did not affect the hcaling rate. Before the zinc was given, these patients had a mean healing rate of - 1 . 1 6 cm" per week,. They then received the drug for from 2.5 to 21.5 weeks (mean 13.3 weeks). While these patients were receiving oral zinc, the healing rate averaged - 0 . 2 6 cm 2 per week. (Table II . )

The healing rates of patients who received zinc were also compared with a comparable number who never received the" drug. No patient whose ulcer healed within nine wceks was included. The patients' age and sex distribution was similar in the two groups, as were d~e size and duration of the ulcer. During the first five weeks, the mean healing rates were almost identical. In the later period, the healing rates were actually higher in those who were not given zinc. (Table 1I.)

It should be noted that in almost every patient the healing rate (cm e per week) was lower at a later period than in the earlier weeks. T1-]s was to be expected due

to the nature of the healing rate curves. A more ac- curate assessment or the effect of a drug or any other therapeutic modality can be made by studying the graphs. (Figures 3 and 4.) if zinc had accelerated healing, there would have been an increase in the slope of the curve. In no instance was this found.

Thus, the effect of zinc on the healing rate of leg ulcers was evaluated by two methods. In the first, the patient served as his own control, and in the second, a group receiving zinc was compared with a similar number who did not. Both methods of assessment gave conclusive evidence that ulcers of patients receiving oral zinc therapy did not heal any more rapidly than ulcers of patients not receiving this ntetal.

Reactions to Oral Zinc

One patient taking zinc sulfate complaincd of nau- sea. On questioning, it was found that she had been taking the metal before meals. A switch to postpran- dial ingestion caused the symptom to disapt)ear. Three patients stated that pain in the leg ulcer was relieved by the drug; and in one of these patients pain returned when the zinc was discontinued. No other side effects were noted.

Comments

Interest in the effect of trace metals in health and healing is increasing with the availability of more ac-

TABLE I! Result,~ of Z inc Therapy

Duration of Ulcer Ulcer Size on Age (yr) (yr) First Visit (cm=)

Number Mean Range Mean Range

Healing Rate (cm~/wk)

Mean Range Mean Range

Pat ients who 16 59 41-70 5.0 1.5-20 received zinc

Patie~.s who ne,~e~ 12 63 54-81 4.2 0.25-15 recei~,~d ~',~ c

29.7 2.6-111.6

32.9 2.6-62.0

First period (no zinc) mean 5.6 wk --1.16 --4.06 to --,32 Second period (zinc) mean 13.3 wk --.26 --1.55 to -F.39

First period (mean 5.0 wk) --1.09 --5.5 to -t-5.4 Seco~ld period (mean 9 wk) --,45 --2.4 to +1.3

Vol. 120, July 1970 79

Myers and Cherry

curate and easier methods of measurement. Zinc, a metal found in many essential enzyme systems, pro- motes synthesis of protein and nucleic acid. Zinc de- ficiency was commonly found in domestic animals, so much so that it is now standard practice to add this metal to their feed. This subject was well covered in a recently published seminar t4].

Miller and others [5] showed that zinc-deficient calves had poorer healing than control animals, and that by adding zinc to their diet, the healing rate re- turned to normal. In a later paper 161, they found that increasing the zinc intake to high levels did not accelerate healing beyond the normal rate.

Zinc deficiency was studied ill human subjects by Sandstread, Prasad, and others 17], carrying out extensive endocrine studies in forty Egyptian boy's with severe growth disturbances and hypogonadism. Along with other deficiencies, they found very low serum zinc levels (median 65 ug per cent; range 35 to 81). Clinical improvement did not occur until zinc was added to their diet. MacMahon, Parker, and McKin- non [81 similarly found two patients with severe real- absorption and poor healing. One also had an intrac- table skin rash. Only after oral zinc did their condition improve.

A recent article by Henzel, DeWeesc, and Pories [9] reviewed tile evidence that zinc deficiency exists in man, and that healing can be improved by its use. Their most impressive evidence was in the closure rate of open pilonidal wounds. The median healing time was halved in patients receiving oral zinc, even though tire zinc-treated wounds were considerably larger at the onset than were tire control wounds.

Kahn and Gordon [10] determined serum and urine zinc levels before and after surgery in nineteen patients. They found no significant changes in the first postoperative weeks; however, during the next seven days, there was an increase in both the serum and the urine zinc levels. Greaves and Boyde [ll] noted low- ered serum zinc levels in patients with a variety of skin lesions, including psoriasis, ichthyosis, and venous leg ulcers. The significance of these two observations re- mains unclear.

Strain, Pories, and Hinshaw [1] discovered that burns and full thickness skin defects in rats healed faster when the animals were fed supplemental zinc and methionine. Zinc or methionine alone did not pro- duce this accelerating effect. Murray and Rosenthal [12] applied topical zinc to healing incised wounds in experimental animals. They found no significant in- crease in tensile strength after application of the metal.

The safety of administration of oral zinc is still un- determined. Soluble salts of zinc, such as zinc sulfatc and zinc chloride, are astringent and necrotizing, and

when taken orally can produce violent vomiting and diarrhea, as well as hepatic and renal damage. Arena [13] lists the fatal dose as in excess of 30 gm of zinc sulfate, but Dreisbach [14] reported a fatality after the ingestion of only 10 gm. Chronic toxicity appar- ently does not exist. The patients reported here re- ceived 660 m g a day, and had no significant side effects; however, extensive hepatic and renal function tests were not carried out.

Our choice of patients with chronic leg ulcers may not have been an ideal one to evaluate the efficacy of supplemental zinc, as undoubtedly many factors are operating to affect tile healing rate. Chief among these are tile daily habits of the patient, since unquestionably those who spend a significant portion of time in bed will have better healing than those who do otherwise. Nevertheless, the technics used present an objective method of following these patients, and almost all of them did have progressive healing on a regimen of cleanliness and external support. The addition of oral zinc did not accelerate the healing rate in any patient.

Summary An objective method of determining the healing rate

in patients with chronic leg ulcers has been used in forty patients to date. Almost all patients showed im- provement on a regimen of cleanliness and external sup- port. The serum zinc levels of twenty-four of tile pa- tients ranged from 39 to 219 ~Lg per cent, but there was no correlation between the healing rate and the serum level. The addition of supplemental oral zinc to the therapeutic regime did not acclerate the healing rate in any patient.

A d d e n d u m

We are presently expressing healing rates as per cent change per week rather than in square centimeters. Since healing curves tend to be asymptotic, each pa- tient then has roughly the same healing rate for any given period of time, and any change effected by ther- apy becomes immediately apparent. Such calculations would not in any way change the conclusions reached in this paper.

Acknowledgment: The serum zinc levels were de- termined through the courtesy of Dr Norman Nelson, Department of Surgery, Louisiana State University School of Medicine.

References 1. Strain WH, Pories W J, Hinshaw JR: Zinc studies in skin

repair. Sure Forum 11: 291, 1960. 2. Prasad AS, Maile A, Farid Z, Sandstread HH, Schubert

AR: Zinc metabol ism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarf-

80 The Amer ican Journa l o f Surgery

Zinc and Chronic Leg Ulcers

ism, and hypogonadism. J Lab C/in Med 61: 537, 1963.

3. Pories W J, Strain WH: Zinc and wound healing. Zinc Metabolism. Springfield, Charles C Thomas, 1966.

4. Prasad AS: Zinc Metabolism. Springfield, Charles C Thomas, 1966.

5. Miller W J, Morton JD, Pitts W J, Clifton CM: Effect of zinc deficiency and restricted feeding on wound healing in the bovine. Proc Soc Exp Bio! Med 118: 427, 1965.

6. Millet W J, Blackmon DM, Hiers JM, Fowler PR, Clifton CM, Gentry RP: Effects of adding two forms of sup- plemental zinc to a practical diet on skin regeneration in Holstein heifers and evaluatio~l of a procedure for determining rate of would healing. J Dairy Sci 50: 715, 1967,

7. Sandstread HH, Prasad AS. et ah Human zinc deficiency, endocrine manifestations and response to treatment. Amer J Ctin Nutr 20: 422, 196'7.

8. MacMahon RA, Parker LeM, McKinnon MC: Zinc treat. ment in malabsorption, Med J Aust 2: 210, 1968.

9. Henzel JH, DeWeese MF, Pories W J: Significance of mag- nesium and zinc metabol ism in the surgical patien t I1. Zinc. Arch Sure 95: 991, 1967.

10. Kahn AM, Gordon HE: Alterat!ons of zinc metabolism following surgical operations. Sure Gynec Obstet 128: 88, 1969.

11. Greaves M, Boyde TRC: Plasma-zinc concentrations in patients with psoriasis, other dermatoses, ar, d venous leg ulceration, Lancet, p 1019, 1967.

12. Murray J, Rosenthal S: The effect of locally applied zinc and aluminum on healing incised wounds. Sure Gynec Obstet 126: 1298, 1968.

13. Arena JM: Poisoning. Springfield. I l l inois, Charles C Thomas, 1963.

14. Dreisbach RH: Handbook of Poisoning. Los Altos, Calif, Lange Medical Publications, 1966.

VoL 120, July 1970 81