@Copyright 1991 by The Humana Press, Inc. All rights of any nature, whatsoever, reserved. 01634984/91/3001-0037 $02.00
Parenteral Supplementation with Zinc in Surgical Patients Corrects Postoperative Serum-Zinc Drop HENRI FAURE, 1'* J E A N - C L A U D E PEYRIN, 2 M A R I E - J E A N N E RICHARD, 1 AND ALAIN FAVIER 1
'Laboratoire de Biochimie C and 2Service de REanimation Cardio-vasculaire, Centre Hospitalier REgional et Universitaire de Grenoble, BP 217 X, 38043 Grenoble Cedex, France Received September 7, 1990; Accepted September 20, 1990
ABSTRACT Zinc has been known for a long time to facilitate wound healing. But, so far, supplementation trials in patients treated by major severity surgery gave either partial or controversial results. In a doubleblind, randomized study including 30 patients, we show that zinc supplements (30 mg/d for 3 d) administered by a drip correct postoperative drop of serum zinc, that this correction concerns the available part of serum zinc (i.e., zinc that is bound to compounds other than alpha-2 macroglobulin in serum), and that this supplementation can improve clinical wound healing. Possible influence of increased urinary output after the intervention is discussed, and we found that serum cortisol remains stable w h e n zinc/albumin ratio is stable, and increases sharply w h e n the same ratio drops. Cortisol, therefore, seems to play a major role in zinc redistribution after surgery. Index Entries: Parenteral zinc supplementation; serum zinc; zinc metabolism; zinc/albumin ratios.
INTRODUCTION Zinc is a n essential trace e l e m e n t ; it is part of m o r e t h a n 200 enz y m e s . S o m e of t h e s e e n z y m e s are i n d i s p e n s a b l e for p r o t e i n synthesis, *Author to whom all correspondence and reprint requests should be addressed. Biological Trace Element Research
37
Vol. 301991
38
Faure et aL
ARN and A D N replication, and cell division (1), so w o u n d healing requires zinc for these processes. Zinc is also a crucial nutritional component, required to maintain i m m u n e functions that are very important for normal and rapid w o u n d healing (2) as well as for good prevention against systemic infections. Although a drop in serum zinc after severe surgical interventions is well k n o w n (3-5), it has not been definitely explained and understood. Urine zinc increases after surgery, but losses through urine cannot explain the serum-zinc drop that occurs just after the intervention; moreover, recent workers on this subject failed to show any significant urine zinc increase after surgical intervention (6) or in severely burnt patients (7). Actually, the serum zinc drop is a result of redistribution in the hours following surgery, the major part being taken up by the liver (8). It has been k n o w n for a long time that zinc a d d e d to the diet facilitates w o u n d healing in rats (9). Surprisingly, in humans, so far, a clinical benefit of zinc supplementation in surgical patients is still controversial (10). Moreover, some authors failed to correct plasma zinc drop after intervention (6) despite parenteral administration of zinc. In a r a n d o m i z e d double-blind study including 30 patients, we s h o w e d that a daily 30-mg zinc supplementation can correct serum zinc after intervention and facilitates w o u n d healing. This study also aimed at investigating zinc metabolism in order to explain the perturbations in zinc body distribution that occur after surgery and subsequently h a m p e r w o u n d healing by depleting serum zinc.
~.TERIALS ArID METHODS
Subjects Thirty patients w h o suffered from abdominal aorta atherosclerosis were treated by reconstructive surgery, consisting in all cases, of installing a prothesis of the bifurcation of aorta. This intervention constitutes a trauma of major severity. This intervention lasted about 4.5 h. All patients received glucose infusion and blood perfusion to maintain their blood volume during the intervention and the day of the intervention. They also received b e t w e e n 1500 and 2000 mL of glucose isotonic solution for 5 d. The patients were administered no other exogenous source of zinc. Patients were randomly placed in two groups; 15 received 30 m g zinc (as zinc gluconate)/d for 3 d and the 15 others received a placebo. Zinc supplements or placebo were administered slowly and intravenously by a drip. Supplementations were made the day before intervention (D - 1), just after intervention (DO), and the day after intervention (D + 1).
Biological Trace Element Research
Vol. 30 1991
Zinc Supplementation in Surgery
39
Mean hospitalization duration was 11.79 d (SD = 2.83 d); all patients were completely examined each day of their hospitalization. They were all seen again b e t w e e n 5 and 6 mo after the intervention.
Blood Sampling and Measurements Blood (30 mL) was collected on D - 1, DO, and D + 2 , b e t w e e n 11:00 AM and 1:00 PM, before any zinc s u p p l e m e n t or placebo. We m e a s u r e d total serum zinc, exchangeable serum zinc, ultrafiltrable zinc, white blood cell zinc, alcaline phosphatases, serum albumin, transferrin, prealbumin, iron, cortisol, insulin, and vitamin A. All zinc m e a s u r e m e n t s w e r e performed by flameless atomicabsorption spectrophotometry. Exchangeable zinc (loosely b o u n d zinc), w h i c h represents the part of serum zinc that is really available for the w o u n d e d tissues, was assessed by ultrafiltration (11), and ultrafiltrable zinc was m e a s u r e d by the same technique. We tested collection tubes and reagents used for zinc analysis, w h i c h were found to be totally zincfree. Granulocytes and monocytes were separated from other blood cells by Ficoll gradient density centrifugation and then analyzed by atomic absorption after acid digestion.
Statistical Anatysis Comparisons b e t w e e n the two groups and a m o n g the different days in the study were m a d e using t w o - w a y analysis of variance. Since granulocyte and m o n o c y t e zinc are not Gaussian (normally distributed), we used the Wilcoxon nonparametric test and the Wilcoxon paired test to compare them.
RESULTS All our results are s u m m a r i z e d in Table 1. Total serum zinc d r o p p e d on DO (Fig. 1), but in the placebo group it kept falling until D + 1. This scheme is typical of a severe surgical-intervention effect on serum zinc and could not be seen in medium-severity intervention (4). On DO, s e r u m zinc fell less in s u p p l e m e n t e d patients than in the placebo group, but the difference b e t w e e n serum zinc in the two groups was not significant (p > 0.05). O n D + 3, a big difference a p p e a r e d (p = 0.003) because in s u p p l e m e n t e d patients serum zinc increased back to normal values, while in the placebo group it decreased to below the DO values (Fig. 1). W h e n comparing serum zinc in the same group b e t w e e n the different days of the study, there was no significant difference (p > 0.05) in the s u p p l e m e n t e d group, but a highly significant drop a p p e a r e d in the
Biological Trace Element Research
Vol. 30 1991
40
F'aure et aL
Table 1 Results o f Blood Parameters During the Study D-1 Mean +/-S.D.
DO Mean +/-S.D.
D+2 Mean +/-S.D.
Serum zinc (80-120 tag/d)
P S
86.4+13.00 86.1+14.76
73.67+18.37c 79.07+20.10
h60.40+11.47d 83.33 +__24.04
LB zinc (60-76 l~g/dl)
P S
68.2+10.64 64.6+11.78
52.13 +._9.76d 53.86+12.99a
h42.13+5.83d 62.47+22.17
Uf zinc ( 1.5-3.5 lag/d)
P S
2.447+0.827 2.147+0.993
2.280+0.586 1.967 +9.462
1.967+0.519a 1.920+0.439
Albumin (35-55 g/L)
P S
44.81+6.11 45.06+7.74
36.64+6.03d 37.66 +_._7.63c
39.28+5.56c 41.87+5.57
Zinc/Albumin (/ug/g)
P S
1.96+0.395 1.93+0.533
2.04+0.579 2.06+0.518
1.57 +._0.402d 1.91 +._0.456
LB zinc/Alb. (IJg/g)
P S
1.54+0.270 1.44+0.345
1.45+0.330 1.45+--0.411
1.09+0.231d 1.44+0.492
Granulocyte zinc (41-93~g/1010 )
P S
85.67+46.34 91.80+65.5
94.85• 82.53+59.31
57.13+20.8a 125.1+85.5
Monocyte zinc (99-177~g/i0 I0)
P S
75.23+29.2 89.80+32.9
102.5+37.07 115.0+37.88
113.1+40.4b 138.9+76.8b
Iron (13-28 pMol/L)
P S
27.16+15.50 19.93+10.87
40.91+12.93a 37.80+12.32d
9.96+10.40d I0.57+7.28c
Prealbumin ( 100-400 rag/L)
P S
327.3+67.6 302.7+86.5
254.3+55.1d 243.6+49.1c
184.7+33.7d 176.6 + 34.4d
Tramsferrin (2-4 g/L)
P S
2.92 +._0.84 2.80+0.54
2.39 +-0.59c 2.27+0.46c
1.87 +-0.49d 1.89 +-0.41d
Insulin (15-25 pU/ml)
P S
27.24+34.10 35.31+36.58
56.42+51.44 49.58&40.37
19.72+12.56 20.01+10.74
CortisoI (275-555 nmol/l)
P S
555.5+301.3 469.7+430.7
478.3 +_229.6 436.3+199.0
799.3+375.7c 745.3_.+343.6b
Vitamin A (1.4-5 t~dol/l)
P S
4.59+1.40 3.86 +__0.95
3.62+i.03d 3.11+0.78d
2.40+0.93d 1.86 +._.0.57d
Numbers in parentheses indicate reference intervals for these tests in a healthy population. P: Placebo S: Supplemented 3x30 mg/j Significance of differences intragroup (in comparison with pre-op value) a p< 0.05, b p
Parenteral Supplementation with Zinc in Surgical Patients Corrects Postoperative Serum-Zinc Drop HENRI FAURE, 1'* J E A N - C L A U D E PEYRIN, 2 M A R I E - J E A N N E RICHARD, 1 AND ALAIN FAVIER 1
'Laboratoire de Biochimie C and 2Service de REanimation Cardio-vasculaire, Centre Hospitalier REgional et Universitaire de Grenoble, BP 217 X, 38043 Grenoble Cedex, France Received September 7, 1990; Accepted September 20, 1990
ABSTRACT Zinc has been known for a long time to facilitate wound healing. But, so far, supplementation trials in patients treated by major severity surgery gave either partial or controversial results. In a doubleblind, randomized study including 30 patients, we show that zinc supplements (30 mg/d for 3 d) administered by a drip correct postoperative drop of serum zinc, that this correction concerns the available part of serum zinc (i.e., zinc that is bound to compounds other than alpha-2 macroglobulin in serum), and that this supplementation can improve clinical wound healing. Possible influence of increased urinary output after the intervention is discussed, and we found that serum cortisol remains stable w h e n zinc/albumin ratio is stable, and increases sharply w h e n the same ratio drops. Cortisol, therefore, seems to play a major role in zinc redistribution after surgery. Index Entries: Parenteral zinc supplementation; serum zinc; zinc metabolism; zinc/albumin ratios.
INTRODUCTION Zinc is a n essential trace e l e m e n t ; it is part of m o r e t h a n 200 enz y m e s . S o m e of t h e s e e n z y m e s are i n d i s p e n s a b l e for p r o t e i n synthesis, *Author to whom all correspondence and reprint requests should be addressed. Biological Trace Element Research
37
Vol. 301991
38
Faure et aL
ARN and A D N replication, and cell division (1), so w o u n d healing requires zinc for these processes. Zinc is also a crucial nutritional component, required to maintain i m m u n e functions that are very important for normal and rapid w o u n d healing (2) as well as for good prevention against systemic infections. Although a drop in serum zinc after severe surgical interventions is well k n o w n (3-5), it has not been definitely explained and understood. Urine zinc increases after surgery, but losses through urine cannot explain the serum-zinc drop that occurs just after the intervention; moreover, recent workers on this subject failed to show any significant urine zinc increase after surgical intervention (6) or in severely burnt patients (7). Actually, the serum zinc drop is a result of redistribution in the hours following surgery, the major part being taken up by the liver (8). It has been k n o w n for a long time that zinc a d d e d to the diet facilitates w o u n d healing in rats (9). Surprisingly, in humans, so far, a clinical benefit of zinc supplementation in surgical patients is still controversial (10). Moreover, some authors failed to correct plasma zinc drop after intervention (6) despite parenteral administration of zinc. In a r a n d o m i z e d double-blind study including 30 patients, we s h o w e d that a daily 30-mg zinc supplementation can correct serum zinc after intervention and facilitates w o u n d healing. This study also aimed at investigating zinc metabolism in order to explain the perturbations in zinc body distribution that occur after surgery and subsequently h a m p e r w o u n d healing by depleting serum zinc.
~.TERIALS ArID METHODS
Subjects Thirty patients w h o suffered from abdominal aorta atherosclerosis were treated by reconstructive surgery, consisting in all cases, of installing a prothesis of the bifurcation of aorta. This intervention constitutes a trauma of major severity. This intervention lasted about 4.5 h. All patients received glucose infusion and blood perfusion to maintain their blood volume during the intervention and the day of the intervention. They also received b e t w e e n 1500 and 2000 mL of glucose isotonic solution for 5 d. The patients were administered no other exogenous source of zinc. Patients were randomly placed in two groups; 15 received 30 m g zinc (as zinc gluconate)/d for 3 d and the 15 others received a placebo. Zinc supplements or placebo were administered slowly and intravenously by a drip. Supplementations were made the day before intervention (D - 1), just after intervention (DO), and the day after intervention (D + 1).
Biological Trace Element Research
Vol. 30 1991
Zinc Supplementation in Surgery
39
Mean hospitalization duration was 11.79 d (SD = 2.83 d); all patients were completely examined each day of their hospitalization. They were all seen again b e t w e e n 5 and 6 mo after the intervention.
Blood Sampling and Measurements Blood (30 mL) was collected on D - 1, DO, and D + 2 , b e t w e e n 11:00 AM and 1:00 PM, before any zinc s u p p l e m e n t or placebo. We m e a s u r e d total serum zinc, exchangeable serum zinc, ultrafiltrable zinc, white blood cell zinc, alcaline phosphatases, serum albumin, transferrin, prealbumin, iron, cortisol, insulin, and vitamin A. All zinc m e a s u r e m e n t s w e r e performed by flameless atomicabsorption spectrophotometry. Exchangeable zinc (loosely b o u n d zinc), w h i c h represents the part of serum zinc that is really available for the w o u n d e d tissues, was assessed by ultrafiltration (11), and ultrafiltrable zinc was m e a s u r e d by the same technique. We tested collection tubes and reagents used for zinc analysis, w h i c h were found to be totally zincfree. Granulocytes and monocytes were separated from other blood cells by Ficoll gradient density centrifugation and then analyzed by atomic absorption after acid digestion.
Statistical Anatysis Comparisons b e t w e e n the two groups and a m o n g the different days in the study were m a d e using t w o - w a y analysis of variance. Since granulocyte and m o n o c y t e zinc are not Gaussian (normally distributed), we used the Wilcoxon nonparametric test and the Wilcoxon paired test to compare them.
RESULTS All our results are s u m m a r i z e d in Table 1. Total serum zinc d r o p p e d on DO (Fig. 1), but in the placebo group it kept falling until D + 1. This scheme is typical of a severe surgical-intervention effect on serum zinc and could not be seen in medium-severity intervention (4). On DO, s e r u m zinc fell less in s u p p l e m e n t e d patients than in the placebo group, but the difference b e t w e e n serum zinc in the two groups was not significant (p > 0.05). O n D + 3, a big difference a p p e a r e d (p = 0.003) because in s u p p l e m e n t e d patients serum zinc increased back to normal values, while in the placebo group it decreased to below the DO values (Fig. 1). W h e n comparing serum zinc in the same group b e t w e e n the different days of the study, there was no significant difference (p > 0.05) in the s u p p l e m e n t e d group, but a highly significant drop a p p e a r e d in the
Biological Trace Element Research
Vol. 30 1991
40
F'aure et aL
Table 1 Results o f Blood Parameters During the Study D-1 Mean +/-S.D.
DO Mean +/-S.D.
D+2 Mean +/-S.D.
Serum zinc (80-120 tag/d)
P S
86.4+13.00 86.1+14.76
73.67+18.37c 79.07+20.10
h60.40+11.47d 83.33 +__24.04
LB zinc (60-76 l~g/dl)
P S
68.2+10.64 64.6+11.78
52.13 +._9.76d 53.86+12.99a
h42.13+5.83d 62.47+22.17
Uf zinc ( 1.5-3.5 lag/d)
P S
2.447+0.827 2.147+0.993
2.280+0.586 1.967 +9.462
1.967+0.519a 1.920+0.439
Albumin (35-55 g/L)
P S
44.81+6.11 45.06+7.74
36.64+6.03d 37.66 +_._7.63c
39.28+5.56c 41.87+5.57
Zinc/Albumin (/ug/g)
P S
1.96+0.395 1.93+0.533
2.04+0.579 2.06+0.518
1.57 +._0.402d 1.91 +._0.456
LB zinc/Alb. (IJg/g)
P S
1.54+0.270 1.44+0.345
1.45+0.330 1.45+--0.411
1.09+0.231d 1.44+0.492
Granulocyte zinc (41-93~g/1010 )
P S
85.67+46.34 91.80+65.5
94.85• 82.53+59.31
57.13+20.8a 125.1+85.5
Monocyte zinc (99-177~g/i0 I0)
P S
75.23+29.2 89.80+32.9
102.5+37.07 115.0+37.88
113.1+40.4b 138.9+76.8b
Iron (13-28 pMol/L)
P S
27.16+15.50 19.93+10.87
40.91+12.93a 37.80+12.32d
9.96+10.40d I0.57+7.28c
Prealbumin ( 100-400 rag/L)
P S
327.3+67.6 302.7+86.5
254.3+55.1d 243.6+49.1c
184.7+33.7d 176.6 + 34.4d
Tramsferrin (2-4 g/L)
P S
2.92 +._0.84 2.80+0.54
2.39 +-0.59c 2.27+0.46c
1.87 +-0.49d 1.89 +-0.41d
Insulin (15-25 pU/ml)
P S
27.24+34.10 35.31+36.58
56.42+51.44 49.58&40.37
19.72+12.56 20.01+10.74
CortisoI (275-555 nmol/l)
P S
555.5+301.3 469.7+430.7
478.3 +_229.6 436.3+199.0
799.3+375.7c 745.3_.+343.6b
Vitamin A (1.4-5 t~dol/l)
P S
4.59+1.40 3.86 +__0.95
3.62+i.03d 3.11+0.78d
2.40+0.93d 1.86 +._.0.57d
Numbers in parentheses indicate reference intervals for these tests in a healthy population. P: Placebo S: Supplemented 3x30 mg/j Significance of differences intragroup (in comparison with pre-op value) a p< 0.05, b p
