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902 BOOSALIS ET AL

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FIG 2. Serum-copper levels (mean ± SEM) in 23 thermal injury patients (upper figure) and in those same patientsgrouped by percent-TBSA burn (lower figure). The normal range is 75-125 �g/dL. The horizontal lines mark the lowerlimit of normal in each case.

Also, the average burn size of these childrenwas 34% compared to a mean burn size of47% in the adults reported in our study.

The decreased level ofceruloplasmin in ouradult patients is noteworthy. Inasmuch as 93-95% of the circulating copper is attached toceruloplasmin, this implies a decrease inserum-copper levels as well. This was, in fact,the case.

The etiology for the observed decrease (in-stead ofincrease) in serum-ceruloplasmin 1ev-

els is likely multifactorial. Assuming the acute-phase response (via Interleukin-1) was signal-ing an increase in the hepatic synthesis ofceruloplasmin, then either synthesis was un-able to keep up with catabolism and/or therewas some factor(S) interfering with the hepaticsynthesis of this protein. With respect to thefirst case, the well-documented loss of proteinfrom a thermal-wound site could cause cern-loplasmin loss to exceed synthesis. In the sec-ond case, silver ions have been reported to in-

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DAYS POST BURN

COPPER AND THERMAL INJURY 903

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FIG 3. ‘Representative serum-copper (Cu) and serum-ceruloplasmin (Cp) levels in three patients with differingseverity of thermal injury. Note that changes in copper concentrations parallel those of ceruloplasmin and that thepatient with the most severe injury has the greatest depression of copper and ceruloplasmin.

terfere with ceruloplasmin synthesis as well asto react antagonistically with copper.

Growth rate was depressed and mortalityincreased when chicks were given supplementsof 50-200 ppm silver (15) with a low-copperdiet but not with a diet high in copper. Ad-dition of silver to the copper-deficient diet alsodepressed hemoglobin levels and the elastincontent ofthe aortas. Injection ofcopper intocopper-deficient rats increased the synthesis ofceruloplasmin (16), yet when Whanger andWeswig (17) injected 20 �sg ofcopper into ratspreviously fed 200 ppm silver, ceruloplasminlevels were significantly lower than in controlrats fed only the basal diet. A similar decreasein ceruloplasmin synthesis was also seen inmice injected with silver as silver nitrate (18).Thus, silver appears to be an effective antag-onist of ceruloplasmin synthesis.

Our thermally injured patients had elevatedserum-silver levels as previously reported (19),presumably due to the cutaneous absorptionof the topical antimicrobial agent, silver sul-fadiazine. Those patients with > 60% TBSAburn had the greatest elevation in serum-silver

levels as well as the greatest and more pro-longed depression ofceruloplasmin levels. Thetotal body burden of silver was also elevatedin these patients, as evidenced by the massiveamounts of silver excreted in the urine (un-published data). This, however, does not provecause and effect but does suggest the possibilityfor an antagonistic relationship between silverions and ceruloplasmin synthesis in burn pa-tients.

The mean level of serum copper was de-pressed throughout the hospital course. Pa-tients with > 40% TBSA burn had meanserum-copper levels below normal rangethroughout the hospital course. In those pa-tients with < 40% TBSA burn, the mean levelofserum copper returned to normal by 45 dayspostburn, and the level of serum copper wasrelated to the serum-ceruloplasmin level (Figs1 and 2).

In a group of thermal-injury patients,LaFargue et al (20) observed low serum-copperlevels initially postburn. The level of copperin the serum returned to normal range by 10-16 days postinjury. Sanchez-Agreda et al (21)

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904 BOOSALIS ET AL

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FIG 4. Urinary-copper excretion (mean ± SEM) in 23 thermal-injury patients (upper figure) and in those samepatients grouped by percent-TBSA burn (lower figure). The normal range is 10-60 �g/24 h. The horizontal lines markthe upper limit ofthe normal range in both figures.

also found low serum-copper levels within thefirst 2 days postburn. In patients with < 60%TBSA burn, serum-copper levels returned tonormal range between days 8 and 14 postburn.In those patients with > 60% TBSA burn, theserum-copper levels had not returned to nor-mal range by 14 days, the end of the study.These results suggest that the greater the se-verity ofthe burn, the longer it takes for serum-copper levels to return to normal.

Cohen et al (22) measured copper levels in16 thermally injured patients and found thatin the majority (1 5 of 16), serum-copper levelswere within normal limits. Most of these de-terminations were performed 1-6 mo post-thermal injury and the percent-TBSA burnwas relatively low. Wood-Walker et al (23) re-ported normal serum-copper levels in childrenwith an average burn size of 9%. Pochon (24)also reported normal serum-copper levels in

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COPPER AND THERMAL INJURY 905

children with an average burn size of 13.5%.

Shakespeare (25) observed essentially normalserum copper levels in 1 1 patients with 8-60%TBSA burn. The normal range used in thatstudy, though, was lower than the level usedin Sanchez-Agreda et al (21) and in our studies.This likely accounts for the difference in find-ings.

Burn patients exhibited the following pat-tern ofurinary-copper excretion: initially (day3 postburn), the mean excretion ofcopper waswithin normal limits; by day 7, excretion wasapproximately twice the upper limit of normal;by 2 wk, excretion was 2.5-3 times normal;by the 7th wk, excretion had returned to nor-mal in the majority ofpatients. Since the totalbody content of copper is low, this copperloss-especially during the peak period around2 wk postburn may be ofsufficient magnitudeto warrant concern. Patients with greaterTBSA burns tended to have greater urinary-copper excretion.

Two other research groups reported an el-evated loss ofurinary copper in thermal injury(22, 26), yet the number ofdays they measuredwere limited. Cohen et al (22) found 2 of 14patients had increased copper losses at 1.5 and2.5 mo postburn. Carr and Wilkinson (26)found an elevated copper excretion at certaintimes during the first 12 days postburn, butthe measurements were not frequent enoughto discern a particular excretory pattern.

Copper is an essential component of manycuproenzymes, so any compromise in copperstatus may affect the synthesis or function ofany one ofthese enzymes. Ceruloplasmin, forexample, has ferroxidase activity that is re-quired for the normal utilization of iron andsubsequent synthesis of hemoglobin. Normallevels and/or activity of lysyl oxidase, a cu-proenzyme required for collagen synthesis,would be critical for wound-healing in a burnpatient. Studies suggesting copper’s involve-ment in the normal immune function of cx-perimental animals (27) have been reported.Burn patients are very susceptible to infection;thus, altered copper metabolism may be espe-cially important in these patients.

In general, a deficiency ofcopper rarely oc-curs in humans. Patients with severe thermalinjury, though, may be an exception and thusrequire further evaluation for biochemical and

clinical evidence of a copper deficiency.Clearly, the status ofcopper is altered in ther-ma! injury. The etiology and clinical ramifi-cations of these changes require furtherelucidation. 13

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