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Zinc Supplementation in Burn Patients

Nancy Caldis-Coutris, RD, Justin P. Gawaziuk, MSc, Sarvesh Logsetty, MD


Micronutrient supplementation is a common practice throughout many burn centers across
North America; however, uncertainty pertaining to dose, duration, and side effects of
such supplements persists. The authors prospectively collected data from 23 hospitalized
patients with burn sizes ranging from 10 to 93% TBSA. Each patient received a daily
multivitamin and mineral supplement, 50 mg zinc (Zn) daily, and 500 mg vitamin C twice
daily. Supplements were administered orally or enterally. Albumin, prealbumin, C-reactive
protein, serum Zn, and serum copper were measured weekly during hospital admission
until levels were within normal reference range. Our study concluded that 50 mg daily
dose of Zn resulted in normal serum levels in 19 of 23 patients at discharge; 50 mg Zn
supplementation did not interfere with serum copper levels; and Zn supplements, regardless
of administration route, did not result in gastrointestinal side effects. (J Burn Care Res
2012;33:678682)

Patients with major burns suffer acute trace element depletion caused by extensive exudative losses
related to loss of the cutaneous barrier, catabolism,
altered distribution, and altered carrier protein concentrations after severe thermal injury.1 Complications such as delayed wound healing are worsened
with trace element deficiency.2 In North American
burn units, patients with thermal injury are routinely
supplemented with micronutrients.3 It has been suggested that full-thickness burns or partial-thickness
burns >20% TBSA receive a multivitamin and mineral supplement: 10,000 IU vitamin A daily, 50 mg
elemental zinc (Zn) daily, and 500 mg vitamin C
twice daily.4,5 Although this is a common practice in
many burn units, evidence to date is limited on what
doses of micronutrients to use and how long to continue supplementation.
It is well established that patients suffering from
major burn injury have elevated metabolic requirements related to their catabolic state. Along with
the surgical and medical demands of the patient,
adequate provision of macronutrients is essential in
meeting these requirements. Micronutrients, such as

From the Firefighters Burn Unit, Health Sciences Centre,


Winnipeg, Manitoba, Canada.
Supported by The Firefighters Burn Fund (Manitoba).
Address correspondence to Sarvesh Logsetty, MD, Manitoba
Firefighters Burn Unit, GC 401A, 820 Sherbrook Street,
Winnipeg, Manitoba, Canada R3A 1R9.
Copyright 2012 by the American Burn Association.
1559-047X/2012
DOI: 10.1097/BCR.0b013e31824799a3

678

Zn and copper (Cu), in patients suffering from burns


have also been shown to play an essential role in
wound healing, immunity, and antioxidant defense
mechanisms.6
Zn, a cofactor for energy and protein metabolism and an essential trace mineral, is required for
growth and development, neurological function,
and immune response.7 Many aspects of cellular
metabolism are Zn-dependent such as cell proliferation and growth. The structure and function of
cell membranes rely on Zn, thus the loss of Zn from
biological membranes increases cell susceptibility to
oxidative damage and impairs cell function. Zn deficiency is associated with delayed wound healing.8
Whole body Zn levels have been shown to be accurately reflected in plasma Zn concentrations.9 Interpretation of plasma Zn concentrations is complicated
by the acute phase response. Protein degradation
coupled with fluid shifts results in decreased values
of negative acute phase proteins such as albumin and
prealbumin, while positive acute phase proteins such
as C-reactive protein (CRP) rapidly increased. Zn is
primarily bound to cellular proteins and will inevitably fall to about half normal and remain depressed
until the acute phase has resolved.10
Cu is essential for tissue regeneration, formation
of red blood cells, absorption and transport of iron,
and fatty acid oxidation. Reduced Cu levels result in
decreased collagen synthesis and loss of body nitrogen. Although Cu deficiency is rare, levels can be
decreased in burn injury.7 Reports have suggested
that when injury involves 20% TBSA, patients can

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lose 20 to 40% of their Cu content within the first


week of injury.11
Of concern are the interactions and physiological
effects of minerals taken above the recommended
daily intake. There is evidence to suggest that Zn
can interfere with the bioavailability of Cu. Excess
Zn exerts an antagonistic effect by inducing the synthesis of thionein, a polypeptide that has a higher
affinity for Cu than for Zn. Once bound, the resultant Cu-metallothionein complex traps Cu in the
enterocyte making it unavailable for transfer into
the plasma.12,13 This process by which Zn decreases
Cu absorption may have adverse effects on wound
healing.
A reported adverse effect of large dose Zn administration is gastrointestinal (GI) tract irritation precipitating nausea and vomiting.4,14 Despite lack of
evidence, it has been proposed that Zn be added
directly to the tube feed to minimize the incidence
of nausea and vomiting. In our current practice, the
provision of Zn is administered orally or enterally;
however, it is not mixed in the tube feed itself.
While there appears to be agreement that the
hypermetabolic state caused by burns requires nutrition support, including micronutrient supplementation, literature discussing the adverse effects of these
supplements or when to stop them is limited.

Objectives
Specifically related to Zn supplementation, our study
set out to determine the following:
1. The length of time Zn supplementation is required
for levels to return to the reference range.
2. Whether Zn supplementation interferes with
Cu absorption.
3. Whether Zn supplementation is related to GI
irritation.

METHODS

Caldis-Coutris, Gawaziuk, and Logsetty 679

supplement containing 7.5 mg Zn (Centrum Forte,


Pfizer Canada, Mississauga, ON). Patients requiring enteral nutrition support received an additional
24 mg/L of tube feed formula. The amount of Zn
provided by the tube feed varied from 58 to 98 mg
per day as the goal rate was patient-specific. Once
enteral feeds were discontinued, supplements were
provided orally until levels normalized in hospital or
until the patient was discharged. Supplements were
not prescribed upon discharge.

Biochemical Parameters
As alteration in acute phase proteins have been
shown to affect Zn and Cu levels, serum Zn concentrations were measured and trended in conjunction
with CRP, albumin, and prealbumin levels. Measuring CRP, albumin, and prealbumin was necessary to
help differentiate between declining serum Zn values
related to the acute phase response vs declining values associated with increased nutrient requirements.
These five parameters were measured weekly while
patients were in hospital. If Zn levels were not normal at discharge, all five parameters were measured
as outpatients until normal.

Gastrointestinal Parameters
Nursing flow sheets and interdisciplinary progress
notes were reviewed to record whether the patient
reported nausea and/or vomiting.

Statistical Analysis
The data did not have normal distribution
(Kolmogorov-Smirnov test) and thus analyzed with
the nonparametric Kruskal-Wallis test with Dunns
post hoc analysis (GraphPad Prism v5.0, La Jolla,
CA). To examine possible correlations between outcome variables, we used Spearmans rank correlation
coefficient (). Group means were defined as significantly different from each other at P < .05.

Patient Population

RESULTS

We prospectively collected data from June 2009 to


April 2011 from 23 hospitalized patients with burn
size 10% TBSA. All burns were a mixture of partial-thickness and full-thickness burns. Our patients
consisted of 7 females and 16 males, age 17.4 to
79.6 years. One patient succumbed to injuries after
7 weeks in hospital. The Health Research Ethics Board
at University of Manitoba approved this study.

Patient Population

Micronutrient Supplementation
Each day, patients received 50 mg Zn, 500 mg vitamin C twice, and a single multivitamin and mineral

We reviewed a total of 23 hospitalized patients, of


whom 14 of 23 had burns 20% TBSA (Table 1).
Mean patient age was 41.6 17.0 years (range:
17.479.6 years), and the mean length of stay (LOS)
was 35.8 47.4 days (range: 7240 days). Mean size
of burn was 30.3 19.4% (range: 1093%) TBSA,
wherein an average of 18 20.1% (range: 076%) was
full-thickness burns. The majority of patients (13/23)
in this study had at least 10% TBSA burned to full
thickness. Patients underwent an average of 2.4 2.2
(range: 08) surgical procedures.

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680 Caldis-Coutris, Gawaziuk, and Logsetty

Table 1. Patient characteristics

Age (yr)
Length of stay (d)
ICU stay (d)
TBSA (%)
TBSA (% full thickness)
Surgical procedures

Mean

SD

Range

41.6
35.8
11.3
30.3
18.0
2.4

17.06
47.4
20.7
19.4
20.1
2.2

18.079.6
7.0240.0
085.7
10.093.0
076.0
08

Biochemical Parameters
The weekly mean albumin levels (range: 20.925.9
g/L, Figure 1A) were below the reference range (33
45 g/L) during inpatient stay. Until week 4, mean
prealbumin levels (range: 0.080.16 g/L,
Figure
1B) were below the reference range (0.1742 g/L)

at which time they normalized. Weekly mean


CRP levels (range: 45.7154.4 mg/L, Figure 1C)
remained above the reference range (<8 mg/L) during the entire inpatient stay.
Weekly mean Zn levels (range: 6.09.8 mol/L,
Figure 1D) were below the reference range (1020
mol/L) until week 3 when levels began to increase
throughout the remaining hospital stay. Nineteen
patients had normal levels before discharge. The four
remaining patients with burn sizes ranging from 12
to 35% TBSA had a LOS less than 3 weeks, and their
Zn levels returned to normal 16 to 85 days postdischarge (data not shown).
Weekly mean Cu levels (range: 11.617.8 mol/L,
Figure 1E) remained within the reference range
(1125 mol/L) during the entire study. Seven
patients (mean % TBSA = 46.1, range: 2093%) had

Figure 1. Weekly measurement of serum markers: (A) albumin, (B) prealbumin, (C) C-reactive protein, (D) Zn, and (E)
Cu. Mean value is shown with shaded area representing reference range. Groups with different superscripts are significantly
different from each other at P < .05. (F) Cu values shown in the three patients with the lowest values at week 1.

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Caldis-Coutris, Gawaziuk, and Logsetty 681

Table 2. Relationship between nadir Zn and


corresponding date-matched % TBSA and LOS
Value at
Week of
Nadir Zn

Spearman

TBSA
LOS

0.520
0.262

0.011
0.228

Significant
No.
at P = .05 Measurements
Yes
No

23
23

LOS, length of stay.

suboptimal Cu levels at some point during hospital


admission, and these levels corrected to normal before
they were discharged without supplementation. The
three patients with lowest Cu at week 1 (Figure 1F)
had large, deep burns (50% full-thickness burns).
Two patients had Cu levels that normalized during their hospital stay (weeks 3 and 5, respectively),
and the third (number 3) (age 75 years, 65% fullthickness burns) succumbed to her injuries while in
hospital despite aggressive treatment.
We were also interested in analyzing possible relationships between Zn, LOS, and %
TBSA (Table 2). We found significant correlation between nadir Zn and % TBSA (Spearman
= 0.520, P = .011) but no statistically significant
correlation between nadir Zn and LOS (P = .228).
In addition, we did not find a relationship between
CRP and Zn levels in this study (data not shown).

Gastrointestinal Parameters
At no point in the study was Zn supplementation
stopped due to nausea or vomiting. All patients continued Zn supplements until serum levels normalized or they were discharged from hospital. Four of
23 patients reported nausea and/or vomiting during
hospitalization. Two patients with nausea/vomiting,
one of whom experienced gastroparesis, had relief of
their symptoms with placement of a small-bowel feeding tube. A third patient experiencing vomiting and
on endoscopy was found to have upper GI ulcers in
the esophagus, stomach, and duodenum with no evidence of obstruction. Although a nasogastric tube was
initially used, it was later replaced with a small-bowel
feeding tube which alleviated his symptoms. The fourth
patient was nauseated throughout their hospital stay
and treated effectively with an antiemetic. This patient
remained nauseated even after Zn levels returned to
normal and supplementation had been discontinued.

DISCUSSION
Zn is an essential trace mineral for DNA and protein
synthesis as well as cell division.15 Nearly 300 enzymes
require Zn for their activities that include processes

involved in tissue regeneration and repair. Nutrient


deficiencies involving Zn, Cu, and vitamins (A, B, and
E) have been described in patients with major burns.11
Nutritional supplementation after a major burn is
common in North America. Graves et al16 indicated
that 95 of 103 burn centers surveyed supply vitamins
and minerals, including Zn. However, there is a paucity of research examining micronutrient supplementation in patients who have suffered a burn injury.
In our study, we found a general trend toward the
reduction of albumin (Figure 1A), prealbumin (Figure 1B), and Zn (Figure 1D) to be below the reference range in most patients. Our data are similar
to a study from Khorasani et al17 that also found a
reduction in Zn in patients with burns 40% TBSA up
to 2 weeks postinjury. We found that the majority of
mean serum Zn levels returned to normal at 3 weeks
of hospital stay. Patients at week 3 were below reference range (n = 4), within reference range (n = 8), not
in hospital (n = 8), or sample was missed (n = 3). Of
the patients below reference range, two were normal
at week 4 and two at week 5. Of the eight patients
discharged at 3 weeks, four had normal levels of Zn
at discharge. The remaining four returned to normal
levels postdischarge without supplementation. These
data suggest that the majority of burn patients benefit
from receiving Zn supplementation until their serum
Zn levels return to reference range (1020 mol/L),
which is usually by week 3 of hospital stay. The lower
Zn levels are associated with bigger burns but do not
result in longer LOS (Table 2).
One concern of Zn supplementation is a reduction
in Cu levels in patients receiving Zn. In our study,
seven patients had Cu levels below the reference
range during hospital admission (Figure 1E). However, unlike the Khorasani group,17 Cu levels in our
patients were not consistently below the reference
range while in hospital. Cu levels corrected to normal, without supplementation, in all but one patient
(age 75 years, 65% full-thickness burns). Thus, a prolonged reduction in patient Cu levels while receiving
Zn supplementation was observed in only one patient
with an extensive, nonsurvivable burn and is not likely
generalizable to the majority of burn patients.
Another concern of Zn supplementation is undesirable GI side effects. It is unlikely that Zn supplementation was related to the four patients experiencing
GI irritation during their hospital admission. Given
the patients medical conditions and complications
such as GI ulcers and gastroparesis, GI irritation is not
uncommon. Although it remains unclear why two of
our patients experienced nausea/vomiting, it was ultimately managed by medication or altering the method
of feeds without discontinuing Zn supplementation.

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682 Caldis-Coutris, Gawaziuk, and Logsetty

Limitations
Graves et al indicate that nutritional supplementation in burn care is common, with 92% of 103 North
American burn centers indicating that they supply
vitamins and minerals, including Zn. In keeping with
the common practice across North America and our
standard practice, we did not feel it was ethical to
withhold Zn from our patient population, especially in
light of measured low values of plasma Zn. At a cost of
30 cents per day, the inpatient micronutrient regime
for burn patients is generally well tolerated and costeffective. Thus, our objective was not whether Zn was
needed but rather at given supplementation levels,
how long levels took to return to normal. We determined that Zn supplementation could be stopped at
3 weeks in the majority of individuals.
Our study did not take into consideration ceruloplasmin levels. Approximately 90% of Cu is bound
to ceruloplasmin. This Cu-carrying protein in the
blood increases during the acute phase response and
in some cases can artificially increase serum Cu levels
30 to 45 mol/L.18 We therefore cannot comment
whether the Cu levels were normal or low but read
as normal due to increased ceruloplasmin levels. If
Cu was high in the acute phase, ceruloplasmin levels
may have been helpful in the interpretation of serum
values. Once the acute phase resolved, Cu levels were
within normal range. Of note is that the majority of
the Cu levels measured were within the upper range
of normal, suggesting that Cu levels were likely normal even if the effect of ceruloplasmin were to be
taken into account (see Figure 1E).
The reliability of sampling was inconsistent such
that not all patients were sampled for all five parameters at every given point. Three patients did not have
serum Cu levels measured. Insufficient sample was
the result of two missed parameters in one patient,
while a missed outpatient follow-up appointment
resulted in missed blood work for another patient.
In addition, when Zn levels returned to normal, we
were unable to determine whether this was due to
the resolution of the acute phase response, micronutrient supplementation, or both.
3

CONCLUSIONS
Our micronutrient supplementation regime resulted in
normal serum Zn levels at 3 weeks in 8 of 12 patients.
When patients were discharged with suboptimal Zn
levels, values returned within reference range at their
outpatient follow-up visits without receiving Zn
supplements at discharge. Although we were giving
high doses of Zn, Cu levels were not affected by Zn

supplements during hospital stay. Finally, it was determined that Zn supplements did not result in adverse
GI symptoms regardless of administration route.
Based on our observations, we will continue to
provide a 50 mg daily dose of Zn in hospital for
3 weeks of hospital stay. In cases where burns are more
severe (>50% TBSA) or patients are of advanced age
(>70 years), we would continue to monitor serum
levels of Zn and supplement until levels normalized
or until discharge.
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