515724

research-article2013

NCPXXX10.1177/0884533613515724Nutrition in Clinical PracticeRech et al

Review

Heavy Metal in the Intensive Care Unit: A Review of

Current Literature on Trace Element Supplementation in
Critically Ill Patients

Nutrition in Clinical Practice

Volume 29 Number 1
February 2014 7889
2013 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0884533613515724
ncp.sagepub.com
hosted at
online.sagepub.com

Megan Rech, PharmD; Long To, PharmD; Alina Tovbin, RPh; Thomas Smoot,
PharmD; and Mark Mlynarek, RPh

Abstract
Trace elements are essential for many physiologic processes. In recent years, supplementation has been studied for a variety of indications,
including glycemic control, wound healing, antioxidant effect, and anemia. Critical illness, especially states such as burns, traumas, and
septic shock, is associated with inflammatory and oxidative stress, immune dysfunction, and malnutrition. In these patients, enteral and
parenteral nutrition or pharmaceutical supplementation is used to provide essential macronutrients, including trace elements. The purpose
of this review is to describe trace element supplementation, including iron, copper, chromium, manganese, selenium, and zinc, and
highlight their mechanism, pharmacology, outcome data, and adverse effects. (Nutr Clin Pract. 2014;29:7889)

Keywords
minerals; trace elements; critical care; sepsis; micronutrients; nutritional support

Critical illness is characterized by inflammation, oxidative

stress, and immune dysfunction. Inflammation leads to impaired
intestinal mucosa integrity, which decreases absorption of
essential nutrients. Systemic inflammatory response syndrome
(SIRS) is associated with redistribution of vitamins and trace
elements (TEs) from systemic circulation to tissues involved in
protein synthesis and immune cell proliferation.1 Also, malnutrition is a common occurrence in critically ill patients and is
associated with impaired ventilatory drive, decreased immune
function, and increased infectious complications.2
TEs are essential for a multitude of functions throughout the
body. In recent years, evidence suggests that supplementing
TEs, through enteral nutrition (EN) or parenteral nutrition (PN)
or pharmaceutical supplementation, may be of benefit in certain
intensive care unit (ICU) patient populations. This review will
focus on the evidence for the use of zinc, iron, copper, manganese, chromium, and selenium in critically ill patients.

Iron
Mechanism of Action
Iron is an essential TE with paradoxical properties. It readily
accepts and donates electrons, converting between the soluble
ferrous form (Fe2+) to the insoluble ferric form (Fe3+). It plays
an integral role in electron transfer, oxygen transport and storage, and adenosine triphosphate and deoxyribonucleic acid
synthesis.3,4 Iron is a vital component of hemoglobin, with
two-thirds of endogenous iron supply found in bone marrow
erythroid progenitors or in circulating red blood cells (RBCs).3
RBCs have a life span of about 120 days due to diminished

intrinsic antioxidant defenses over time and radical oxygen

species damage. Iron, along with zinc, folate, and cyanocobalamin, is also an important cofactor in erythropoiesis.5
Iron deficiency is a major cause of anemia,4 resulting in
fatigue and decreased sense of well-being.6 Poor oral intake,
blood loss, medications that reduce stomach acidity, and interference with absorption are common causes of iron deficiency.4,7 In the critically ill population, both iron deficiency
and inflammation contribute to anemia.3 In these patients, the
RBC life span is shortened due to surgeries and invasive procedures, phlebotomy, hemolysis, and impaired mucosal integrity
causing gastrointestinal (GI) occult blood loss.5 Iron deficiency
occurs in up to 75% of critically ill patients,8,9 with persistent
anemia months after intensive care discharge.9 Blood transfusions should be restricted to patients with severe anemia
(hemoglobin <7 mg/dL) due to risk of infection transmission,
cost, limited supply, and adverse outcomes such as transfusionrelated acute lung injury (TRALI) or transfusion-associated
circulatory overload (TACO).10,11 Erythrocyte-stimulating
agents (ESAs) are not recommended in critically ill patients.12
Therefore, iron supplementation may be needed to correct anemia due to iron deficiency.
From Henry Ford Hospital, Detroit, Michigan, USA.

Financial disclosure: None declared.

This article originally appeared online on December 12, 2013.
Corresponding Author:
Megan Rech, Loyola University Medical Center, Maywood, IL 60153,
USA.
Email: Mrech@lumc.edu

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Table 1. Iron Preparations.4,18

Iron Salt
Ferrous sulfate
Ferrous gluconate
Ferrous fumarate
Polysaccharide iron
complex
Ferric bisglycinate
Sodium ferric
gluconate
Iron sucrose
Iron dextran

Percentage
Elemental Iron

Dosage Forma

20
12
33
100

325-mg tablets
225- to 325-mg tablets
90- to 150-mg tablets
28- to 200-mg tablets

20
100

29-mg tablet
12.5 mg/mL, up to 1 g IV

100
100

20 mg/mL, up to 1 g IV
50 mg/mL, up to 1 g IV

IV, intravenously.
a
Usual oral dose of iron is 23 mg/kg per day of elemental iron in divided
doses.

Caution should be exercised in the critically ill population

because of irons ability to induce oxidative stress and to promote bacterial growth. It appears that excess unbound iron may
act as nutrients for invading microbials,13 and decreased serum
iron concentrations in critically ill patients may be a defense
mechanism against bacterial proliferation.3 However, studies
in critically ill patients14 and patients with end-stage renal disease15 have not demonstrated this effect. In addition, iron deficiency has been linked to impaired immune response,16 which
may explain an association between iron deficiency and
increased incidence of infection.17 Overall, excess iron should
be avoided because of the potential risk of infection, but iron
therapy to replete deficiency may be considered a therapeutic
option in patients in whom blood transfusions are not
warranted.3

Pharmacology and Dosing

Several formulations of oral and parenteral iron are available
(Table 1). Ferrous iron is available as ferrous fumarate, ferrous
sulfate, and ferrous gluconate, and ferric iron is available as
bisglycinate.4 A polysaccharide iron complex also exists.
Following oral administration, ferrous salts are absorbed better
than ferric iron. Ferrous fumarate has the highest percentage of
iron absorption; however, ferrous sulfate or ferrous gluconate
are preferred because of their higher bioavailability. Because
of the long life span of RBCs, oral iron supplementation takes
several weeks to restore iron stores and improve hemoglobin
concentrations.4 Thus, the utility of enteral iron is limited in
critically ill patients.
Three parenteral iron preparations are available in the
United States: iron dextran, sodium ferric gluconate, and iron
sucrose. Overall, ferric gluconate and iron sucrose preparations have been associated with fewer side effects than iron
dextran. Iron dextran is slowly released from its complex,
while gluconate and sucrose are immediate.4 Table 2 lists the

American Society for Parenteral and Enteral Nutrition

(A.S.P.E.N.) recommendations for oral and parenteral TE
supplementation.19 Of note, these recommendations are for
average patients receiving PN; therefore, hypermetabolic
critically ill patients (ie, burns, traumas, etc) may have
increased nutrition requirements to maintain metabolic
function.

Outcome Data
Table 3 lists clinical studies for all of the TEs discussed in
this review. Well-designed trials of iron use in critically ill
patients are limited. Pieracci et al14 performed a double-blind,
multicenter placebo-controlled trial including 200 critically
ill surgical patients, of whom 35% suffered from burn injuries, with an anticipated length of stay 5 days who were randomized to receive either ferrous sulfate 325 mg 3 times daily
or placebo until hospital discharge. Patients treated with iron
were less likely to receive an RBC transfusion (29.9% vs
44.7%; P = .03) and had a lower daily transfusion rate (22
mL/d vs 29.9 mL/d; P = .03). Of note, there were no differences between the 2 groups in terms of infection rates, antimicrobial days, length of stay, or mortality.14 Another
observational study of 863 anemic patients undergoing cardiopulmonary bypass surgery compared patients who
received intravenous (IV) iron plus erythropoietin therapy vs
blood transfusions postoperatively. Again, no difference was
noted in the incidence of infections.20 Further research is warranted to elucidate the role of parenteral iron therapy in critically ill patients.

Adverse Effects
Oral iron is associated with GI effects, such as such as nausea
and constipation. Ferric bisglycinate is enteric coated and
delayed release, minimizing GI discomfort.
Medications that raise gastric pH reduce absorption of oral
iron. These include H2 antagonists, antacids, and proton pump
inhibitors.4
IV iron can cause anaphylaxis, particularly with iron dextran. Other effects include myalgias and fevers. A test dose of
no more than 100 mg of iron dextran is recommended to assess
patient response. Iron sucrose and sodium ferric gluconate
have a lower incidence of adverse effects.4

Chromium
Mechanism of Action
Chromium is one of the most common elements found in the
earths crust and in seawater. Physiologically, it plays a major
role in glucose control and insulin resistance. Chromium binds
directly to insulin, stabilizing the hormone structure and potentiating the effects of insulin. It has been shown to improve

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Nutrition in Clinical Practice 29(1)

Table 2. Recommendations for Daily Oral and Parenteral Micronutrient Requirements for Adults.19,a
Dosage Form
Oral
Male
Female
Pregnant
Lactating
Parenteral

Zinc

Copper

Manganese

Selenium

Iron

Chromiumb

11 mg
8 mg
11 mg
12 mg
2.55 mg

900 g
900 g
1000 g
1300 g
0.30.5 mgc

2.3 mg
1.8 mg
2 mg
2.6 mg
0.055 mg

55 g
55 g
60 g
70 g
60100 g

8 mg
18 mg
27 mg
9 mg
2550 mg/mod

3035 g
2025 g
30 g
45 g
1015 g

Hypermetabolic critically ill patients, including states such as burns, traumas, sepsis, etc, may have increased requirements.
A chromium-free multitrace element formulation product is recommended for patients at risk of chromium toxicity.
c
Current recommendation is 0.30.5 mg/d, but the currently available products have 1 mg/d.
d
Not routinely added to parenteral nutrition in the United States (given as separate intravenous infusion when indicated).
b

Table 3. Summary of Trace Element Trials.

Trace
Element, Trial
Iron
Pieracci el
al (2009)14

Torres et al
(2006)20

Chromium
Drake et al
(2012)21
Balk et al
(2007)22

Copper
Berger et al
(2006)23

Purpose

Study Design

Determine the efficacy

Randomized placeboof enteral iron
controlled trial (N
supplementation of
= 200)
anemic critically ill
surgical patients
Assess postoperative
Observational,
infection rates in patients
prospective singleundergoing cardiothoracic
centered cohort (N
surgery who received IV
= 863)
iron supplementation

Outcomes

Control: placebo
Treatment: ferrous
sulfate 325 mg by
mouth 3 times daily

Iron supplementation decreased RBC

transfusions (29.9% vs 44.7%; P =
.03) and lowered transfusion rate

Control: blood
transfusions, no IV
iron
Treatment: IV iron and
erythropoietin as
indicated

IV iron did not increase the risk of

infection
After adjustment for comorbidities,
there was still no difference in risk
of infection

Investigate the effects of

Retrospective review IV chromium
IV chromium on insulin
of 14 patients
administration in
requirements
insulin resistance
Determine the effect of
Meta-analysis (N = 41 Various chromium
chromium supplementation
studies)
supplements
on glucose metabolism and
lipid levels

Significant decrease in insulin

requirements after chromium
administration
Chromium supplementation
improved hyperglycemia in
noncritically ill patients with
diabetes

Evaluate the effect of trace

element supplementation
on nosocomial or ICUacquired pneumonia

Lower number of nosocomial

infections in TE group (3.5 1.2
vs 2.0 1; P < .001), including
lower nosocomial pneumonia

Combined results of 2 Control = IV placebo

randomized, double- Treatment = IV TEs
blinded, placebocontaining copper,
controlled trials (N
selenium, and zinc
= 41)

Selenium
Manzanares Evaluate the efficacy of high- Prospective,
dose selenium on clinical
randomized,
et al
outcome in critically ill
placebo-controlled,
(2011)24
patients with SIRS
single-blinded (N
= 35)
Angstwurm
et al
(2007)25

Interventions

Evaluate the effect of high- Prospective

dose supplementation of
randomized,
sodium-selenite in patients
placebo-controlled,
with severe sepsis and
multicenter trial (N
septic shock
= 249)

Control: placebo
Treatment: 2000 g
selenite IV bolus,
followed by continuous
infusion of 1600 g/d
for 10 days
Control: placebo
Treatment: 1000 g
of sodium-selenite
as a bolus IV on
day 1, followed by
continuous infusions
of 1000 g daily IV
for 14 days

SOFA score decreased significantly

in the selenite group at day 10 (P
= .0001)
Early VAP rate was lower in the
selenite group (P = .04); HAP was
lower after ICU discharge (P = .03)
28-day mortality reduction was not
significant the intention-to-treat
analysis (P = .109) and significant
in the per-protocol group (P = .049)
Mortality rates were significantly
lower in patients with DIC (P =
.018), >3 organ dysfunctions (P =
.039), and in severely ill (P = .04)
(continued)

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Table 3.(continued)
Trace
Element, Trial

Purpose

Study Design

Interventions

Forceville et Assess plasma selenium

Prospective,
levels in patients admitted
al (1998)26
observational study
to the ICU and correlate
(N = 134)
it to presence or absence
of SIRS, sepsis, or direct
ischemia-reperfusion

No intervention

Meta-analysis (N =
Manzanares Determine if exogenous
supplementation TEs and
20) of randomized
et al
vitamins could restore
controlled trials
(2012)27
antioxidant statue and
improve clinical outcomes
in critically ill patients

Any antioxidant
micronutrients vs
placebo

Zinc
Berger et al
(2006)23

Young et al
(1996)28

Manganese
Klein et al
(2008)29

Outcomes
Early 40% decrease in plasma
selenium in severely ill ICU
patients with SIRS
Selenium concentration lower than
0.7 mol/L was associated with
a 4-fold increase in mortality and
a 3-fold increase in new organ
failure and VAP
Significant reduction in mortality
with antioxidant micronutrients
supplementation (RR 0.82, 95% CI
0.720.93, P = .002)
Selenium alone: trend toward a lower
mortality with 500 g/d (RR =
0.80, 95% CI 0.631.02, P = .07)
whereas lower doses had no effect

Determine the effect of trace Two aggregated

Study 1
element supplementation
prospective,
Control: placebo
on overall morbidity and
randomized, double- Treatment: IV selenium
wound healing in severe
blind, placebo315 g/d, IV copper
burn patients
controlled trials (N
gluconate 2.5 mg/d,
= 41)
zinc gluconate 26.2
mg/d
Study 2
Control: placebo
Treatment: IV selenium
380 mcg/day, IV
copper gluconate
3.1 mg/day, IV zinc
gluconate 31.4 mg/day
Evaluate effects of zinc
Prospective, doubleControl: 2.5 mg elemental
supplementation on
blinded, randomized
zinc (in PN)
neurologic recovery
controlled trial (N
Treatment: 812 mg IV
= 68)
the first 2 weeks (in
PN), then oral zinc
gluconate 168 mg for
total 3 mo after injury

Treatment group had significantly

less nosocomial pneumonia (P <
.001) and VAP (P = .023)
Length of stay was reduced in
supplemented patients, median 0.63
days vs 0.99 days per percentage of
burned BSA (P = .002)

Evaluate the loss of TEs

following traumatic injury
in patients with normal
renal function and those
on CVVH or CVVHD

Average manganese loss:

Normal renal function: 2.6% of PN
content
CVVH: 21% of PN content
CVVHD: 73% of PN content

Observational cohort
(N = 12)
Normal: n = 6
CVVH: n = 2
CVVHD: n = 4

All patients received

PN with 300 g/d
of manganese; urine
and effluent from the
artificial kidney were
collected for 3 days

Zinc supplementation improves rate

of neurologic recovery
Mean motor GCS higher with
zinc-supplemented group on days
15 and 21 (P = .005, P = .02,
respectively)

BSA, body surface area; CVVH, continuous veno-venous hemofiltration; CVVHD, continuous veno-venous hemodialysis; DIC, disseminated
intravascular coagulopathy; GCS, Glascow coma scale; HAP, hospital-acquired pneumonia; ICU, intensive care unit; IV, intravenous; N, number; RBC,
red blood cells; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; TEs, trace elements; PN, total parenteral
nutrition; VAP, ventilator-associated pneumonia.

insulin receptor and postreceptor signaling, which leads to

increased glucose transport via the glucose transporter 4.
Chromium is also thought to reduce insulin resistance.30,31
Although this mechanism is unclear, it may be related to its
ability to inhibit phosphotyrosine phosphatase, the enzyme that

cleaves phosphate groups from the insulin receptor leading to

decreased insulin sensitivity.32
Chromium serum concentrations are decreased in patients
under metabolic stress, including those with trauma, burns, and
infection.33 Hyperglycemia in acute infections may be

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Nutrition in Clinical Practice 29(1)

explained by chromium deficiency.34 It also alleviates oxidative stress and insulin resistance through interaction with many
cellular pathways, including decreasing tumor necrosis factor
alpha (TNF-), interleukin-6, resistin, and increasing in vitamin C or adiponectin.35
Chromium deficiency has been described in patients receiving long-term PN without supplementation.18,36 Signs of chromium deficiency are exhibited as peripheral neuropathy,
weight loss, hyperglycemia, elevated fatty acid concentrations,
and increased insulin requirements. Supplementation of chromium can reverse of the signs of deficiency.18

Pharmacology and Dosing

Chromium exists in multiple oxidative states, including trivalent and hexavalent forms.37 The hexavalent form is considered
toxic and therefore not available pharmaceutically. Trivalent
chromium is found naturally in many food sources including
yeast, beer, oysters, grains, milk, and vegetables. Picolinic acid
is a metal chelator, which is combined with trivalent chromium
to allow for greater bioavailability and utilization. Absorption
of trivalent chromium from the small bowel ranges from
0.4%2.5% and is increased by aspirin and starches and
decreased by zinc, iron, manganese, and calcium. It is transported in the blood by transferrin and albumin.32,37
Serum chromium concentrations range from 15 g/L;
however, levels are not a meaningful index of tissue stores due
to lack of equilibration. Supplementing deficiency may result
in normalization of the glucose tolerance curve from the diabetic-like curve typical of chromium deficiency.38 This
response is a more meaningful indicator of chromium nutrition
than serum levels. Chromium excretion via the kidneys ranges
from 350 g/d, and dose reduction should occur in renal failure. Biliary excretion via the small intestine may be an ancillary route of elimination.38
Chromium picolinate is available as a nutrition supplement
containing 200600 g per tablet or capsule.32 Table 2 displays
A.S.P.E.N. recommendations for oral and parenteral chromium
supplementation.19 PN routinely supplements chromium as a
multiple TE formula (410 g per vial).37 Chromium contamination is commonly found in PN products, which may provide
much more than the daily recommended amount and lead to
toxicity. A.S.P.E.N. recommends that TE supplements without
chromium should be marketed and more research is needed to
determine the effects of contamination on requirement for
supplementation.19

Outcome Data
Approximately 5%20% of critically ill patients have diabetes.39 Hyperglycemia is commonly a complication in these
patients. In a large randomized trial of treatment of hyperglycemia in the ICU, baseline blood glucose was 144 49
mg/dL.40 Guidelines for the management of hyperglycemia

in the critically ill patient suggest a glucose goal of 100150

mg/dL.41 Insulin resistance in a mixed medical-surgical
intensive care setting has been reported in up to 60% of
patients, and hyperglycemia in this population is independently associated with increased mortality.42 This is potentially modifiable through insulin administration43; novel
therapies such as chromium may be useful in critically ill
insulin-resistant patients.
Chromium administration for hyperglycemia in the ICU
has been limited to case reports.44-46 It has been used in insulin
resistance in patients with pancreatitis, cardiac procedures,
solid organ transplants, trauma, esophagus surgery, and thymus surgery. In all cases, insulin requirements decreased after
initiation of IV chromium with doses ranging from 320 g/h
for 10 hours up to 4 days.21,45,46 A case series of 3 patients
treated with corticosteroids demonstrated that chromium
administration can reduce insulin and oral hypoglycemic
requirements in corticosteroid-induced hyperglycemia.29 This
may be useful in a critically ill population, although further
exploration is needed.
Clinical studies evaluating the effect of chromium use on
carbohydrate metabolism in noncritically ill patients with
diabetes have revealed conflicting results due to variability in
dosing and product formulation, lack of randomization and
blinding, different endpoints, heterogeneity of patient populations, and lack of power.47 Chromium appears to have positive
clinical effect in patients with insulin-resistant diabetes.
Results of a meta-analysis of 41 randomized controlled trials
of patients with type 2 diabetes demonstrated that chromium
supplementation improved glycosylated hemoglobin levels by
0.6% (95% confidence interval [CI], 0.9 to 0.2) and fasting glucose by 1.0 mmol/L (18 mg/dL; CI, 1.4 to 0.5),
although almost half of the studies were of poor quality. This
benefit was not retained in patients without diabetes, and no
effect was seen on lipids.22 Further research through randomized controlled trials is necessary to determine if chromium
would have a beneficial impact on insulin resistance and glucose control in critically ill patients with diabetes. Table 3
summarizes these trials.

Adverse Effects
Toxicity varies depending on valency. Hexavalent chromium,
found in dust, is carcinogenic; exposure has been associated
with lung cancer and dermatitis. In clinical trials, up to 1000 g
per day of trivalent chromium for as long as 64 months has not
resulted in toxicity.48 This form, found in food and oral supplements, exhibits poor absorption, and therefore adverse effects
are uncommon. Although rare, isolated case reports exist of
renal and hepatic failure with high-dose oral chromium supplementation (oral chromium picolinate 600 g/d and 2400 g/d,
respectively).37,49 Parenteral chromium administration (0.15
g/kg per day) in pediatric patients receiving long-term PN has
been implicated as a cause of renal dysfunction.37

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Copper
Mechanism of Action
Copper is an essential nutrient in human physiology that is a
component of many enzyme systems. Copper-containing ferroxidases catalyze the oxidation of ferrous iron, aiding in the
transfer of iron from storage sites in the liver and spleen to the
bone marrow for hemoglobin synthesis. In addition to preventing anemia, copper is vital in connective tissue formation and
bone regulation. Copper is also a component of copper/zinc
superoxide dismutase, which acts as a free radical scavenger.
Finally, it is needed to facilitate the conversion of dopamine to
norepinephrine and synthesis of serotonin through monoamine
oxidase within the central nervous system.50
Copper deficiency is rare in humans but produces a variety
of sequellae. It can result from severe malabsorption syndromes, long-term PN without copper supplementation, lead
poisoning, hemochromatosis, excessive ingestion of soft
drinks, and bariatric surgery.50 Deficiency can manifest as irondeficiency anemia, leukopenia, thrombocytopenia, and
impaired bone, connective tissue, and blood vessel formation.34,51 Neurologic abnormalities similar to those caused by
vitamin B12 deficiency (pernicious anemia) can also occur.
Melanin synthesis is copper dependent, so skin hypopigmentation may occur.52 Symptoms improved after several weeks of
supplementation.

placebo-controlled trials of 41 severely burned patients.

Patients were treated up to 21 days. Neither trial was adequately powered to detect a difference in nosocomial infection,
so the results were combined. A small but significant reduction
in the number of nosocomial infections was observed in the
supplemented patients compared with placebo (3.5 1.2 vs 2.0
1; P < .001). This reduction was primarily observed in nosocomial pneumonia and ventilator-associated pneumonia.23
Further research is needed to elucidate the effects of copper in
critically ill patients, especially pertaining to prevention and
treatment of anemia, as no studies have explored this effect.

Adverse Effects
Toxicity has rarely occurred from consumption of beverages
stored in copper containers or from contaminated water but has
been reported in patients receiving long-term PN. Accumulation
can lead to toxic levels in the liver, brain, and kidney, producing characteristics similar to that of Wilsons disease. This rare
genetic syndrome leads to renal impairment, severe neurologic
toxicity, or hepatic damage due to abnormal copper storage.53
For PN patients, A.S.P.E.N. recommends copper supplementation in TE formulations of 0.30.5 mg/d. Copper doses
should be decreased or omitted in patients with significant cholestasis or hepatic dysfunction.19

Selenium
Pharmacology and Dosing

Mechanism of Action

Copper is absorbed from the stomach and small intestines. The

average dietary oral intake is 11.6 mg daily. It is primarily
eliminated through the bile, with ancillary excretion through
urine, sweat, and menstrual blood. It is transported by albumin
or transcuprein to the liver, where it is stored. The optimal
daily copper supplement for patients receiving PN is 0.30.5
mg/d (see Table 2). Patients with cholestasis will have
decreased copper elimination and may need only 0.15 mg/d,
while those with diarrhea may have increased losses and
require 0.40.5 mg/d. Copper is available in most trace metal
combinations (0.41 mg), orally (2-mg and 5-mg tablets), or as
an injection (0.42 mg/mL).19

Selenium is an essential TE with antioxidant, immunological,

and anti-inflammatory properties. Selenocysteine is an enzymatic cofactor that is located on the 21st amino acid of more
than 25 genes that encode for selenoproteins.55 Selenium deficiency and mutations or polymorphisms in selenoprotein genes
are implicated in a variety of diseases, including skeletomuscular, neurologic, and cardiovascular disorders; thyroid disorders; immune dysfunction; cancer; and endocrine function.56
Selenium exhibits several mechanisms through which it
may benefit critically ill patients. First, glutathione peroxidases, selenium-dependent antioxidants, prevent free radical
induced injury to cells, including the endothelial tissues.
Selenoprotein P accounts for most of the selenium serum concentration and is produced in the liver and then transported to
tissues throughout the body, including the kidneys, thyroid,
testes, pancreas, brain, and muscle. During inflammatory
states, it binds to the endothelium and may have high antioxidant potential.57 Furthermore, during inflammatory states such
as sepsis or trauma, selenium exhibits a biphasic action.58
Initially it produces a pro-oxidant effect, which leads to phagocytosis.59 However, once incorporated into selenoenzymes, it
acts as an antioxidant, suppressing interleukins and TNF-.60
Selenium deficiency lowers antioxidant effects, thereby
impairing free radical neutralization.61

Outcome Data
Table 3 summarizes clinical trials for copper. Copper supplementation is recommended in critically ill patients receiving
PN.19,53 Studies in ICU patients have been limited to major
burn victims, in whom copper is thought to aid in wound healing through collagen synthesis. These patients differ from
other critically ill patients that in acute early TE losses, including copper, arise due to loss of the dermal barrier resulting
from the burn injury.54 Berger et al23 studied the effects of copper, selenium, and zinc in 2 randomized double-blind,

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Nutrition in Clinical Practice 29(1)

In sepsis, selenium, like other TEs, escapes to the interstitial compartment via capillary leakage. Fluid losses, phlebotomy, malnutrition, and renal replacement therapy may
further deplete selenium stores. Critical illness is associated
with decreased glutathione peroxidase and selenoprotein P
activity and increased oxidative stress. Other factors including medications (ie, statins, corticosteroids, and diuretics),
smoking, alcoholism, human immunodeficiency virus, malnutrition, and dehydration also contribute to decreased selenium concentrations.62

Pharmacology and Dosing

The principal dietary sources of selenium are bread, cereals,
dairy, eggs, fish, meat, and nuts. Supplements exist in many
formulations, ranging from 50200 mg. Most selenium supplements are selenium yeast, selenomethionine, selenite, and selenate. Both selenite and selenate are inorganic forms of
selenium and have an absorption rate of about 50%. Organic
forms, selenium yeast or selenomethionine, are safer and more
readily absorbed. Of the selenium supplements, selenomethionine has the best bioavailability, with an absorption rate of
90%. It is also available parenterally (40 g/mL).63,64
Selenium is stored throughout the body, and the highest
concentrations are found in the kidney, liver, and muscle.65
Selenoprotein P accounts for 60% of the total plasma selenium,
while glutathione peroxidases and albumin comprise 30% and
6%10%, respectively. Ionized selenium accounts for <1% of
the total plasma content.66
Selenium is available alone or in combination with other
TEs. Parenterally, it can be given as a bolus dose or continuous
infusion. Most intervention trials in the ICU have been performed using parenteral selenium, although no comparative
data are available between EN and PN supplementation.62
Table 2 shows A.S.P.E.N. dosing recommendations19; however, recent evidence suggests that high-dose parenteral selenium is associated with a trend toward decreased mortality.61
Favorable clinical outcomes in patients with SIRS have been
reported with very high doses (10001600 g/d). The optimum
dose and method of administration remain controversial.24,66

Outcome Data
Selenium therapy has been studied in many critically ill populations. The most significant trial of selenium supplementation
in the ICU as a single nutrient is the Selenium in Intensive Care
(SIC) study.25 This was a prospective, randomized, placebocontrolled trial of 249 patients with severe sepsis or septic
shock. Patients received a 1000-g bolus of sodium selenite on
day 1 followed by a continuous infusion of 1000 g/d or placebo for 14 days.25 Although the reduction in 28-day mortality
for selenium-supplemented patients failed to reach statistical
significance in the intention-to-treat analysis (50.0% vs 39.7%;
P = .11), mortality was significantly lower in the per-protocol

analysis (189 patients, 56.7% vs 42.6%; P = .05). Patients with

disseminated intravascular coagulation (DIC; P = .018), >3
organ failures (P = .04), and Acute Physiology and Chronic
Health Evaluation III (APACHE III) score >102 (P = .04)
experienced the greatest benefit.25
In a single-center randomized controlled trial, 35 patients
with SIRS and APACHE II score 15 received selenious acid
(2000-g bolus then 1600 g/d) or placebo. After 10 days of
therapy, Sequential Organ Failure Assessment (SOFA) scores
decreased significantly in the selenite group (1.3 1.2 vs 4.6
2.0; P < .01). In addition, the rates of early ventilator-associated pneumonia (VAP; 6.7% vs 37.5%; P = .04) and hospitalacquired pneumonia were lower after ICU discharge (0% vs
18.8%; P = .03).24
Selenium status correlates with clinical outcome and may
be useful as an early predictor of survival in the ICU.62 One
study demonstrated that plasma levels decreased by 40% with
critical illness, especially in septic shock patients. In addition,
concentrations <0.7 mmol/L were associated with a 4-fold
increase in mortality and a 3-fold increase in new organ failure
and VAP.26 Another analysis showed that plasma selenium has
a relatively good predictive value for ICU mortality (P = .03).67
The mortality benefit observed in critically ill patients
might be dose dependent. A recent meta-analysis of 20 randomized controlled trials of antioxidant micronutrients showed
a significant reduction in mortality with supplementation (relative risk [RR], 0.82; 95% confidence interval [CI], 0.720.93;
P = .002). When selenium alone was investigated, a trend
toward a lower mortality rate was observed with least 500 g/d
(RR, 0.80; 95% CI, 0.631.02; P = .07), whereas lower doses
had no effect.27 See Table 3 for a summary of the selenium
literature.

Adverse Effects
Oral selenium supplements are generally not associated with
side effects if taken at recommended doses. There is a relatively narrow margin between selenium intakes that result in
deficiency or toxicity. Selenosis is a result of acute or chronic
selenium intoxication secondary to high concentrations in food
or drinking water, environmental exposure, or oral supplementation. Signs and symptoms include GI upset, changes in nails
and hair, fatigue, irritability, and garlicky breath. More severe
manifestations, such as neurotoxicity, anemia, and liver dysfunction, have also been observed.62 Short-term parenteral selenite as a high-dose bolus injection followed by continuous
infusion is well tolerated.66

Zinc
Mechanism of Action
Zinc is an important TE that has many biological roles in maintaining normal growth, immune function, DNA repair, protein

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synthesis, glucose control, and wound healing.68 Its anti-oxidant

properties serve to protect normal cells by competing with
harmful metals at their binding sites. Zinc is a cofactor of collagenases, stromelysins, and gelatinases, which are proteins
responsible for wound healing through debridement and reepithelialization. Finally, it also serves as a co-factor and aids in
the secretion and storage of insulin within the islet cells.68,69
Low levels of zinc have been documented in critically ill
patients, especially in septic shock.70,71 During stressful states,
such as burn, sepsis, and trauma, zinc is redistributed from the
serum to the tissues to meet the high metabolic demands as the
body attempts to repair itself. This can result in an apparent
state of zinc deficiency.69 Zinc deficiency leads to apoptosis of
lymphocytes, causing loss of immature T and B cells, which
predisposes patients to infection.68 Wound healing is also
impaired because of inadequate skin regeneration. Glucose
control is also compromised. As reviewed in the Chromium
section, uncontrolled hyperglycemia can result in increased
morbidity and mortality in ICU patients.72 Zinc is a vital cofactor in the synthesis of insulin in the pancreas. Within the
islet cells, it aids in the secretion and storage of insulin and is
also co-secreted with insulin. As insulin and zinc secretion are
increased during hyperglycemia, increased urinary excretions
of zinc are also present, contributing to its loss. With less zinc
available to protect the islet cells from oxidative stress, cell
damage and impaired synthesis of insulin occur.68

Pharmacology and Dosing

Zinc supplementation may be administered parenterally or
orally. Zinc sulfate and zinc chloride are the most common formulations used for supplementation in PN. Absorption of oral
zinc occurs through active transport in the duodenum and the
proximal small intestine. Bioavailability ranges from 20%
40%.68,69 Once absorbed, zinc is distributed mainly to the liver,
pancreas, kidney, bone, and muscles and is excreted in the
feces.68,69
Zinc dosing varies depending on the type and severity of
illness. Table 2 shows A.S.P.E.N. recommendations for oral
and parenteral zinc. Higher doses may be necessary in certain
patient populations, including those with high-output fistulas,
burns, or severe diarrhea.19
In patients with head injury, 12 mg of IV zinc was used in
PN, followed by 168 mg of oral zinc gluconate for a total of 3
months.1,28 Studied doses in burn patients were 26.231.4 mg
per day of IV zinc gluconate in combination with copper and
selenium.73 Oral zinc sulfate 200 mg 3 times a day has been
shown to improve wound healing in patients with lower
extremity ulcers.1

Outcome Data
Zinc trials are displayed in Table 3. Several studies have confirmed that critically ill patients often present with low serum

zinc levels, but few have demonstrated a mortality benefit with

supplementation.70,74-77 In addition, studies have not identified
a correlation between low zinc levels in critically ill patients
and adverse outcomes, and regular monitoring of serum concentrations has not been associated with any benefit.56,59 A prospective, double-blinded, randomized controlled trial was
performed of 68 patients to evaluate the effects of 12 mg of
zinc compared with a standard dose (2.5 mg) on the neurologic
recovery of patients with moderate to severe closed head injury
with Glasgow Coma Scale (GSC) scores of 410. There were
no significant differences in the raw GCS score between the 2
groups. However, analysis of covariance adjustment of baseline GCS scores showed that the zinc group had a higher GCS
score than the control group from day 15 (P < .01) up to day 21
(P = .02). This demonstrates that zinc may improve the rate of
neurologic recovery, possibly because of enhanced protein
metabolism.28 It should be noted that this was a small trial, and
no other studies have been able to report similar results.
As discussed in the Selenium section, 1 study of supplementation with a combined TE product (selenium, copper, and
zinc) demonstrated a decrease in incidence of nosocomial
pneumonia and improved wound healing in severely burned
patients; however, this was a pilot study of only 41 patients.23
It is important to note that burn patients have different loss of
TEs compared with other critically ill patients. These small
studies reported positive outcomes with TE combination products specifically in burn patients; data are lacking to support
the routine use of zinc supplementation in all critically ill
patients.
Based on the limited data available, zinc supplementation
could be considered for specific patient populations such as
alcoholism, burn, and trauma patients, who are known to have
accelerated zinc loss or chronic zinc deficiency that can lead to
impaired wound healing and infection. Most data examine TE
supplementation in PN. No studies exist that suggest that zinc
supplementation to all critically ill patients is beneficial,
although further research is through randomized controlled
trials.

Adverse Effects
When used within the recommended daily dose, zinc supplementation rarely exhibits detectable side effects.78 Acute ingestion of >200 mg orally can result in GI side effects such as
epigastric abdominal pain, nausea and vomiting, and diarrhea.
Chronic ingestion of >20 mg orally per day has been found to
be associated with decreased serum copper levels, microcytosis, neutropenia, reduced high-density lipoprotein cholesterol,
and impaired immune function.68,69 In extreme cases, supraphysiological doses of zinc can cause copper deficiency, which
can lead to cardiac abnormalities (myocardial infarction,
tachycardia, hypotension, arrhythmias). In addition, the literature has reported sideroblastic anemia,79 microcytic anemia,
and neutropenia.80

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Manganese
Mechanism of Action
Approximately 1012 mg of manganese is present in the average human body, where it is incorporated into several metalloenzymes found mainly in the mitochondria.81 These enzymes
function as catalytic cofactors for multiple reactions, such as
cholesterol synthesis and protein metabolism. Manganese is a
vital portion of the enzyme manganese superoxide dismutase,
which functions to reduce oxidative stress in the mitochondria
through the conversion of radical oxygen species to hydrogen
peroxide.82
Evidence of clinically significant cases of manganese deficiency is limited. However, case reports and small observational studies have described similar findings that developed
over weeks to months of low or no dietary manganese
intake.82,83 In one case report, a man was started on a diet that
inadvertently contained no manganese, and after 3.5 months,
he developed transient dermatitis and hypocholesterolemia.83
In a small observational study, healthy volunteers were fed a
diet that contained very low amounts of manganese. After 5
weeks, symptoms of deficiency included dermatitis, decreased
cholesterol, and elevation of serum calcium and phosphate.82
Several other observational studies have noted low serum manganese levels in diseases such as epilepsy, multiple sclerosis,
and amyotrophic lateral sclerosis.83-86

Pharmacology and Dosing

The current dosing recommendations for manganese supplementation vary based on the route of administration. The
A.S.P.E.N. dosing recommendations are listed in Table 2.19 It
is important to note that parenteral TE formulations in use
today were approved by the Food and Drug Administration
under guidelines published in 1979 and contain 0.50.8 mg
of manganese, which is much higher than the current
recommendation.19,81
Absorption and clearance of manganese varies considerably between patients. Studies evaluating the absorption of
manganese in healthy subjects have identified several factors
influencing the oral bioavailability, which ranges from 3%
50%.81 For example, the amount of oral manganese ingested is
inversely correlated with the amount of manganese absorbed.
Multiple studies have also shown that oral manganese absorption and serum manganese levels increase when iron stores and
iron intake are low.33,87 Manganese passes through the enterohepatic circulation and is cleared primarily though the hepatobiliary system. This process helps to maintain an appropriate
balance by altering excretion in response to changing levels of
manganese. However, if a patient has or develops hepatic
insufficiency or cholestasis, manganese can accumulate,
quickly leading to toxicity. These patients should receive
reduced or no manganese supplementation.19 Another issue to

consider is that manganese has been identified as a contaminant

in IV medications, and studies evaluating PN formulations
have found that products without labeled manganese content
contain anywhere from 538 g per liter.81 A.S.P.E.N.s most
recent recommendation is to limit manganese contamination to
<0.04 mg per day.19 Careful monitoring is required in critically
ill patients to ensure that they do not receive excess manganese
or develop signs and symptoms of manganese toxicity

Outcome Data
There is limited research regarding the use of manganese in
the critically ill population. However, findings from studies
performed in noncritically ill patients can be applied to the
critically ill population. Most of the studies evaluating the balance and supplementation of manganese address possible toxicity and suggest caution, especially with parenteral use. A
study of 11 patients receiving home PN found that all patients
had magnetic resonance imaging evidence of manganese
accumulation, and 1 of those patients developed symptoms of
manganese toxicity.88 These patients were found to have
serum manganese concentrations that were twice that of the
control population.
One study conducted in critically ill patients evaluated the
balance of several TEs in men with traumatic injuries and different renal function (see Table 3). In this study, the subjects
were classified as having adequate renal function, requiring
continuous venovenous hemodiafiltration (CVVHD) or continuous venovenous hemofiltration (CVVH).29 These patients
were provided PN containing 300 g per day, and then their
urine or effluent (from artificial kidney) manganese losses
were collected. The losses from subjects with normal renal
function averaged at 2.6% of the amount in the PN, those on
CVVHD lost an average of 73% of the amount in the PN, and
those on CVVH lost an average of 21% of the amount in the
PN. Given the daily manganese requirements, these patients
were retaining excessive manganese, and the authors suggest
manganese dosing should be reduced in the critically ill trauma
population.
In critically ill patients who are at risk or who have preexisting hepatic dysfunction, caution must be used when supplementing manganese and other TEs, especially parenterally.
When given parenterally, the mechanism for the regulation of
manganese absorption is bypassed, leading to higher serum
manganese concentrations, which has been shown to increase
the risk of accumulation in the brain.81 If the patient also has or
develops hepatic dysfunction, manganese can no longer be
cleared appropriately, increasing accumulation and risk for
toxicity. Currently, the content of parenteral TE compounds
contain more than the recommended intake for an otherwise
healthy patient. When providing PN to a critically ill patient,
this must be considered, and changes to the composition of the
PN may be warranted.

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Adverse Effects
Manganese toxicity can lead to hepatic dysfunction and several
neurologic complications. It is not commonly associated with
oral supplementation, as the body is able to regulate absorption
and excretion. However, with hepatic dysfunction, toxicity
may still occur. Manganese has an affinity for the extrapyramidal system, and it has been shown to accumulate in the caudate
nucleus, the quadrigeminal plate, and the global pallidus.
Neurotoxicity is thought to be secondary to oxidative stress
caused by manganese, and accumulation can lead to symptoms
that mimic Parkinson disease.89 The mechanism for hepatic
injury is not well understood, but patients have been shown to
develop impaired biliary excretion. The exact amount of manganese needed to cause toxic symptoms is not well known, and
case reports show varying amounts of ingestion. However, toxicity has occurred with parenteral intake as low as 0.3 mg in an
adult patient. Given the low incidence of symptomatic deficiency in the general population and the potential for significant accumulation and toxicity in the critically ill population,
supplementation must occur with caution.81

TE Contamination
Although many TE studies have demonstrated a benefit in
certain critically ill patient populations, contamination of PN
is a concern. TEs, including zinc, copper, manganese, chromium, and selenium, have all been found as contaminants in
PN. Other nonnutrient constituents have also been identified
(ie, arsenic and strontium).19 One study in animals demonstrated that contaminants were found in amino acids, dextrose, calcium gluconate, dipotassium phosphate, lipid
emulsion, and vitamin components of PN. The degree of contamination varied based on nutrition formulation and brand
of ingredients.90 PN and EN requirements, additives, and
contaminants should be considered when supplementing TEs
so as to avoid toxicity.

Conclusion
TEs are responsible for a variety of functions in the human
body. In recent years, supplementation of these agents has been
explored in critical illness. Although each TE has a role in a
specific patient population, few studies have demonstrated an
overall mortality benefit. Iron therapy may decrease transfusion requirements in critically ill patients with iron-deficiency
anemia. Chromium deficiency may present as insulin resistance in the critically ill or in patients receiving long-term PN
without TE supplementation. Outcome data in intensive care
patients are limited to case reports of insulin resistance in various patient populations. The study of copper deficiency in
intensive care patients has been limited to a small controlled
prospective trial in burn patients. Although an exact mechanism is unknown, nosocomial infections were reduced in the

group receiving copper. Evidence supports that critically ill

patients are selenium deficient. Supplementation with parenteral selenium in high doses may have potential mortality and
morbidity benefit, but further studies are needed to confirm.
Data supporting the routine use of zinc supplementation in
critically ill patients are lacking; however, it may be considered in trauma and burn patients in whom infection control and
wound healing are important. Finally, manganese plays a role
in the synthesis of proteins and cholesterol, but supplementation should be used cautiously in critically ill patients, especially those with renal or hepatic dysfunction due to risk of
accumulation. Additional research is needed to determine optimal monitoring parameters and dosing and to explore further
the role of these agents in critical illness.

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