Oxidative Stress in Critically Ill Patients

Caryl Goodyear-Bruch and Janet D. Pierce

Am J Crit Care 2002;11:543-551
© 2002 American Association of Critical-Care Nurses
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AJCC, the American Journal of Critical Care, is the official peer-reviewed research
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CE Article

OXIDATIVE STRESS IN CRITICALLY ILL PATIENTS

By Caryl Goodyear-Bruch, RN, MSN, CCRN, and Janet D. Pierce, DSN ARNP, CCRN. From Nurse Anesthesia
Education (CG-B) and School of Nursing (JDP), University of Kansas, Kansas City, Kan.

Oxygen-derived free radicals play an important role in the development of disease in critically ill
patients. Normally, oxygen free radicals are neutralized by antioxidants such as vitamin E or enzymes
such as superoxide dismutase. However, in patients who require intensive care, oxygen free radicals
become a problem when either a decrease in the removal or an overproduction of the radicals occurs.
This oxidative stress and the damage due to it have been implicated in many diseases in critically ill
patients. Many drugs and treatments now being investigated are directed toward preventing the damage
from oxidative stress. The formation of reactive oxygen species, the damage caused by them, and the
body’s defense system against them are reviewed. New interventions are described that may be used in
critically ill patients to prevent or treat oxidative damage. (American Journal of Critical Care.
2002;11:543-551)

CE
Notice to CE enrollees:
A closed-book, multiple-choice examination following this
article tests your understanding of the following
objectives:
• Identify intensive care unit syndromes and
diseases linked to damage caused by reactive
oxygen species
• Describe the impact of oxidative stress on critical
illness
• Discuss the biological measurement of oxidative
stress
To purchase reprints, contact The InnoVision Group, 101 Columbia, Aliso
Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax,
(949) 362-2049; e-mail, reprints@aacn.org.
O
xygen removes electrons from other mol-
ecules in the cell to form reactive oxygen
species (ROS). These species are a major con-
tributing factor in diseases in critically ill patients.
ROS are controlled by a defense system that depends
on the activity of enzymes and other nonenzyme sub-
stances. The imbalance between ROS and the body’s
defense system is called oxidative stress. Scavengers
of ROS and antioxidants are important in treating and
preventing the damage caused by such stress.1,2
Understanding the formation of ROS and oxida-
tive damage is important in order to initiate appro-
priate nursing strategies. Measurements of ROS
activity and damage due to oxidative stress should be
an important assessment in patients in the intensive
care unit (ICU). Currently available medications can
be used to treat oxidative stress and establish an
effective defense system. For example, treatment
with N-acetylcysteine (Mucomyst) reduces oxidative
stress in diseases and syndromes such as acute respi-
ratory distress syndrome (ARDS),3-5 infection with
human immunodeficiency virus,6 and chronic obstruc-
tive pulmonary disease.7 N-acetylcysteine may also
increase phagocytosis by neutrophils in patients with
sepsis or systemic inflammatory response syndrome.8

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 In this article, we provide essential information
about oxidative stress that can be used to enhance
direct care of patients.
Background
Oxygen is necessary in the metabolic production
of energy. Mitochondria, through the electron trans-
port chain, use oxygen to oxidize other molecules and
generate energy in the form of adenosine triphos-
phate.1,9 During this process, oxygen is reduced to
water, producing several intermediary ROS. The pro-
duction of ROS is one reason the administration of high
concentrations of oxygen may be toxic to ICU patients;
an increase in oxygen concentration leads to the forma-
tion of these species.10 Table 1 lists ICU syndromes and
diseases attributed to damage caused by ROS.
The discovery of superoxide dismutase (SOD),
a free-radical scavenger, in 1969 by McCord and
Fridovich generated a wave of research on the balance
between oxidants and antioxidants.9 An accumulation
of oxidants is due to either pathophysiological pro-
cesses or the inability of antioxidants to counter the
accumulation. A lack of production of antioxidants or
a destruction of scavengers causes the overproduction
of free radicals. An imbalance between production of
ROS and production of antioxidants results in oxida-
tive stress.11 Definitions of oxidative stress and other
related terms are given in Table 2.
Several studies14,15 indicate that oxidative stress
occurs in critical illnesses, specifically in sepsis,
shock, organ dysfunction, ARDS, and disseminated
intravascular coagulation. In patients with ARDS, a
reduction in the plasma levels of nutrients with antiox-
idant properties is evidence of oxidative stress.16 Acute
pancreatitis17 and fatigue of the diaphragm muscle2 are
also associated with damage caused by ROS.
Table 1 Intensive care unit syndromes and diseases linked
to damage due to reactive oxygen species
Septic shock
Acute respiratory distress syndrome
Systemic inflammatory response syndrome
Disseminated intravascular coagulation
Multiple organ dysfunction
Burns
Cardiovascular disease
Diabetes mellitus
Trauma
Reperfusion Injury
Cancer
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Because oxidative stress is associated with severity
of illness, the care of critically ill patients depends on
preventing and controlling production of ROS. Critical
care nurses should recognize the importance of oxida-
tive stress in critically ill patients, because nursing
activities may actually potentiate oxidative damage.
Routine and usual nursing activities such as turning and
suctioning may contribute to the production of ROS.
Research is being done to determine the presence
of oxidative stress in critically ill patients and possible
options to treat and prevent disease. Nurses are just
beginning to investigate the molecular damage caused
by specific nursing interventions.
Formation of ROS
During chemical processes, molecules can be
reduced or oxidized. A molecule with an unpaired elec-
tron can combine with a molecule capable of donating
an electron. The donation of an electron is called oxida-
tion. The gain of an electron is called reduction. During
these reactions, the molecule that donates the electron
is oxidized and the molecule that accepts the electron
is reduced. Reduction and oxidation can leave the
reduced molecule unstable and free to react with other
molecules to cause damage to cell membranes, pro-
teins, and DNA. These reduced substances are called
free radicals.9
In homeostasis, the rates of reduction and oxidation
are equal. The reduction-oxidation (redox) balance is
maintained by physiological defenses such as special-
ized enzymes and antioxidants. These antioxidants and
enzymes remove or inactivate the free radicals. Some of
the most common enzymes and antioxidants are listed
in Table 3. The enzymes and antioxidants can become
overwhelmed by an increase in reduced molecules or
by a decrease in the defense system, allowing the
accumulation of free radicals.1,9,13
ROS are molecules or atoms formed by reduction
of oxygen and can be either free radicals or nonradi-
cals. Within cells, free radicals can be produced by
absorption of radiant energy, metabolism of drugs,
normal metabolic processes, and transition metals.18
These radicals are designated by using the superscript
dot; for example, the hydroxyl radical is designated
OH•. The oxygen nonradicals can act as oxidizing
agents or can be easily converted into radicals.12 The
most commonly known ROS are superoxide (O2–•),
hydrogen peroxide (H2O2), and OH• (Figure 1).
A process in which 4 electrons must be added to
the structure of oxygen reduces oxygen. In the first
step, an electron is added, and O2–• is produced. At
this point, some O2–• can leak out of the mitochondria
and set up other chemical reactions, leading to cellular
 Table 2 Definitions of terms

Term Definition

Free radicals Substances containing 1 or more unpaired electrons in the outer orbit capable of reacting
with many substances; are responsible for many chemical reactions in the body that can lead
to cellular damage.12

Reactive oxygen species Molecules or atoms formed by reduction of oxygen; can be either free radicals or
nonradicals. The most commonly known are superoxide (O2–•), hydrogen peroxide (H2O2),
and the hydroxyl radical (OH•).12

Oxidation The loss of electrons in chemical reactions.13

Reduction The gain of electrons in chemical reactions.13

Reduction-oxidation (redox) Term used to represent the balance of reduction-oxidation reactions involving loss and gain
of electrons during chemical reactions.1

Oxidative stress A condition in which accumulation of free radicals or the inability of antioxidants to counter
the accumulation of the free radicals creates an imbalance between production of reactive
oxygen species and protection of antioxidants.1,9,13

Antioxidant Diet-derived substance that can decrease the accumulation of free radicals by removing
them or countering their damaging effects on the cell.1

damage.2 Superoxide acts as a reducing agent and Hydrogen peroxide, which is produced mainly by
helps produce other oxidants through chemical reac- the mitochondria, is the most stable of the ROS. SOD,
tions. The subsequent steps of adding electrons to a ROS scavenger enzyme, removes O2–• in a reaction
oxygen produce other types of ROS (ie, H2O2 and that produces H2O2. Hydrogen peroxide can inactivate
OH•) until oxygen is fully reduced1 (Figure 2). enzymes, cross cell membranes, and react with both
Many other molecules in the body, such as iron and copper ions to produce OH•.9
adrenalin, steroids, and folates, can react with oxygen The hydroxyl radical is very damaging and can
to produce O2–•. Phagocytes are another important pro- react with many substances. Hydroxyl radicals are
ducer of O2–•. The phagocytes use O2–• as a defense usually produced through the Fenton reaction, in
against foreign organisms. Defense mechanisms that which O2–•, H2O2, and iron are teamed to form OH•.
are a vital part of the immune system can also be DNA damage is a major injury caused by OH•.13 DNA
destructive. Many inflammatory diseases are character- damage due to OH• is a contributing factor in cancer
ized by tissue damage produced by ROS.19 Although and other diseases.12,19
O2–• is not considered highly reactive, it is involved in Ischemia-reperfusion injury is also associated with
other chemical reactions that produce free radicals. the formation of oxygen free radicals. Endothelial cells
respond to ischemia and produce xanthine oxidase.
The xanthine oxidase is responsible for the formation
Table 3 Enzymatic and nonenzymatic oxidant defense of O 2 –• during reperfusion. Endotoxin, cytokines,
systems
System Components
Enzymatic Superoxide dismutases Superoxide (O2–•)
Catalase -1
Peroxidases
H
Glutathione system
Thioredoxin reductase system Hydrogen peroxide
Lipoamide system H
Nonenzymatic Thiols
Ascorbic acid
Urates Hydroxyl radical (OH•) H
Vitamin E
Vitamin A and carotenes
Ubiquinones and ubiquinol Figure 1 Electron structure of reactive species.

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 age caused by ROS; however, oxidative stress can
O2 → O2–• → H2O2 → OH• → H2O
damage DNA by causing strand breaks, base modifi-
Oxygen Superoxide Hydrogen Hydroxyl Water cation, and cross-linking. 12 Hydroxyl radicals can
anion peroxide radical
attack thymine, change its chemical structure, and
Figure 2 During the reduction of oxygen, electrons are remove it as a base. The modified thymine and other
added at each step, resulting in 3 reactive oxygen species: changed DNA by-products can be detected in the
superoxide anion, hydrogen peroxide, and the hydroxyl
radical.
urine and are an indication of oxidant activity.9 Other
damage caused by ROS is noted in Table 4.

neutrophil adherence, and acidosis can all trigger
production of xanthine oxidase in endothelial cells.13
ROS and Damage
The free radicals O2–•, H2O2, and OH• are responsi-
ble for damage to lipids, proteins, and DNA (Figure 3).
Hydroxyl radicals can initiate lipid peroxidation in the
cell membrane. Within the lipid part of the membrane,
OH• removes hydrogen from unsaturated fatty acids.
This reaction produces a lipid radical that removes
another hydrogen molecule from the next molecule
and thus creates another lipid radical. The entire pro-
cess is the chain reaction called lipid peroxidation.
This reaction can cause cell death and can induce an
inflammatory response. As neutrophils invade, they
release more ROS and the cycle continues.18
Proteins, particularly enzymes, are damaged by
ROS. Hydroxyl radicals oxidize amino acids such as
lysine, serine, arginine, and proline. Enzymes modi-
fied by oxidation are inactive or may be changed in
such a way that the immune system interprets them as
foreign and produces autoantibodies to them.9 The
human body has a tremendous capacity to repair dam-
Enzyme and Nonenzyme
Defenses Against ROS
Oxidants are balanced by the activities of
enzymes and nonenzymes called antioxidants. This
vitally important defense system controls the produc-
tion and elimination of oxidants and is essential in con-
trolling the damage that occurs during oxidative stress.
Normally, production of ROS is balanced by the activity
of antioxidants. However, when the body is over-
whelmed by increased production of oxidative agents
and defense against these agents is decreased, the ensu-
ing damage contributes to cellular derangements, cell
injury, and death. These pathological changes are mani-
fested through critical illnesses and diseases.1,12
Defenses against ROS include enzyme scavengers
and dietary antioxidants (Table 3). The human body
maintains a balance between the necessary oxidant
actions involved in cell processes and the damage
done by oxidants both by preventing formation of free
radicals (through scavenging or removing ROS) and
by repairing the damage done by ROS.1,9,12
The main scavengers responsible for inactivation
and termination of free oxygen radicals are SOD,

Table 4 Damage caused by reactive oxygen species

General condition Specifics of damage

DNA damage Base modification, strand breaks, and cross-linking. Hydroxyl radical can attack thymine,
1 of the bases of DNA. Thymine is changed to thymine glycol and removed from the DNA.9
The DNA mutates and may cause cells to become cancerous.19

Lipid peroxidation A chain reaction in which a hydroxyl radical initiates removal of hydrogen from a lipid
molecule in the cell membrane, making the lipid a free radical that can then react with
an oxygen radical, creating a peroxy radical. The peroxy radical then obtains another
hydrogen molecule from the next lipid molecule, creating lipid peroxide and another
peroxy radical.9

Protein damage Reactive oxygen species modify enzymes by oxidizing amino acids such as lysine, serine,
arginine, and proline that are the building blocks of enzymes. The modified enzymes are
inactive and may stop cellular processes. The inactive enzymes may also induce the
development of autoantibodies.9

Redox signaling During redox imbalance, cellular increases in reactive oxygen species can cause changes in
signaling and thus changes in cell activities such as cell proliferation, apoptosis, gene
regulation, and necrosis.1,20

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catalase, and the glutathione system (Figure 3). The
intracellular antioxidant SOD catalyzes the conversion
of O 2 –• to oxygen and H 2 O 2 . The H 2 O 2 is then
reduced by either catalase or glutathione peroxidase.
Catalase is the oldest known enzyme that converts
H2O2 to water and oxygen within the membrane of the
cell. Catalase plays a major role in the removal of
H2O2 from muscle cells in the myocardium.21
Glutathione peroxidase is an antioxidant enzyme
containing both selenium and glutathione. It is found
in the cytoplasm and mitochondria. Glutathione con-
sists of glutamine, cysteine, and glycine.21 N-acetyl-
cysteine is chemically similar to glutathione and has
been studied as a scavenger.3-7,22,23 Destruction of H2O2
by glutathione peroxidase produces glutathione disul-
fide and water.1 In another reaction, glutathione disul-
fide is reduced back to glutathione. This whole system
regenerates glutathione to be used again and again.
Oxidative stress can be measured by determining the
amount of both glutathione and glutathione disulfide
and by estimating the ratio of one to the other. The
ratio of glutathione to glutathione disulfide should be
ROS scavengers
Superoxide Catalase Glutathione
dismutase
O2 → O2–• → H2O2 → OH• → H2O
Oxygen Superoxide Hydrogen Hydroxyl Water
anion peroxide radical
ROS damage
Lipid peroxidation
Protein damage
DNA damage
Figure 3 The scavengers superoxide dismutase, catalase,
and glutathione are responsible for inactivation of reactive
oxygen species (ROS) and thus provide a defense against
lipid peroxidation, protein damage, and DNA damage due
to ROS.
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high, but if the amount of glutathione is less than the
amount of glutathione disulfide, a toxic amount of
H2O2 can accumulate.21 Selenium levels have also
been used to determine oxidative stress.16,24
Vitamins are scavengers of oxygen free radicals.1
Ascorbic acid decreases lipid peroxidation and levels
of H2O2. It is one of the most effective antioxidants in
serum. Vitamin E (α-tocopherol) is an important fat-
soluble antioxidant in the prevention of lipid peroxida-
tion. It can protect the polyunsaturated fatty acids in
cell membranes from the autocatalytic chain reaction
of lipid peroxidation.1 Outside cell membranes, vita-
min E is a poor antioxidant.
Extracellularly, both plasma and red blood cells
have scavenger and antioxidant qualities. When
O2–•enters red blood cells, catalase can destroy the
free radicals. Red blood cells may increase the levels
of glutathione peroxidase, thus preventing damage
caused by free radicals.9,13
Oxidative Stress in Critically Ill Patients
Results of evidence-based research have linked
oxidative stress to many ICU syndromes and diseases,
including cardiogenic shock, sepsis, ARDS, diaphragm
fatigue, and burns.1,2,13,16,25 Oxidative stress results in
lipid peroxidation, protein oxidation, and mutations in
mitochondrial DNA and has been implicated in pro-
ducing cell death and in contributing to these disease
processes. Indicators of ROS production and antioxi-
dant activity have been linked to several critical ill-
nesses. Diseases such as cardiovascular disorders26,27
and diabetes mellitus28 that affect critical illness are
also linked to ROS formation and redox imbalance.
Critically ill patients can have increases in the
level of ROS14 or decreases in antioxidant defenses.15
Many biological indicators of oxidative damage are
being investigated in clinical trials, and the results
may assist clinicians in determining if ROS damage is
occurring. Any of the substances given in Table 5 may
become a commonly used indicator or biomarker of
oxidative stress. In addition to laboratory values that
indicate production of ROS, measurements of antioxi-
dant levels (α-tocopherol, β-carotene, selenium) and
enzyme activity (SOD, catalase, glutathione) have
been investigated in patients thought to have oxidative
stress.1,16,24,33,40-42 Further clinical research is needed to
determine which biomarker or indicator is the most
specific and sensitive sign of oxidative stress.
The body’s antioxidant defense system becomes
overwhelmed in patients who have life-threatening ill-
nesses. The amount of oxidants drastically increases
with decreases in tissue perfusion and induction of the
immune response. ROS can stimulate the inflammatory
547
 Table 5 Biological measurements of oxidative stress
Measured in Substance
Serum Reduced and total glutathione29,30
Gluthathione peroxidase24,31
Superoxide dismutase24,30,32
Lipid peroxides29,33,34
Protein carbonyls34
Malondialdehyde16,31,32,35
Catalase16,36
Tocopherol1,16,33
Carotene16,33
Selenium16,24,33
Ascorbate16
Urine F2-isoprostanes37
Thiobarbituric acid–reacting substances30
8-Oxo-7,8-dihydro-2-deoxyguanosine38
Exhaled breath Hydrogen peroxide7
Alkane output: methylated alkane
contour,39 pentane,33 and ethane33
8-Isoprostane20
Thiobarbituric acid–reacting substances7
system by causing an increase in cytokines (eg, inter-
leukins, tumor necrosis factor) and cell adhesion.
Endothelial cells are stimulated to increase vascular
permeability, causing capillary leakage. Neutrophils
and macrophages are chemically attracted to areas of
lipid peroxidation, causing these phagocytes to
migrate into tissues and release more ROS.13
Both cytokines and ROS can enter the circulation
and mediate many systemic inflammatory responses
linked with clinical conditions.13 In studies of ARDS
and sepsis, levels of antioxidants were decreased and
amounts of ROS were increased.1 The roles of ROS
and xanthine oxidase activity in relation to the severity
of sepsis and organ dysfunction have been studied.
Galley et al43 found that critically ill patients with sep-
sis who died had lower levels of xanthine oxidase,
greater production of free radicals, and higher levels
of lactate than did critically ill patients with sepsis
who lived. This finding suggests that ROS generation
plays a key role in survival for sepsis patients.
Metnitz et al 1 6 found evidence of increased
oxidative stress and decreased levels of nutrients
with antioxidant properties in patients with ARDS.
Lipid peroxidation increased continuously in patients
with ARDS throughout the course of their illness.16
In another study, 4 4 use of a new enteral formula
(Oxepa) for tube feeding in patients with ARDS sig-
nificantly improved lung microvascular function and
thus decreased the ICU length of stay. The new for-
mula contains eicosapentaenoic acid (from sardine
oil), γ-linolenic acid (from borage oil), and antioxi-
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dants and provides completely balanced nutrition for
patients with ARDS.
Glutamine is severely depleted during stress and
injury. In critically ill patients, production of ROS
combined with glutathione deficiency contributes sig-
nificantly to mortality.10 Recent developments in phar-
macological therapy indicate that peroxynitrite
decomposition catalysts and SOD mimetics may have a
role in preventing organ injury associated with shock,
inflammation, and ischemia-reperfusion injury.45
Diaphragm fatigue is common in patients being
weaned from mechanical ventilation. The fatigue is
caused by an imbalance between energy supply and
energy demand. Increasing the flow of oxygen-rich
blood may prevent diaphragm fatigue. Research11,22,40-42,46-49
supports the observation that strenuous activity of the
diaphragm muscle can produce ROS and damage the
diaphragm, leading to muscle fatigue. The fatigue
may be due to injury to the muscle cells (specifically,
lipid peroxidation, DNA lesions, or protein damage).
Anzueto et al40 determined diaphragm function at rest
and during resistive breathing in rats with vitamin E
deficiency. A reduction in diaphragmatic contractile
function, occurrence of lipid peroxidation, and
increased activation of glutathione during resistive
breathing were correlated with vitamin E deficiency.
Vitamin E is the major lipid-soluble antioxidant that
protects the lipid part of cell membranes. N-acetylcys-
teine, another antioxidant and specific ROS scavenger,
can decrease the rate of diaphragmatic fatigue.22
In other studies, lidocaine was given as an antiox-
idant agent for treatment of hyperoxia-induced50 and
sepsis-induced51 diaphragmatic dysfunction in ham-
sters. Lidocaine attenuated fatigue and inhibited lipid
peroxidation. Supinski2 suggested that ROS are pro-
duced in contracting muscles and that administration
of scavenger agents attenuates development of
diaphragm fatigue. In another study, Supinski et al49
found that chronic diaphragm fatigue in rats increased
the occurrence of lipid peroxidation. Chronic resistive
loading in these rats elicited oxidative stress. Thus,
diaphragm fatigue was due to damage by ROS and in
humans may be a reason for prolonged weaning from
mechanical ventilation.
Cardiovascular disease is prevalent in patients in
the ICU and can increase the risk of mortality. High
levels of oxidative stress are involved in the pathogen-
esis of vascular diseases such as hypertension and
atherosclerosis.26 Free radicals are involved throughout
the process of atherosclerosis. ROS are associated
with an increase in the growth of vascular smooth
muscle cells and with an increase in apoptosis.
Inactivation of nitric oxide resulting in endothelial
dysfunction is linked to the production of ROS. ROS
can recruit monocytes into the vessel wall, leading to
atherosclerosis.26 Vitamin E is used to protect against
oxidation in patients with atherosclerosis by prevent-
ing lipid peroxidation.27
Another disease common in patients in the ICU is
diabetes mellitus. Plasma markers of lipid peroxida-
tion are higher in patients with diabetes mellitus than
in patients without the disease. DNA damage is 4
times higher in patients with diabetes mellitus than in
patients without diabetes.28 Hyperglycemia may con-
tribute to oxidative stress by formation of ROS
through glucose auto-oxidation. Acute increases in
glucose level may also depress natural antioxidant
defenses. Patients with diabetes mellitus can have a
decrease in the amount of erythrocytic glutathione and
an increase in lipid peroxidation. A decreased glu-
tathione level has a strong negative correlation with
control of glucose as assessed by measurement of
hemoglobin A 1c levels. Two scavengers, SOD and
catalase, can prevent hyperglycemia-related endothelial
dysfunction and decreased vasodilatory response to
nitric oxide. SOD potentiates the effect of nitric oxide
and plays a major role in countering the negative effect
of high glucose on endothelial cell function.28
Implications for Practice
In today’s ICU environment, nurses provide care
for critically ill patients who have damage due to ROS
and the resultant oxidative stress. Currently, no pub-
lished data on the possible potentiation of oxidative
stress by nursing care activities are available. Because
research on oxidative stress is needed to guide critical
care nursing practice, studies on such stress may begin
Table 6 Nursing research opportunities and clinical impact
Research opportunity
Investigation of nursing practice and how specific nursing
interventions prevent or treat production of reactive oxygen
species. Nursing practices may include
Turning
Suctioning
Positioning
Music therapy
Maintenance of fluid balance
Administration of medications
Investigation of monitoring practices and how they relate to
measurements of oxidative stress. Monitoring practices may
include
Continuous monitoring of exhaled hydrogen peroxide
Periodic measurements of serum levels of superoxide
dismutase
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soon. Consequently, critical care nurses must under-
stand oxidative stress and how new therapies for this
condition will affect critically ill patients.
Many researchers have detected oxidative stress
by measuring either the activities of specific enzymes
and antioxidants or by-products of damage due to
ROS. Measurements include plasma levels of micro-
nutrients, markers of lipid peroxidation, xanthine
oxidase, SOD, glutathione, selenium, catalase, and
O2–•, and breath tests to detect lipid peroxidation.16,24,32,33,36
These measurements are likely to become common-
place in determining the oxidative status of patients, in
evaluating treatments, and in guiding nursing practice.
Until the usefulness of such measurements is sup-
ported by research, theory-based nursing practice may
be the only guide to care for patients experiencing
imbalances between oxidants and antioxidants. Table
6 is a list of several nursing research topics and the
clinical impact the results of such research may have
on patients’ care. In the future, these therapies may be
used to prevent or treat damage due to ROS and to
improve patients’ outcomes. Thus, nurses may have an
expanded repertoire of interventions, including
administration of medications, nutritional supple-
ments, or specific scavengers, to decrease oxidative
stress in ICU patients.
One critically important task of nurses is the care
of patients being weaned from mechanical ventilation.
Because data suggest that an increase in ROS is asso-
ciated with diaphragm fatigue, nurses must begin the
search for interventions that would decrease produc-
tion of ROS. Thus, ensuring adequate perfusion to the
diaphragm would be one way to prevent oxidative
stress. When the work of breathing is increased during
Clinical impact
Data to support which nursing interventions help or hinder
the formation of oxidative stress.
Ability to determine which monitoring practices may be
sensitive for detection of oxidative stress.
549
weaning, administration of a vasodilator drug (such as
low-dose dopamine) may provide increased blood
flow to the diaphragm52 and thus prevent damage due
to ROS.
Administration of supplemental vitamin E may be
beneficial in preventing atherosclerosis and in attenu-
ating diaphragm fatigue. A deficiency in this antioxi-
dant in rats decreased diaphragmatic contractile
function in resistive breathing.40 Patients who may
have vitamin E deficiency (eg, patients with alco-
holism, malnutrition, or chronic jaundice) might bene-
fit from the administration of supplements of this
natural antioxidant. Such supplementation could be
used to treat critical illness and as prophylaxis for
high-risk patients.13 Clinical trials to define dosing,
end points of therapy, and the boundaries of use for
vitamin E are needed before supplementation with this
antioxidant becomes a standard for practice.
Espat and Helton13 recommend giving ascorbic
acid (1 g/d) and vitamin E (1000 mg/d) to critically ill
patients, such as patients with alcoholism, who were
depleted before hospitalization. In addition, Espat and
Helton suggest giving ascorbic acid at a dose of at
least 1 g/d to patients with normal renal function who
are being treated with mechanical ventilation at high
concentrations of oxygen.
Supplementation with antioxidants must be used
cautiously. Oversupplementation may prevent activa-
tion of normal defense mechanisms. Some antioxi-
dants may induce chemical reactions with substances
such as metals that can create an increase in free rad-
ical formation. 1 2 Thus, the dosage and route of
administration of supplements of antioxidants need
more investigation.
Treatment with ROS scavengers is already being
used in the ICU. For example, pretreatment with SOD
protected against oxygen poisoning in patients who
were receiving a high concentration of oxygen. 10
Providing ROS scavengers during ischemia or at the
onset of reperfusion can decrease formation of ROS
and result in less damage to tissues. Existing treat-
ments for prevention of ischemia are being reexam-
ined because of the damage due to ROS. Drugs
commonly used in the ICU may be beneficial in termi-
nating the damage caused by ROS. Research on
N-acetylcysteine and lidocaine indicated that both
attenuated diaphragm fatigue by preventing produc-
tion of ROS and subsequent lipid peroxidation.22,50,51
Other common drugs, such as β-blockers, angiotensin-
converting enzyme inhibitors, and the “statins,” have
some antioxidant activity.27 The increasing use of these
drugs as scavengers promises more effective prevention
and treatment of ROS formation in ICU patients.
550 AMERICAN JOURNAL OF CRITICAL CARE, November 2002, Volume 11, No. 6
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Nursing practice will be affected by current and
future research on oxidative stress. As we strive to
increase quality of care, nursing activities should be
reviewed in relation to their contribution to the forma-
tion of ROS. Nursing activities and how they influence
production of ROS can be investigated by using these
measurements. Studies on the use of common medica-
tions as antioxidants or scavengers may be done.
Newly developed drugs used as scavengers or antioxi-
dants will emerge and will affect patients’ outcomes.
Summary
The concept that ROS are a major contributing
factor in disease is important for both scholarly
research and therapeutic practice. In critically ill
patients, oxidative stress can induce inflammatory
responses and cellular destruction and even lead to an
increased mortality rate. Studies have indicated a rela-
tionship between oxidative stress and common ICU
syndromes and diseases that affect critically ill patients.
Scavengers play an important role in terminating the
activity of ROS.1,2 Use of antioxidants is also beneficial
in preventing disease.
A deeper understanding of the formation of ROS
and the subsequent oxidative stress is important for
effective nursing care of critically ill patients.
Measurements that indicate cellular damage due to
oxidative stress need to be established and should be
monitored in the ICU environment. Current drug ther-
apies and other therapeutic measures such as adminis-
tration of N-acetylcysteine may improve the quality of
patients’ care. New laboratory tests for measuring
oxidative stress must be examined in relation to specific
nursing interventions. All of these aspects of care
could revolutionize how nurses evaluate the effective-
ness of their practice.
ACKNOWLEDGMENTS
This article was supported by grant 1R01NR05317-01A1 from the National Institute of
Nursing Research, National Institutes of Health. We thank Dr Sue Popkess-Vawter,
School of Nursing, University of Kansas, and Ruth Ohm, RN, MSN, and Sharon Little-
Stoetzel, RN, MSN, Graceland University, for their assistance.
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551
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CE Test Form
Oxidative Stress in Critically Ill Patients
Objectives
1. Identify intensive care unit syndromes and diseases linked to damage caused by reactive oxygen species
2. Describe the impact of oxidative stress on critical illness
3. Discuss the biological measurement of oxidative stress

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CE Test Questions
Oxidative Stress in Critically Ill Patients

1. Among the reactive oxygen species, which is 6. Which of the following terms is defined as “the gain
considered the most stable? of electrons in chemical reactions”?
a. Hydrogen peroxide a. Oxidation
b. Superoxide b. Reduction
c. Hydroxyl radical c. Reduction-oxidation
d. Peroxidase d. Redox

2. Which of the following is a major injury caused by 7. Which of the following is a biological measurement
hydroxyl radical? of oxidative stress that can be measured in the urine?
a. DNA damage a. Lipid peroxides
b. RNA damage b. 8-isoprostane
c. Ischemia-reperfusion injury c. F2-isoprostanes
d. Mitochondrial damage d. Ascorbate

3. Which of the following is not a reactive oxygen 8. Which of the following is not considered a
species scavenger? scavenger of oxygen free radicals?
a. Superoxide dismutase a. Vitamins
b. Catalase b. Bilirubin
c. Glutathione c. Uric acid
d. Hydrogen peroxide d. Sodium bisulfate

4. Intensive care unit syndromes and diseases that are 9. Treatment with which supplement has been shown
linked to damage caused by reactive oxygen species to alleviate diaphragm fatigue in patients being
include all of the following except which condition? weaned from mechanical ventilation?
a. Disseminated intravascular coagulation a. Ascorbic acid
b. Acute respiratory distress syndrome b. Vitamin A
c. Diabetes c. Vitamin E
d. Acute renal failure d. Selenium

5. Which of the following conditions causes changes 10. Which of the following nursing interventions has the
in cell activities such as cell proliferation and potential to contribute to the production of reactive
apoptosis? oxygen species during critical illness?
a. Lipid peroxidation a. Turning
b. Protein damage b. Music therapy
c. DNA damage c. Ambulation
d. Redox signaling d. Exercise

AMERICAN JOURNAL OF CRITICAL CARE, November 2002, Volume 11, No. 6 553

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