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CE Article

Oxidative Stress in Critically Ill Patients

	Abstract

Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

 
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.

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

Understanding the formation of ROS and oxidative damage is important in order to initiate appropriate 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 respiratory distress syndrome (ARDS),^3–5 infection with human immunodeficiency virus,⁶ and chronic obstructive pulmonary disease.⁷ N-acetylcysteine may also increase phagocytosis by neutrophils in patients with sepsis or systemic inflammatory response syndrome.⁸

In this article, we provide essential information about oxidative stress that can be used to enhance direct care of patients.

	Background

Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

 
Oxygen is necessary in the metabolic production of energy. Mitochondria, through the electron transport chain, use oxygen to oxidize other molecules and generate energy in the form of adenosine triphosphate.^1,9 During this process, oxygen is reduced to water, producing several intermediary ROS. The production 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 formation of these species.¹⁰ Table 1 lists ICU syndromes and diseases attributed to damage caused by ROS.

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 oxidative 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

Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

 
During chemical processes, molecules can be reduced or oxidized. A molecule with an unpaired electron can combine with a molecule capable of donating an electron. The donation of an electron is called oxidation. 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, proteins, 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 specialized 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

View larger version (9K): [in this window] [in a new window]   Figure 1 Electron structure of reactive species.

View larger version (7K): [in this window] [in a new window]   Figure 2 During the reduction of oxygen, electrons are added at each step, resulting in 3 reactive oxygen species: superoxide anion, hydrogen peroxide, and the hydroxyl radical.

Hydrogen peroxide, which is produced mainly by the mitochondria, is the most stable of the ROS. SOD, a ROS scavenger enzyme, removes O₂^–• in a reaction that produces H₂O₂. Hydrogen peroxide can inactivate enzymes, cross cell membranes, and react with both iron and copper ions to produce OH^•.9

The hydroxyl radical is very damaging and can react with many substances. Hydroxyl radicals are usually produced through the Fenton reaction, in which O₂^–• , H₂O₂, and iron are teamed to form OH^• DNA damage is a major injury caused by OH^•.13 DNA damage due to OH^• is a contributing factor in cancer and other diseases.^12,19

Ischemia-reperfusion injury is also associated with the formation of oxygen free radicals. Endothelial cells respond to ischemia and produce xanthine oxidase. The xanthine oxidase is responsible for the formation of O₂^–• during reperfusion. Endotoxin, cytokines, neutrophil adherence, and acidosis can all trigger production of xanthine oxidase in endothelial cells.¹³

	ROS and Damage

Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

 
The free radicals O₂^–•, H₂O₂, and OH^• are responsible 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 process 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

View larger version (16K): [in this window] [in a new window]   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.

	Enzyme and Nonenzyme Defenses Against ROS

Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

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, catalase, and the glutathione system (Figure 3). The intracellular antioxidant SOD catalyzes the conversion of O₂^–• to oxygen and H₂O₂. The H₂O₂ 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 consists of glutamine, cysteine, and glycine.²¹ N-acetylcysteine is chemically similar to glutathione and has been studied as a scavenger.^3–7,22,23 Destruction of H₂O₂ by glutathione peroxidase produces glutathione disulfide and water.¹ In another reaction, glutathione disulfide 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 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 (-tocopherol) is an important fat-soluble antioxidant in the prevention of lipid peroxidation. It can protect the polyunsaturated fatty acids in cell membranes from the autocatalytic chain reaction of lipid peroxidation.¹ Outside cell membranes, vitamin 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

Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

 
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 producing cell death and in contributing to these disease processes. Indicators of ROS production and antioxidant activity have been linked to several critical illnesses. Diseases such as cardiovascular disorders^26,27 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 antioxidant levels (-tocopherol, ß-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.

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 sepsis 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 al¹⁶ 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,⁴⁴ use of a new enteral formula (Oxepa) for tube feeding in patients with ARDS significantly improved lung microvascular function and thus decreased the ICU length of stay. The new formula contains eicosapentaenoic acid (from sardine oil), -linolenic acid (from borage oil), and antioxidants 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 significantly to mortality.¹⁰ Recent developments in pharmacological 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. Research^{11,22,40–42,46–49} 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-acetylcysteine, another antioxidant and specific ROS scavenger, can decrease the rate of diaphragmatic fatigue.²²

In other studies, lidocaine was given as an antioxidant agent for treatment of hyperoxia-induced⁵⁰ and sepsis-induced⁵¹ diaphragmatic dysfunction in hamsters. Lidocaine attenuated fatigue and inhibited lipid peroxidation. Supinski² suggested that ROS are produced 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 pathogenesis 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 preventing lipid peroxidation.²⁷

Another disease common in patients in the ICU is diabetes mellitus. Plasma markers of lipid peroxidation 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 contribute 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 glutathione 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

Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

 
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 published 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 soon. Consequently, critical care nurses must understand 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 commonplace in determining the oxidative status of patients, in evaluating treatments, and in guiding nursing practice.

Until the usefulness of such measurements is supported 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 supplements, or specific scavengers, to decrease oxidative stress in ICU patients.

Administration of supplemental vitamin E may be beneficial in preventing atherosclerosis and in attenuating diaphragm fatigue. A deficiency in this antioxidant in rats decreased diaphragmatic contractile function in resistive breathing.⁴⁰ Patients who may have vitamin E deficiency (eg, patients with alcoholism, malnutrition, or chronic jaundice) might benefit 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 activation of normal defense mechanisms. Some antioxidants may induce chemical reactions with substances such as metals that can create an increase in free radical formation.¹² 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 treatments for prevention of ischemia are being reexamined because of the damage due to ROS. Drugs commonly used in the ICU may be beneficial in terminating the damage caused by ROS. Research on N-acetylcysteine and lidocaine indicated that both attenuated diaphragm fatigue by preventing production of ROS and subsequent lipid peroxidation.^22,50,51 Other common drugs, such as ß-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.

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 formation of ROS. Nursing activities and how they influence production of ROS can be investigated by using these measurements. Studies on the use of common medications as antioxidants or scavengers may be done. Newly developed drugs used as scavengers or antioxidants will emerge and will affect patients’ outcomes.

	Summary

Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

 
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 relationship 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 therapies and other therapeutic measures such as administration 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 effectiveness 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.

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{at}aacn.org.

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Top Abstract Background Formation of ROS ROS and Damage Enzyme and Nonenzyme Defenses... Oxidative Stress in Critically... Implications for Practice Summary References

 

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