Antioxidants in Critical Illness
Eileen M. Bulger, MD; Ronald V. Maier, MD
Oxidative stress has been implicated in the
manifestations of critical illnesses, including ischemia and reperfusion injury
and systemic inflammatory states. This review describes the evidence for
increased oxidative stress in critically ill patients and explores the data
regarding antioxidant therapy for these conditions. Antioxidant therapies
reviewed include N-acetylcysteine,
selenium, vitamins E and C, superoxide dismutase, catalase, lazaroids, and
allopurinol. We focus on the results of these interventions in animal models
and human trials, when available.
Arch Surg. 2001;136:1201-1207
Increasing evidence supports the role of
systemic oxidative stress in the development and manifestation of critical
illness. Oxidative stress is
defined as a state in which the level of toxic reactive oxygen intermediates
(ROI) overcomes the endogenous antioxidant defenses of the host. Oxidative
stress can result, therefore, from either an excess in oxidant production, or
depletion of antioxidant defenses. Reactive oxygen intermediates are produced
as a result of normal physiologic processes, including leakage of electrons
from cellular electron transfer chains, and as byproducts of membrane lipid
metabolism (Figure 1).
During illness, ROI are produced by phagocytic cells as a mechanism to kill
invading microorganisms. When inflammation becomes systemic, however, as in
sepsis or the systemic inflammatory response syndrome, loss of control of ROI
production may lead to nondiscriminant bystander injury in the host. Reactive
oxygen intermediates cause direct cellular injury by oxidative injury to
cellular proteins and nucleic acids, and by inducing lipid peroxidation, which
leads to the destruction of the cell membrane.
In addition to causing direct cytotoxicity, ROI
also play a role as second messengers in the intracellular signaling pathways
of inflammatory cells. In particular, the activation of the critical nuclear
transcription factor, nuclear factor B (NF-B), has been
induced by hydrogen peroxide and blocked by several antioxidants, including
vitamin E.1, 2 Nuclear factor B is a central
transcription factor involved in the regulation of numerous proinflammatory
genes, including many cytokines (tumor necrosis factor, interleukin [IL]-1,
IL-6, IL-8, IL-2), hematopoetic growth factors (granulocyte-macrophage
colony-stimulating factor, macrophage colony-stimulating factor, granulocyte
colony-stimulating factor), cell adhesion molecules (CAM) (intercellular CAM-1,
endothelial-leukocyte adhesion molecule 1, vascular CAM-1) and nitric oxide
synthase (iNOS).3 Nuclear factor B has been
demonstrated as an important mediator in the signal transduction for both
endotoxin and inflammatory cytokine-induced activation.3 A second major
transcription factor, activator protein 1 (AP-1), also seems to be regulated by
changes in the redox state of the cell and can be activated by both oxidants
and antioxidants depending on the cell type and on intracellular conditions.4-6 In addition, several
inflammatory genes have promotor sites for AP-1, although its role in
inflammatory signaling remains less well documented than NF-B.4 Thus, altering the
redox state of the cell may contribute to the ongoing inflammatory cytokine
production and progression of systemic inflammation, leading to organ injury.
This may be manifest by the development of the acute respiratory distress
syndrome (ARDS) or multiple organ failure syndrome.
In addition to states of systemic inflammation,
oxidative stress has been implicated in the manifestations of another common
cause of critical illness: ischemia and reperfusion injury. Ischemia of tissue
beds followed by reperfusion with oxygenated blood, during resuscitation, leads
to significant production of ROI. This is primed by the increased activity of
xanthine oxidase and increased production of hypoxanthine due to loss of
adenosine triphosphate during ischemia. When oxygen is reintroduced, there is
both increased substrate and increased enzyme activity for the following
reaction:
Xanthine or Hypoxanthine + H2O + 2O2
uric acid + 2O2- + 2H+
Ischemia and reperfusion injury occurs, on a systemic
basis, during hypovolemic shock and resuscitation. It also occurs focally in
several clinical scenarios, including limb ischemia with revascularization or
fasciotomy, myocardial infarction with thrombolysis, and following organ
transplantation.
To combat the threat of oxidative stress, there
exists a number of endogenous antioxidant defenses. These include vitamins E
and C, provitamin A (-carotene),
glutathione, superoxide dismutase and catalase, bilirubin, urate, and other
plasma proteins. These antioxidants can be divided into enzymatic and
nonenzymatic groups (Table 1).
The enzymatic antioxidants include superoxide dismutase, which catalyzes the
conversion of O2- to H2O2 and H2O;
catalase, which then converts H2O2 to H2O and
O2; and glutathione peroxidase, which reduces H2O2
to H2O by oxidizing glutathione (GSH). Re-reduction of the oxidized
form of glutathione (glutathione disulfide) is then catalyzed by glutathione
reductase. These enzymes also require trace metal cofactors for maximal
efficiency, including selenium for glutathione peroxidase; copper, zinc, or
manganese for superoxide dismutase; and iron for catalase.
The nonenzymatic antioxidants include the
lipid-soluble vitamins (vitamin E, and vitamin A or -carotene) and the water-soluble vitamins (vitamin C and
glutathione). Vitamin E has been described as the major chain-breaking
antioxidant in humans.7 Vitamin E is a generic
term encompassing a collection of tocopherols and tocotrienols obtained from
plant oils. The most biologically active form is -tocopherol. Because of its lipid solubility, vitamin E is located
in cell membranes where it interrupts lipid peroxidation and plays a role in
modulating intracellular signaling pathways that rely on ROI.8, 9(p371)10-12 Vitamin E can also
directly quench ROI, including O2-, HO, and 1O2.
Vitamin A is a term encompassing a collection of retinols obtained in the diet
primarily from dairy products, eggs, liver, and fortified cereals. -Carotene is found
in a variety of fruits and vegetables, and it provides approximately 25% of the
vitamin A in Western diets. Dietary -carotene
is converted to retinol at the level of the intestinal mucosa, and it functions
as a chain-breaking antioxidant.
Vitamin C (ascorbic acid), obtained primarily
from citrus fruits, functions as a water-soluble antioxidant capable of broadly
scavenging ROI, including the major neutrophil oxidants: HO, H2O2,
and hypochlorous acid. Under certain circumstances, vitamin C has been shown to
have pro-oxidant properties as well. For example, when combined with iron, it
has been shown to accelerate lipid peroxidation, which leads to cellular
membrane damage.13 Finally, GSH, which
is synthesized intracellularly from cysteine, glycine, and glutamate, is
capable of either directly scavenging ROI, or enzymatically doing so via
glutathione peroxidase (Figure 2).
In addition, GSH is crucial to the maintenance of enzymes and other cellular
components in a reduced state. The majority of GSH is synthesized in the liver,
and approximately 40% is secreted in the bile.
The enzymatic and nonenzymatic antioxidant
systems are intimately linked to one another, as illustrated in Figure 2.
Both vitamin C and GSH have been implicated in the recycling of -tocopherol radicals.9(p269) In addition, the
trace elements selenium, manganese, copper, and zinc play important roles as
nutritional antioxidant cofactors. Selenium is a cofactor for the enzyme
glutathione peroxidase; and manganese, copper, and zinc are cofactors for
superoxide dismutase. Zinc also acts to stabilize the cellular metallothionein
pool, which has direct free radical quenching ability.14 The complex
interactions of these different antioxidant systems may imply that successful
therapeutic strategies will depend on the use of a combination of various
antioxidants rather than a single agent.
Numerous investigators have evaluated the
systemic oxidant state of critically ill and injured patients. Surrogate by-products
of membrane lipid peroxidation are elevated in the serum of several critically
ill patient populations.15-19 In addition, there
is evidence of increased oxidant activity in the lungs of patients with the
acute respiratory distress syndrome (ARDS) as manifest by increased
myeloperoxidase activity and products of lipid peroxidation detected in the
bronchoalveolar lavage fluid.17 Measurement of
antioxidant defenses has consistently demonstrated depressed plasma levels of
vitamins E and C in patients with sepsis and ARDS.15-17, 20-23 Low plasma vitamin
C levels have also been shown to be predictive of the development of multiple
organ failure syndrome in populations at risk.24 Similarly,
glutathione levels are depressed in the plasma of patients with hepatic
failure, in polytrauma patients, and in the bronchoalveolar lavage fluid of
those with ARDS.19, 25-27
A recently developed assay measuring total serum
antioxidant status has also been applied to several populations of critically
ill patients.28, 32 This assay is based
on the inhibition by serum antioxidants of the absorbance of the radical cation
2,2'-azino-bis-(3-ethylbenzo-thiazoline-6-sulphonic acid) (ABTS). These studies
have demonstrated mixed results; however, on the whole they support the
presence of increased systemic oxidative stress and the depletion of
antioxidant defenses during critical illness. As a result, several
investigators have sought to evaluate the usefulness of antioxidant therapy for
these patients.
N-Acetylcysteine
The most widely used antioxidant in experimental and clinical models is N-Acetylcysteine (NAC). Nacetylcysteine is converted, in vivo, to
L-cysteine, which is used to replete intracellular stores of glutathione. The
thiol group on the NAC molecule affords it direct antioxidant activity as well.33 N-Acetylcysteine is an attractive agent
for clinical trials, as it has been safely used in humans for several years for
the treatment of acetaminophen overdose, and as a mucolytic agent in patients
with obstructive pulmonary disease.34 N-Acetylcysteine can be administered
orally, intravenously, or as an inhalation agent. The oral administration of
NAC increases GSH levels in the liver, plasma, and bronchoalveolar lavage
fluid, suggesting a widespread systemic effect.35
Use of NAC in animal models of ischemia and
reperfusion injury and ARDS has demonstrated encouraging results.36-45 In models of acute
lung injury, based on the intratracheal administration of lipopolysaccharide or
IL-1, there was attenuation of pulmonary injury and a significant reduction in
lung permeability and lipid peroxide production, even when NAC was administered
up to 2 hours after endotoxin or IL-1 challenge.37, 42 A more recent study
has demonstrated that liposomal encapsulation of NAC, administered
intratracheally, leads to a prolonged protective effect in a rat model of acute
lung injury.46
Based on the encouraging results in animal studies,
several human trials of NAC for the treatment of ARDS have been completed.26, 47-49 Recent studies of
patients with ARDS have confirmed the ability of parenteral NAC administration
to increase GSH levels in the bronchoalveolar lavage fluid and within pulmonary
granulocytes.50, 51 Clinical trials to
demonstrate benefit in patients with ARDS, however, have had equivocal results.
Jepsen et al,47 in a prospective,
randomized, double-blinded trial of NAC vs a placebo in patients with
established ARDS, were unable to show any difference in the PaO2-FiO2
ratio or survival between the groups. Similarly, Domenighetti et al49 were unable to
demonstrate any change in outcome parameters for patients with established
ARDS.49 However, Suter
et al,26 in a similar
group of patients, demonstrated improved oxygenation and a decreased need for
ventilatory support in the NAC-treated group. Bernard et al,48 in a prospective,
randomized, double-blinded trial of NAC, or procysteine vs placebo, were able
to show an increase in red blood cell GSH levels, suggesting that the drugs
were active and that the number of days of acute lung injury were significantly
reduced. There was no difference in mortality in any of these studies, but all
had relatively small sample sizes. Further trials are needed to determine
whether patients at an earlier stage in the disease process, or preferably,
those at risk for the development of ARDS, will benefit from NAC treatment.
Trials of NAC for other critically ill patient
populations have also had mixed results. No overall outcome benefit was seen in
a mixed population of patients in an intensive care unit.52 Two studies of NAC
administration to patients undergoing a liver transplantation have demonstrated
contradictory results, with one showing no benefit, and the other showing
improved liver function and better graft survival in the NAC-treated group.53, 54 A study of the
hemodynamic effects of NAC administration in patients with sepsis, revealed
that 45% of patients given NAC demonstrated an increase in oxygen consumption,
which was associated with an increase in gastric mucosal pH.55 These NAC responders
had a better survival rate than nonresponders. Similarly, a more recent study
of NAC administration to patients with sepsis demonstrated attenuation of
oxidative stress and improvement in clinical scores for these patients.56 Lastly, NAC
administration has demonstrated significant benefit in the treatment of
fulminant hepatic failure secondary to acetaminophen toxicity, and it is widely
used for this indication.57, 58
Additional clinical trials with larger numbers
of patients are needed to better define which population of critically ill
patients may benefit from NAC therapy. In addition, it will be important to
define the appropriate timing for intervention in each disease process. As
suggested by the results of the ARDS trial, patients with established disease
may not benefit, as the oxidant damage has been done. It may be more
appropriate to target patients early in the inflammatory process or at the time
of reperfusion following ischemic insults.
Selenium
Another strategy to indirectly alter the oxidant-antioxidant balance is the
repletion of the trace element selenium. Selenium is a critical cofactor for
the function of the enzyme glutathione peroxidase, which is involved in the
oxidation of glutathione. One study has evaluated selenium supplementation in
patients with systemic inflammatory response syndrome, in which all patients
had low serum selenium levels at the onset of the study.59 These authors
demonstrate a lower frequency of renal failure, a more rapid resolution of
organ dysfunction, and a trend toward a decreased mortality rate for patients
receiving selenium supplementation. Further study is needed to fully elucidate
the mechanism of benefit and clinical usefulness of this approach in different
patient populations.
Vitamin E
Serum and tissue -tocopherol
levels fall steadily and dramatically in the first 24 hours following endotoxin
infusion or cecal ligation and puncture.60, 61 Several investigators
have demonstrated improved survival following -tocopherol treatment in these animal models of sepsis.62-64 In addition, -tocopherol
treatment in animals with sepsis has been shown to decrease hepatic lipid
peroxidation, attenuate disseminated intravascular coagulation, and reduce
plasma lactate levels.63, 65, 66 Additional models of
excessive inflammation in which -tocopherol has been shown to have beneficial effects include a
murine hepatic ischemia-reperfusion model, a rat renal ischemia-reperfusion
model and in pulmonary inflammation following zymosan-induced peritonitis in
rats.67-69 In the
liver ischemia-reperfusion study, the -tocopherol–treated group demonstrated decreased lipid
peroxidation, enhanced adenosine triphosphate generation, increased survival,
and attenuation of hepatic damage.68 In a model of renal
warm ischemia, -tocopherol
pretreatment had protective effects on the kidney, as evidenced by enhanced
adenosine triphosphate levels during reperfusion and lower serum creatinine
levels. Increased survival was also noted in ischemic rats following treatment
with -tocopherol.69 In the case of
zymosan-induced peritonitis, administration of -tocopherol immediately following intraperitoneal zymosan
injection lead to a decrease in production of pulmonary lipid peroxidation
by-products, and attenuation of pulmonary tissue damage when compared with
controls.67 This
attenuation of pulmonary injury may be due to the marked inhibition of the
alveolar macrophage proinflammatory response, which we have demonstrated
following enteral -tocopherol
supplementation.70
A recent study has examined the effect of oral
vitamin E supplementation on human monocyte function in healthy volunteers, who
were given 1200 IU of -tocopherol for
8 weeks.71 Their
monocytes were then harvested and found to have significantly suppressed
responses to endotoxin, including decreased ROI production during the
respiratory burst, decreased IL-1
production, and inhibition of monocyte-endothelial adhesion.
Despite encouraging results in animal studies
and the several reports of decreased levels of vitamin E in critically ill
patients, there has been only 1 clinical trial. This is likely owing to the
lack of an intravenous preparation. As a result, studies are limited to the
oral route, which may lead to impaired drug absorption in this patient
population. One study has involved enteral vitamin E supplementation in
patients with ARDS.72 In this study, serum -tocopherol
levels, following 1-g/d supplementation, were not increased in the ARDS
patients to the same degree as controls. However, it is unclear whether this
was due to excessive consumption of vitamin E in these patients, or
malabsorption due to severity of illness. Clearly, more well-controlled,
randomized, prospective studies are needed. In addition, supplementation with
higher doses of vitamin E, comparable to the efficacious animal studies, may be
necessary to document a protective effect.
Vitamin C
Despite demonstration of depressed vitamin C levels in critically ill patients,
supplementation with vitamin C alone has not been studied.21, 23, 24 This may be because
of the appropriate concern that under conditions of severe oxidant stress,
vitamin C can function as a pro-oxidant by promoting iron-catalyzed reactions
as an electron donor.73 Infusion of vitamin C
in patients with sepsis results in rapid consumption, due to either the
promotion of redox cycling of iron or as a result of radical scavenging. There
seems to be a differential handling of infused vitamin C in patients with
sepsis vs healthy subjects, and further studies are needed to elucidate the
relative antioxidant and pro-oxidant mechanisms potentially involved.73
Superoxide Dismutase and
Catalase
Results of superoxide dismutase administration in animal models of sepsis have
been variable. In general, superoxide dismutase is effective when administered
before the onset of sepsis,74, 76 but when administered
after sepsis, it has been established that it may be harmful.76, 77 Superoxide dismutase
scavenges superoxide but produces hydrogen peroxide, which requires clearance
by catalase. If hydrogen peroxide is not effectively cleared, levels of the
highly reactive hydroxyl radical may increase. Therefore, in this situation,
superoxide dismutase may act predominantly as a pro-oxidant. Thus, it seems
logical that use of superoxide dismutase therapy must include the addition of
catalase administration. A potential limiting factor for both agents is their
distribution. Both are large molecules, and are restricted largely to the
extracellular, nonmembrane-bound space. As such, their effectiveness may be
limited. Use of the 2 agents in combination has been investigated in one study
of dogs with endotoxemia, and demonstrated no benefit from the combined
administration whether given before or after endotoxin challenge.78
Combination Therapy
Based on the recognition that lipid-soluble and water-soluble antioxidants may
act in a synergistic fashion, such as during the recycling of vitamin E by
vitamin C, it has been suggested that a more appropriate clinical approach
involves the replacement of a "cocktail" of antioxidants rather than
a single agent.79 Two clinical trials
have investigated this approach. Galley et al80 administered a
combination of NAC, vitamin C, and -tocopherol to patients in septic shock. They demonstrated a
transient beneficial hemodynamic response, but did not assess the effect on
outcome. A second study evaluated a supplemented enteric formulation with
increased levels of vitamins E and C and -carotene
in patients with ARDS.81 Patients on this diet
required less ventilatory support, had a shorter stay in the intensive care
unit, and had a decrease in the development of organ failure when compared with
control patients. However, this modified diet also had alterations in the lipid
content, with selective increase in the proportion of -3 fatty acids. Thus, it is unclear whether the benefits seen in
this study are due to an increase in antioxidant activity, or to the effects of
altered lipid metabolism on inflammatory cells.
Lazaroids
Lazaroids are 21-aminosteroids, which are nonglucocorticoid analogs of
methylprednisolone with multiple actions, including the scavenging of ROI, the
attenuation of inflammation, and the stabilization of biological membranes.
Lazaroids seem promising in animal models of endotoxemia, inhalational injury,
and acute lung injury.82-86 It is likely that
human trials are forthcoming. Currently, it remains unclear whether their
primary effect is due to the scavenging of ROI, or modulation of the
inflammatory response via inhibition of cytokine production.
Allopurinol
During ischemia and reperfusion injury, up-regulation of xanthine oxidase
contributes to increased ROI production (Figure 1).
Allopurinol is an inhibitor of xanthine oxidase, which has been studied as a
potential therapy to down-regulate this process. Allopurinol is effective at
attenuating the damage from ischemia and reperfusion injury in a number of
animal models87-90; however, the
results in sepsis models have been variable.91, 92 This suggests that
the primary mechanism for free radical production in sepsis is not dependent on
the xanthine oxidase pathway. Use of allopurinol in human trials has been
confined to its preoperative administration to patients undergoing coronary
bypass surgery, during which it has proven beneficial in attenuating the
cardiac ischemia and reperfusion injury associated with this procedure.93-95 Based on these
data, studies in patients undergoing resuscitation for hemmorhagic shock are
warranted.
Toxic ROI play a role in the manifestations of
critical illness due to both ischemia or reperfusion injury and systemic
inflammation. Reactive oxygen intermediates clearly cause direct tissue injury,
which can lead to organ failure. In addition, recent studies demonstrate their
immunomodulatory role as second messengers within inflammatory cells.
Supplemental antioxidant therapy seems promising in the regulation of the
uncontrolled production of ROI in these situations. Prior to instituting this
therapy, however, we must define the appropriate time points for intervention
in each disease process. It seems that treatment becomes increasingly difficult
as the inflammatory process and the damage induced becomes irreversible with
time. In addition, we need to explore combinational therapy, as it is likely
that repletion of both lipid-soluble and water-soluble antioxidants will be
required. Lastly, the relatively inexpensive nature of these agents makes
funding from industrial partners highly unlikely. A significant challenge lies
in finding agencies willing to support encouraging therapeutics such as
"simple antioxidants."
Author/Article Information
From the Department of Surgery, Harborview Medical Center, Seattle, Wash.
Corresponding author: Eileen M. Bulger, MD, Assistant Professor of Surgery, Box
359796, Harborview Medical Center, 325 Ninth Ave, Seattle, WA 98104 (e-mail: [log in to unmask]).
1.
Schreck R, Rieber P, Baeuerle PA.
Reactive oxygen intermediates as apparently widely used messengers in the
activation of the NF-kB transcription factor and HIV-1.
EMBO J.
1991;10:2247-2258.
MEDLINE
2.
Suzuki Y, Packer L.
Inhibition of Nf-kB activation by vitamin E derivatives.
Biochem Biophys Res Commun.
1993;193:277-283.
MEDLINE
3.
Baeuerle PA, Henkel T.
Function and activation of NF-kB in the immune system.
Annu Rev Immunol.
1994;12:141-179.
MEDLINE
4.
Sen C, Packer L.
Antioxidant and redox regulation of gene transcription.
FASEB J.
1996;10:709-720.
MEDLINE
5.
Pinkus R, Weiner L, Daniel V.
Role of oxidants and antioxidants in the induction of AP-1, NF-kB, and
glutathione S-transferase gene expression.
J Biol Chem.
1996;271:13422-13429.
MEDLINE
6.
Meyer M, Pahl HL, Baeuerle PA.
Regulation of the transcription factors NF-kB and AP-1 by redox changes.
Chem Biol Interact.
1994;91:91-100.
MEDLINE
7.
Packer L.
Interactions among antioxidants in health and disease: vitamin E and its redox
cycle.
Proc Soc Exp Biol Med.
1992;200:271-276.
MEDLINE
8.
Kagan V, Serbinova E, Bakalova R, et al.
Mechanisms of stabilization of biomembranes by alpha-tocopherol.
Biochem Pharmacol.
1990;40:2403-2413.
MEDLINE
9.
Azzi A, Bartoli G, Boscoboinik D, Hensey C, Szewczyk A.
-Tocopherol and
protein kinase C regulation of intracellular signaling.
In: Packer L, Fuchs J, eds. Vitamin E in
Health and Disease. New York, NY: Marcel Dekker Inc; 1993.
10.
Bulger EM, Garcia I, Maier RV.
The differential effects of the membrane antioxidant: vitamin E on macrophage
activation.
Surg Forum.
1996;47:92-95.
11.
Bulger EM, Garcia I, Maier RV.
The role of vitamin E as a modulator of macrophage activation.
In: Faist E, ed. Fourth International
Congress on the Immune Consequences of Trauma, Shock and Sepsis: Mechanisms and
Therapeutic Approaches. Bologna, Italy: Monduzzi Editore;
1997:349-353.
12.
Mendez C, Garcia I, Maier RV.
Antioxidants attenuate endotoxin induced activation of alveolar macrophages.
Surgery.
1995;118:412-420.
MEDLINE
13.
Chojkier M, Houglum K, Solis-Herruzo J, Brenner DA.
Stimulation of collagen gene expression by ascorbic acid in cultured human
fibroblasts: a role for lipid peroxidation?
J Biol Chem.
1989;264:16957-16962.
MEDLINE
14.
Bray TM, Bettger WJ.
The physiological role of zinc as an antioxidant.
Free Radic Biol Med.
1990;8:281.
MEDLINE
15.
Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR.
Decreased antioxidant status and increased lipid peroxidation in patients with
septic shock and secondary organ dysfunction [comments].
Crit Care Med.
1995;23:646-651.
MEDLINE
16.
Takeda K, Shimada Y, Amano M, Sakai T, Okada T, Yoshiya I.
Plasma lipid peroxides and alpha-tocopherol in critically ill patients.
Crit Care Med.
1984;12:957-959.
MEDLINE
17.
Metnitz PG, Bartens C, Fischer M, Fridrich P, Steltzer H, Druml W.
Antioxidant status in patients with acute respiratory distress syndrome.
Intensive Care Med.
1999;25:180-185.
MEDLINE
18.
Leff JA, Parsons PE, Day CE, et al.
Serum antioxidants as predictors of adult respiratory distress syndrome in
patients with sepsis.
Lancet.
1993;341:777-780.
MEDLINE
19.
Kretzschmar M, Pfeiffer L, Schmidt C, Schirrmeister W.
Plasma levels of glutathione, alpha-tocopherol and lipid peroxides in
polytraumatized patients: evidence for a stimulating effect of TNF alpha on
glutathione synthesis.
Exp Toxicol Pathol.
1998;50:477-483.
MEDLINE
20.
Bertrand Y, Pincemail J, Hanique G, et al.
Differences in tocopherol-lipid ratios in ARDS and non-ARDS patients.
Intensive Care Med.
1989;15:87-93.
MEDLINE
21.
Cross CE, Forte T, Stocker R, et al.
Oxidative stress and abnormal cholesterol metabolism in patients with adult
respiratory distress syndrome.
J Lab Clin Med.
1990;115:396-404.
MEDLINE
22.
Richard C, Lemonnier F, Thibault M, Couturier M, Auzepy P.
Vitamin E deficiency and lipoperoxidation during adult respiratory distress
syndrome.
Crit Care Med.
1990;18:4-9.
MEDLINE
23.
Schorah CJ, Downing C, Piripitsi A, et al.
Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in
plasma of critically ill patients.
Am J Clin Nutr.
1996;63:760-765.
MEDLINE
24.
Borrelli E, Roux-Lombard P, Grau GE, et al.
Plasma concentrations of cytokines, their soluble receptors, and antioxidant
vitamins can predict the development of multiple organ failure in patients at
risk.
Crit Care Med.
1996;24:392-397.
MEDLINE
25.
Loguercio C, Del Vecchio Blanco C, Coltorti M, Nardi G.
Alteration of erythrocyte glutathione, cysteine and glutathione synthetase in
alcoholic and non-alcoholic cirrhosis.
Scand J Clin Lab Invest.
1992;52:207-213.
MEDLINE
26.
Suter PM, Domenighetti G, Schaller MD, Laverriere MC, Ritz R, Perret C.
N-acetylcysteine enhances recovery from acute lung injury in man: a randomized,
double-blind, placebo-controlled clinical study.
Chest.
1994;105:190-194.
MEDLINE
27.
Bunnell E, Pacht ER.
Oxidized glutathione is increased in the alveolar fluid of patients with the
adult respiratory distress syndrome.
Am Rev Respir Dis.
1993;148:1174-1178.
MEDLINE
28.
Cowley HC, Bacon PJ, Goode HF, Webster NR, Jones JG, Menon DK.
Plasma antioxidant potential in severe sepsis: a comparison of survivors and
nonsurvivors.
Crit Care Med.
1996;24:1179-1183.
MEDLINE
29.
Dasgupta A, Malhotra D, Levy H, Marcadis D, Blackwell W, Johnston D.
Decreased total antioxidant capacity but normal lipid hydroperoxide
concentrations in sera of critically ill patients.
Life Sci.
1997;60:335-340.
MEDLINE
30.
MacKinnon KL, Molnar Z, Lowe D, Watson ID, Shearer E.
Measures of total free radical activity in critically ill patients.
Clin Biochem.
1999;32:263-268.
MEDLINE
31.
Pascual C, Karzai W, Meier-Hellmann A, et al.
Total plasma antioxidant capacity is not always decreased in sepsis.
Crit Care Med.
1998;26:705-709.
MEDLINE
32.
Tsai K, Hsu T, Kong C, Lin K, Lu F.
Is the endogenous peroxyl-radical scavenging capacity of plasma protective in
systemic inflammatory disorders in humans?
Free Radic Biol Med.
2000;28:926-935.
MEDLINE
33.
Aruoma OI, Halliwell B, Hoey BM, Butler J.
The antioxidant action of N-acetylcysteine: its reaction with hydrogen
peroxide, hydroxyl radical, superoxide, and hypochlorous acid.
Free Radic Biol Med.
1989;6:593-597.
MEDLINE
34.
Walsh TS, Lee A.
N-acetylcysteine administration in the critically ill [editorial].
Intensive Care Med.
1999;25:432-434.
MEDLINE
35.
Ruffmann R, Wendel A.
GSH rescue by N-acetylcysteine.
Klin Wochenschr.
1991;69:857-862.
MEDLINE
36.
Nakano H, Boudjema K, Alexandre E, et al.
Protective effects of N-acetylcysteine on hypothermic ischemia-reperfusion
injury of rat liver.
Hepatology.
1995;22:539-545.
MEDLINE
37.
Davreux CJ, Soric I, Nathens AB, et al.
N-acetyl cysteine attenuates acute lung injury in the rat.
Shock.
1997;8:432-438.
MEDLINE
38.
Cuzzocrea S, Mazzon E, Costantino G, Serraino I, De Sarro A, Caputi AP.
Effects of n-acetylcysteine in a rat model of ischemia and reperfusion injury.
Cardiovasc Res.
2000;47:537-548.
MEDLINE
39.
Weinbroum AA, Rudick V, Ben-Abraham R, Karchevski E.
N-acetyl-L-cysteine for preventing lung reperfusion injury after liver
ischemia-reperfusion: a possible dual protective mechanism in a dose-response
study [comments].
Transplantation.
2000;69:853-859.
MEDLINE
40.
Mayer H, Schmidt J, Thies J, et al.
Characterization and reduction of ischemia/reperfusion injury after
experimental pancreas transplantation.
J Gastrointest Surg.
1999;3:162-166.
MEDLINE
41.
DiMari J, Megyesi J, Udvarhelyi N, Price P, Davis R, Safirstein R.
N-acetyl cysteine ameliorates ischemic renal failure.
Am J Physiol.
1997;272(pt 2):F292-F298.
MEDLINE
42.
Leff JA, Wilke CP, Hybertson BM, Shanley PF, Beehler CJ, Repine JE.
Postinsult treatment with N-acetyl-L-cysteine decreases IL-1–induced neutrophil
influx and lung leak in rats.
Am J Physiol.
1993;265(pt 1):L501-L506.
MEDLINE
43.
Bernard GR, Lucht WD, Niedermeyer ME, Snapper JR, Ogletree ML, Brigham KL.
Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake
sheep and upon in vitro granulocyte function.
J Clin Invest.
1984;73:1772-1784.
MEDLINE
44.
Wagner PD, Mathieu-Costello O, Bebout DE, Gray AT, Natterson PD, Glennow C.
Protection against pulmonary O2 toxicity by N-acetylcysteine.
Eur Respir J.
1989;2:116-126.
MEDLINE
45.
Wegener T, Sandhagen B, Saldeen T.
Effect of N-acetylcysteine on pulmonary damage due to microembolism in the rat.
Eur J Respir Dis.
1987;70:205-212.
MEDLINE
46.
Fan J, Shek PN, Suntres ZE, Li YH, Oreopoulos GD, Rotstein OD.
Liposomal antioxidants provide prolonged protection against acute respiratory
distress syndrome.
Surgery.
2000;128:332-338.
MEDLINE
47.
Jepsen S, Herlevsen P, Knudsen P, Bud MI, Klausen NO.
Antioxidant treatment with N-acetylcysteine during adult respiratory distress
syndrome: a prospective, randomized, placebo-controlled study.
Crit Care Med.
1992;20:918-923.
MEDLINE
48.
Bernard GR, Wheeler AP, Arons MM, et al.
A trial of antioxidants N-acetylcysteine and procysteine in ARDS: the Antioxidant
in ARDS Study Group.
Chest.
1997;112:164-172.
MEDLINE
49.
Domenighetti G, Suter PM, Schaller MD, Ritz R, Perret C.
Treatment with N-acetylcysteine during acute respiratory distress syndrome: a
randomized, double-blind, placebo-controlled clinical study.
J Crit Care.
1997;12:177-182.
MEDLINE
50.
Ortolani O, Conti A, De Gaudio AR, Masoni M, Novelli G.
Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of
the lung epithelium during the adult respiratory distress syndrome.
Shock.
2000;13:14-18.
MEDLINE
51.
Laurent T, Markert M, Feihl F, Schaller MD, Perret C.
Oxidant-antioxidant balance in granulocytes during ARDS: effect of
N-acetylcysteine.
Chest.
1996;109:163-166.
MEDLINE
52.
Molnar Z, MacKinnon KL, Shearer E, Lowe D, Watson ID.
The effect of N-acetylcysteine on total serum anti-oxidant potential and
urinary albumin excretion in critically ill patients.
Intensive Care Med.
1998;24:230-235.
MEDLINE
53.
Steib A, Freys G, Collin F, Launoy A, Mark G, Boudjema K.
Does N-acetylcysteine improve hemodynamics and graft function in liver
transplantation?
Liver Transpl Surg.
1998;4:152-157.
MEDLINE
54.
Thies JC, Teklote J, Clauer U, et al.
The efficacy of N-acetylcysteine as a hepatoprotective agent in liver
transplantation.
Transpl Int.
1998;11(suppl 1):S390-S392.
MEDLINE
55.
Spies CD, Reinhart K, Witt I, et al.
Influence of N-acetylcysteine on indirect indicators of tissue oxygenation in
septic shock patients: results from a prospective, randomized, double-blind
study.
Crit Care Med.
1994;22:1738-1746.
MEDLINE
56.
Ortolani O, Conti A, De Gaudio AR, Moraldi E, Cantini Q, Novelli G.
The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in
patients with early septic shock.
Am J Respir Crit Care Med.
2000;161:1907-1911.
MEDLINE
57.
Harrison PM, Keays R, Bray GP, Alexander GJ, Williams R.
Improved outcome of paracetamol-induced fulminant hepatic failure by late
administration of acetylcysteine.
Lancet.
1990;335:1572-1573.
MEDLINE
58.
Keays R, Harrison PM, Wendon JA, et al.
Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a
prospective controlled trial.
BMJ.
1991;303:1026-1029.
MEDLINE
59.
Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R.
Selenium replacement in patients with severe systemic inflammatory response
syndrome improves clinical outcome.
Crit Care Med.
1999;27:1807-1813.
MEDLINE
60.
Sugino K, Dohi K, Yamada K, Kawaski T.
Changes in the levels of endogenous antioxidants in the liver of mice with
experimental endotoxemia and the protective effects of antioxidants.
Surgery.
1989;105:200-206.
MEDLINE
61.
Takeda K, Shimada Y, Okada T, Amano M, Sakai T, Yoshiya I.
Lipid peroxidation in experimental septic rats.
Crit Care Med.
1986;14:719-723.
MEDLINE
62.
Powell RJ, Machiedo GW, Rush BF Jr, Dikdan GS.
Effect of oxygen-free radical scavengers on survival in sepsis.
Am Surg.
1991;57:86-88.
MEDLINE
63.
McKechnie K, Furman B, Parratt J.
Modification by oxygen free radical scavengers of the metabolic and
cardiovascular effects of endotoxin infusion in conscious rats.
Circ Shock.
1986;19:429-439.
MEDLINE
64.
Sugino K, Dohi K, Yamada K, Kawaski T.
The role of lipid peroxidation in endotoxin-induced hepatic damage and the
protective effect of antioxidants.
Surgery.
1987;101:746-752.
MEDLINE
65.
Yoshikawa T, Murakami M, Kondo M.
Endotoxin-induced disseminated intravascular coagulation in vitamin E deficient
rats.
Toxicol Appl Pharmacol.
1984;74:173-178.
MEDLINE
66.
Pekkanen T, Lindberg P, Sankari S.
The effect of pretreatment with vitamin E on the effects of endotoxin on rat.
Acta Pharmacol Toxicol (Copenh).
1983;53:64-69.
MEDLINE
67.
Demling R, LaLonde C, Ikegami K, Picard L, Nayak U.
Alpha-tocopherol attenuates lung edema and lipid peroxidation caused by acute
zymosan-induced peritonitis.
Surgery.
1995;117:226-231.
MEDLINE
68.
Marubayashi S, Dohi K, Ochi K, Kawasaki T.
Role of free radicals in ischemic rat liver cell injury: prevention of damage
by alpha-tocopherol administration.
Surgery.
1986;99:184-192.
MEDLINE
69.
Takenaka M, Tatsukawa Y, Dohi K, Ezaki H, Matsukawa K, Kawasaki T.
Protective effects of alpha-tocopherol and coenzyme Q10 on warm ischemic
damages of the rat kidney.
Transplantation.
1981;32:137-141.
MEDLINE
70.
Bulger EM, Helton WS, Clinton CM, Roque RP, Garcia I, Maier RV.
Enteral vitamin E supplementation inhibits the cytokine response to endotoxin.
Arch Surg.
1997;132:1337-1341.
MEDLINE
71.
Devaraj S, Li D, Jialal I.
The effects of alpha-tocopherol supplementation on monocyte function.
J Clin Invest.
1996;98:756-763.
MEDLINE
72.
Seeger W, Ziegler A, Wolf H.
Serum alpha-tocopherol levels after high-dose enteral vitamin E administration
in patients with acute respiratory failure.
Intensive Care Med.
1987;13:395-400.
MEDLINE
73.
Galley HF, Davies MJ, Webster NR.
Ascorbyl radical formation in patients with sepsis: effect of ascorbate
loading.
Free Radic Biol Med.
1996;20:139-143.
MEDLINE
74.
Warner BW, Hasselgren PO, Fischer JE.
Effect of allopurinol and superoxide dismutase on survival rate in rats with
sepsis.
Curr Surg.
1986;43:292-293.
MEDLINE
75.
Broner CW, Shenep JL, Stidham GL, Stokes DC, Hildner WK.
Effect of scavengers of oxygen-derived free radicals on mortality in
endotoxin-challenged mice.
Crit Care Med.
1988;16:848-851.
MEDLINE
76.
Hoffman H, Siebeck M, Welter HF, et al.
High dose superoxide dismutase potentiates respiratory failure in septicemia
[abstract].
Am Rev Respir Dis.
1987;135:78.
MEDLINE
77.
Traber DL, Adams T Jr, Sziebert L, Stein M, Traber L.
Potentiation of lung vascular response to endotoxin by superoxide dismutase.
J Appl Physiol.
1985;58:1005-1009.
MEDLINE
78.
Novotny MJ, Laughlin MH, Adams HR.
Evidence for lack of importance of oxygen-free radicals in Escherichia coli
endotoxemia in dogs.
Am J Physiol.
1988;254(pt 2):H954-H962.
MEDLINE
79.
Kelly F.
Vitamin E supplementation in the critically ill patient: too narrow a view?
Nutr Clin Pract.
1994;9:141-145.
MEDLINE
80.
Galley HF, Howdle PD, Walker BE, Webster NR.
The effects of intravenous antioxidants in patients with septic shock.
Free Radic Biol Med.
1997;23:768-774.
MEDLINE
81.
Gadek J, DeMichele SJ, Karlstad MD, et al.
Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and
antioxidants in patients with acute respiratory distress syndrome: Enteral
Nutrition in ARDS Study Group.
Crit Care Med.
1999;27:1409-1420.
MEDLINE
82.
Krysztopik RJ, Bentley FR, Spain DA, Wilson MA, Garrison RN.
Free radical scavenging by lazaroids improves renal blood flow during sepsis.
Surgery.
1996;120:657-662.
MEDLINE
83.
Krysztopik RJ, Bentley FR, Spain DA, Wilson MA, Garrison RN.
Lazaroid improves intestinal blood flow in the rat during hyperdynamic
bacteraemia.
Br J Surg.
1997;84:1717-1721.
MEDLINE
84.
Altavilla D, Squadrito F, Serrano M, et al.
Inhibition of tumour necrosis factor and reversal of endotoxin-induced shock by
U-83836E, a "second generation" lazaroid in rats.
Br J Pharmacol.
1998;124:1293-1299.
MEDLINE
85.
Wang S, Lantz RC, Vermeulen MW, et al.
Functional alterations of alveolar macrophages subjected to smoke exposure and
antioxidant lazaroids.
Toxicol Ind Health.
1999;15:464-469.
MEDLINE
86.
Nakayama M, Hasegawa N, Oka Y, Lutzke B, McCall JM, Raffin TA.
Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung
injury in minipigs.
Crit Care Med.
1998;26:538-547.
MEDLINE
87.
Allan G, Cambridge D, Lee-Tsang-Tan L, Van Way CW, Whiting MV.
The protective action of allopurinol in an experimental model of haemorrhagic
shock and reperfusion.
Br J Pharmacol.
1986;89:149-155.
MEDLINE
88.
Flynn WJ Jr, Hoover EL.
Allopurinol plus standard resuscitation preserves hepatic blood flow and
function following hemorrhagic shock.
J Trauma.
1994;37:956-961.
MEDLINE
89.
Deitch EA, Bridges W, Baker J, et al.
Hemorrhagic shock-induced bacterial translocation is reduced by xanthine
oxidase inhibition or inactivation.
Surgery.
1988;104:191-198.
MEDLINE
90.
Yamakawa Y, Takano M, Patel M, Tien N, Takada T, Bulkley GB.
Interaction of platelet activating factor, reactive oxygen species generated by
xanthine oxidase, and leukocytes in the generation of hepatic injury after
shock/resuscitation.
Ann Surg.
2000;231:387-398.
MEDLINE
91.
Kunimoto F, Morita T, Ogawa R, Fujita T.
Inhibition of lipid peroxidation improves survival rate of endotoxemic rats.
Circ Shock.
1987;21:15-22.
MEDLINE
92.
Shatney CH, Toledo-Pereyra LH, Lillehei RC.
Experiences with allopurinal in canine endotoxin shock.
Adv Shock Res.
1980;4:119-137.
MEDLINE
93.
Movahed A, Nair KG, Ashavaid TF, Kumar P.
Free radical generation and the role of allopurinol as a cardioprotective agent
during coronary artery bypass grafting surgery.
Can J Cardiol.
1996;12:138-144.
MEDLINE
94.
Castelli P, Condemi AM, Brambillasca C, et al.
Improvement of cardiac function by allopurinol in patients undergoing cardiac
surgery.
J Cardiovasc Pharmacol.
1995;25:119-125.
MEDLINE
95.
Coghlan JG, Flitter WD, Clutton SM, et al.
Allopurinol pretreatment improves postoperative recovery and reduces lipid
peroxidation in patients undergoing coronary artery bypass grafting.
J Thorac Cardiovasc Surg.
1994;107:248-256.
MEDLINE
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.