Antioxidants in Critical Illness
Author Information
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#aainfo> 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
SRV1000
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
<http://archsurg.ama-assn.org/issues/v136n10/fig_tab/srv1000_f1.html> ).
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 kappaB (NF-kappaB), has been induced by hydrogen peroxide and
blocked by several antioxidants, including vitamin E. 1
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r1> , 2
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r2> Nuclear factor
kappaB 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r3> Nuclear factor
kappaB has been demonstrated as an important mediator in the signal
transduction for both endotoxin and inflammatory cytokine-induced
activation. 3 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r3> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r4> In addition,
several inflammatory genes have promotor sites for AP-1, although its role
in inflammatory signaling remains less well documented than NF-kappaB. 4
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r4> 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 arrowuric 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 (beta-carotene), glutathione, superoxide dismutase and catalase,
bilirubin, urate, and other plasma proteins. These antioxidants can be
divided into enzymatic and nonenzymatic groups ( Table 1
<http://archsurg.ama-assn.org/issues/v136n10/fig_tab/srv1000_t1.html> ). 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 beta-carotene) and the water-soluble vitamins (vitamin C
and glutathione). Vitamin E has been described as the major chain-breaking
antioxidant in humans. 7
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r7> Vitamin E is a
generic term encompassing a collection of tocopherols and tocotrienols
obtained from plant oils. The most biologically active form is
alpha-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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r8> , 9
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r9> (p371) 10-12
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r10> 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. beta-Carotene is found
in a variety of fruits and vegetables, and it provides approximately 25% of
the vitamin A in Western diets. Dietary beta-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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r13> 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
<http://archsurg.ama-assn.org/issues/v136n10/fig_tab/srv1000_f2.html> ). 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
<http://archsurg.ama-assn.org/issues/v136n10/fig_tab/srv1000_f2.html> . Both
vitamin C and GSH have been implicated in the recycling of alpha-tocopherol
radicals. 9 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r9> (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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r14> 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.
EVIDENCE OF OXIDATIVE STRESS IN CRITICAL ILLNESS
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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r15>
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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r17> Measurement of
antioxidant defenses has consistently demonstrated depressed plasma levels
of vitamins E and C in patients with sepsis and ARDS. 15-17
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r15> , 20-23
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r20> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r24> 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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r19>
, 25-27 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r25>
A recently developed assay measuring total serum antioxidant status has also
been applied to several populations of critically ill patients. 28
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r28> , 32
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r32> 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.
ANTIOXIDANT THERAPY
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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r33>
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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r34>
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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r35>
Use of NAC in animal models of ischemia and reperfusion injury and ARDS has
demonstrated encouraging results. 36-45
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r36> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r37> , 42
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r42> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r46>
Based on the encouraging results in animal studies, several human trials of
NAC for the treatment of ARDS have been completed. 26
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r26> , 47-49
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r47> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r50> , 51
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r51> Clinical trials to
demonstrate benefit in patients with ARDS, however, have had equivocal
results. Jepsen et al, 47
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r47> 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 al 49
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r49> were unable to
demonstrate any change in outcome parameters for patients with established
ARDS. 49 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r49> However,
Suter et al, 26 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r26> 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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r48> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r52> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r53> , 54
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r54> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r55> 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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r56>
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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r57> , 58
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r58>
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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r59> 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 alpha-tocopherol levels fall steadily and dramatically in
the first 24 hours following endotoxin infusion or cecal ligation and
puncture. 60 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r60> , 61
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r61> Several
investigators have demonstrated improved survival following alpha-tocopherol
treatment in these animal models of sepsis. 62-64
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r62> In addition,
alpha-tocopherol treatment in animals with sepsis has been shown to decrease
hepatic lipid peroxidation, attenuate disseminated intravascular
coagulation, and reduce plasma lactate levels. 63
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r63> , 65
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r65> , 66
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r66> Additional models
of excessive inflammation in which alpha-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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r67> In the liver
ischemia-reperfusion study, the alpha-tocopherol–treated group demonstrated
decreased lipid peroxidation, enhanced adenosine triphosphate generation,
increased survival, and attenuation of hepatic damage. 68
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r68> In a model of
renal warm ischemia, alpha-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 alpha-tocopherol. 69
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r69> In the case of
zymosan-induced peritonitis, administration of alpha-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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r67> This attenuation
of pulmonary injury may be due to the marked inhibition of the alveolar
macrophage proinflammatory response, which we have demonstrated following
enteral alpha-tocopherol supplementation. 70
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r70>
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
alpha-tocopherol for 8 weeks. 71
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r71> Their monocytes
were then harvested and found to have significantly suppressed responses to
endotoxin, including decreased ROI production during the respiratory burst,
decreased IL-1beta 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r72> In this study,
serum alpha-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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r21> , 23
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r23> , 24
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r24> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r73> 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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r73>
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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r74> , 76
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r76> but when
administered after sepsis, it has been established that it may be harmful.
76 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r76> , 77
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r77> 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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r78>
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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r79> Two clinical
trials have investigated this approach. Galley et al 80
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r80> administered a
combination of NAC, vitamin C, and alpha-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 beta-carotene in patients with ARDS. 81
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r81> 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 omega-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
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r82> 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
<http://archsurg.ama-assn.org/issues/v136n10/fig_tab/srv1000_f1.html> ).
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 models 87-90 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r87>
; however, the results in sepsis models have been variable. 91
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r91> , 92
<http://archsurg.ama-assn.org/issues/v136n10/rfull/#r92> 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 <http://archsurg.ama-assn.org/issues/v136n10/rfull/#r93> Based on
these data, studies in patients undergoing resuscitation for hemmorhagic
shock are warranted.
SUMMARY
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] <mailto:[log in to unmask]> ).
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Diplomat American Board of Palliative Medicine.
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