Critical Care Clinics

Volume 16 Number 2 April 2000

Copyright 2000 W. B. Saunders Company
SEPSIS AND SEPTIC SHOCK
PATHOGENESIS AND MANAGEMENT OF MULTIPLE ORGAN DYSFUNCTION
OR FAILURE IN SEVERE SEPSIS AND SEPTIC SHOCK
Robert A. Balk MD
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Department of Internal Medicine, Section of Pulmonary and Critical Care Medicine, Rush
Medical College and Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois
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Address reprint requests to
Robert A. Balk, MD
Section of Pulmonary and Critical Care Medicine
Rush-Presbyterian-St. Luke's Medical Center
1753 West Congress Parkway
Chicago, IL 60612
email: rbalk@rush.edu
Improvements in initial resuscitation efforts coupled with advancements in technological
support and knowledge of disease process have improved the survival of critically ill patients
and resulted in a relatively new disorder, multiple organ dysfunction/failure. [2] [6] [13]
These advances in supportive care coupled with longer survival time allow the critically ill
patient to develop later stages of their illness and become susceptible to the common
complications of critical illness. [6] In prior years, patients would have died much earlier in
their disease course, long before they would develop the evidence of organ dysfunction that
we now refer to as multiple organ dysfunction syndrome (MODS) or multiple organ failure
(MOF). The initial reports of MOF were in 1969. [13] It was evident that survival was
dependent on factors other than the initial disease process for which the patient was
admitted. Multiple organ dysfunction/failure is now regarded as the most common cause of
death among patients in the noncoronary critical care unit and also is a frequent cause of
morbidity, prolonged hospitalization, and increased cost of care. [2]
DEFINITION OF MULTIPLE ORGAN DYSFUNCTION SYNDROME OR MULTIPLE ORGAN
FAILURE
Unfortunately, there is not a uniformly accepted definition for MODS/MOF. [42] In addition,
there is no agreement as to the exact definition of specific organ system dysfunction or
failure. More importantly there are no data to guide the clinician in ascertaining when organ
dysfunction is reversible or when it is irreversible. In an attempt to eliminate some of the
confusion and to bring a degree of uniformity to the definitions for MODS/MOF, a Consensus
Conference was held by the American College of Chest Physicians (ACCP) and the Society of
Critical Care Medicine (SCCM). [45] The consensus conference put forward an operational
definition for multiple organ failure/dysfunction and proposed the acronym MODS for the
multiple organ dysfunction syndrome. [45] MODS was defined as the presence of altered
organ function in an acutely ill patient such that homeostasis could not be maintained
without intervention. [45] The consensus statement also reaffirmed the belief that the
dysfunction could be absolute or relative and recognized that there is a continuum of change
from dysfunction to failure (see Display Box 1 ).

Box 1. Display Box 1. ACCP/SCCM Consensus Conference Definitions
Systemic Inflammatory Response Syndrome (SIRS)
The systemic inflammatory response to a wide variety of severe clinical insults, manifested
by two or more of the following conditions:
1. Temperature > 38 C or < 36 C
2. Heart rate > 90 beats/min
3. Respiratory rate > 20 breaths/min or Pa CO2 < 32 mm Hg
4. WBC count > 12,000/mm3 , < 4000/mm3 , or > 10% immature (band) forms.
Sepsis
The systemic inflammatory response to infection. In association with infection,
manifestations of sepsis are the same as those previously defined for SIRS. It should be
determined whether they are a direct systemic response to the presence of an infectious
process and represent an acute alteration from baseline in the absence of other known
causes for such abnormalities. The clinical manifestations would include two or more of the
following conditions as a result of a documented infection:
1. Temperature > 38 C or < 36 C
2. Heart rate > 90 beats/min
3. Respiratory rate > 20 breaths/min or Pa CO2 < 32 mm Hg
4. WBC count > 12,000/mm3 , < 4000/mm3 , or > 10% immature (band) forms.
Severe Sepsis/SIRS. Sepsis (SIRS) associated with organ dysfunction,
hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may
include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental
status.
Sepsis (SIRS) Induced Hypotension. A systolic blood pressure < 90 mm Hg or a
reduction of 40 mm Hg from baseline in the absence of other causes for
hypotension.
Septic Shock/SIRS Shock. A subset of severe sepsis (SIRS) and defined as sepsis
(SIRS) induced hypotension despite adequate fluid resuscitation along with the
presence of perfusion abnormalities that may include, but are not limited to, lactic
acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic
or vasopressor agents may no longer be hypotensive by the time they manifest
hypoperfusion abnormalities or organ dysfunction, yet they would still be considered
to have septic (SIRS) shock.
Multiple Organ Dysfunction Syndrome (MODS). Presence of altered organ function in an
acutely ill patient such that homeostasis cannot be maintained without intervention.
It also was recognized that the initial injury may produce direct organ system injury or be
accompanied by hemodynamic alterations, such as hypotension and/or decreased cardiac
output, which could result in organ dysfunction/failure. [50] This condition has been termed
primary MODS. Secondary MODS is the term used to describe the onset of organ
dysfunction/failure that develops later in the course of illness and is frequently related to
shock and sepsis. [50]
INCIDENCE AND EPIDEMIOLOGY
Given the difficulties with accepted definitions, it is not surprising that the actual incidence of
MODS/MOF is unknown. In part, this uncertain incidence is related to lack of a uniformly
accepted definition, but there also is uncertainty concerning how to factor in pre-existing
organ dysfunction/failure. Major risk factors include sepsis and the systemic inflammatory
response syndrome (SIRS), shock and prolonged periods of hypotension, trauma, bowel
infarction, hepatic dysfunction, increased age, and alcohol abuse. Nonetheless, MODS/MOF
is currently recognized as a major cause of mortality in SIRS, trauma, sepsis, the acute
respiratory distress syndrome (ARDS), and other critical illnesses. [3] [20] [31] [33] [47] [51]
[60] [61]
Potential Mediators
The frequent association of MODS/MOF with sepsis, SIRS, ARDS, and other inflammatory
processes suggests that there may be a causal link to the complex pathophysiologic
processes that are characteristic of SIRS. [20] [22] [24] [37] [39] [43] [46] Recent evidence
has suggested that the SIRS response is rapidly followed in most patients by a compensatory
anti-inflammatory response syndrome (CARS), which represents the body's attempt to limit
the SIRS response so that it is not counterproductive. [10] The subsequent balance between
the proinflammatory (SIRS) and anti-inflammatory (CARS) response has been referred to as
the mixed antagonistic response syndrome or MARS. [10] Typically, this delicate balance is
difficult to achieve and there is a predominance of either the inflammatory response or the
anti-inflammatory response. When there is an excessive inflammatory reaction, organ
dysfunction is likely to ensue [10] ; when there is an excessive anti-inflammatory response,
the patient is at risk for opportunistic or secondary infections. [10] Development of
subsequent infections may serve as an additional insult to again trigger the SIRS response.
There are a variety of potential mediators for the injury process seen in sepsis and other
causes of SIRS. [10] [14] [19] [21] [22] [26] [30] [39] [41] [49] [50] [53] [59] A number of
the potential humoral, cellular, and exogenous mediators are listed below:
Potential Mediators Involved in the Pathogenesis of MODS/MOF
Potential Humoral Mediators
Complement
Products of Arachidonic Acid Metabolism
Lipoxygenase products
Cyclooxygenase products
Tumor Necrosis Factor
Interleukins (1-13)
Growth Factors
Adhesion Molecules
Platelet Activating Factor
Procoagulants
Fibronectin and Opsonins
Toxic Oxygen Free Radicals
Endogenous Opioids-Endorphins
Vasoactive Polypeptides and Amines
Bradykinin and Other Kinins
Neuroendocrine Factors
Myocardial Depressant Factor
Coagulation Factors and Their Degradation Products
Cellular Inflammatory Mediators
Polymorphonuclear Leukocytes
Monocytes/Macrophages
Platelets
Endothelial Cells
Exogenous Mediators
Endotoxin
Exotoxin and Other Toxins
The humoral mediators include components of the complement system, products of
arachidonic acid metabolism (both lipoxygenase and cyclooxygenase metabolites), tumor
necrosis factor (TNF), interleukins 1 to 15 (IL 1-15), various growth factors, adhesion
molecules, platelet activating factor (PAF), nitric oxide, procoagulants, fibronectin and
opsonins, toxic oxygen free radicals, endogenous opiods (endorphins), vasoactive
polypeptides and amines, bradykinin and other kinins, neuroendocrine factors, myocardial
depressant factor, and coagulation factors and their degradation products.
Cellular inflammatory mediators also may be involved in the production of this injury state.
Among the cellular inflammatory mediators are polymorphonuclear leukocytes (PMNLs),
monocytes and macrophages, platelets, and endothelial cells. In addition, there may be
exogenous mediators such as endotoxin, exotoxin, and other toxins that may be instrumental
in the production of organ or tissue injury. It is likely that no single mediator is the key to the
production of MODS/MOF in all settings. In fact, it is extremely probable that there are
multiple pathways that result in the organ system dysfunction/damage, and it is likely that
these pathways are operational in most patients who develop this complication of critical
illness. The fact that there is no single pathway for organ system dysfunction/failure makes
treatment extremely difficult and has generated the current enthusiasm toward defining
methods of prevention. The impact of MODS/MOF on patient outcome, resource use, and
cost of care are enormous and support the vigorous attempts to define ways to prevent and
treat organ system dysfunction/failure. [12]
Potential Pathophysiologic Mechanisms of Multiple Organ Dysfunction Syndrome/Multiple
Organ Failure
The exact pathophysiology of the development of MODS/MOF has not been completely
defined. [6] [20] It is likely that there are multiple pathways that can result in the organ
damage. In the typical clinical setting, several of these pathways are likely to be operational in
a given patient. In some cases one mechanism may be instrumental early in the course of
illness and subsequent organ function may be adversely affected through other pathways
that accompany later inflammatory cascades or hits. This chain of event has led some to
suggest that there may be multiple hits that eventually result in the development of
MODS/MOF. [50] Further injury may ensue and be fueled by a variety of mediators and the
interaction of multiple pathways. The proponents of translocation of intestinal bacteria
and/or endotoxin (see farther on), possibly as a result of intestinal ischemia or
ischemia/reperfusion, suggest that this is an extremely likely pathway for the development of
MODS/MOF. [5] [17] This hypothesis is supported by the demonstration of circulating levels
of endotoxin in the peripheral blood of critically ill patients with sepsis and SIRS. [14] Reports
of endotoxemia in these critically ill patients, even without clinical or microbiologic evidence
of infection with gram-negative organisms supports the potential role of translocation in the
production of MODS/MOF. [5] [17] [27] As previously mentioned, it is likely that multiple
pathophysiologic mechanisms and mediators may be involved in the pathogenesis of this
injury process. A number of the potential pathophysiologic mechanisms, which may act
individually or collectively in the production of organ system dysfunction, are listed below.
Potential Pathophysiologic Mechanism(s) Involved in the Production of MODS/MOF
Primary cellular injury
Inadequate tissue/organ perfusion
Hypoperfusion
Ischemia/Reperfusion
Microaggregation and/or disseminated intravascular coagulation
Diffuse endothelial cell injury
Circulating humoral factors (i.e., myocardial depressant substance)
Circulating immune/inflammatory mediators
Protein calorie malnutrition
Bacterial-toxin translocation
Defective red blood cells
Adverse effect of directed treatment or medication
Primary cellular injury may result from the direct effect of the underlying disease process or
from the direct toxicity of the systemically released mediators of the SIRS response. [20] [22]
[41] [49] There may be inadequate tissue perfusion or the maldistribution of blood flow
which contains oxygen, nutrients, and other important substrates required to support cellular
and organ function necessary to preserve the integrity of the cell or organ. [20] [22] [37]
[42] [43] [50] The maldistribution of perfusion may be the result of decreased delivery,
decreased oxygen uptake, impaired metabolism, or a combination of these factors. In the
setting of sepsis and SIRS there is commonly a decrease in the cardiac output, decreased
systemic perfusion pressure, or a selective alteration in the perfusion of an individual organ
system, which may result in hypoperfusion or ischemia of the organ system. [20] The period
of ischemia may be followed by reperfusion and oxidative injury, which may produce organ
system dysfunction/failure. [20] Tissue ischemia also may result from the microaggregation
of microthrombi composed of platelets, PMNLs, RBCs, and fibrin, which may obstruct the
small capillaries and impair the delivery of blood and substrate to the tissues. [20] [50] These
intravascular clots are similar to lesions described in experimental models of acute lung injury
and sepsis and may represent a subclinical form of disseminated intravascular coagulation
(DIC). [29] Some authors have speculated that even though adequate blood flow may reach
the various tissue beds, there may be an inability of the mitochondria or cells to take up or
use the delivered oxygen and substrate. [20] [26] The ischemic or poorly perfused intestinal
tract may have altered barrier function and give rise to translocation of intestinal bacteria and
toxins, which may further the injury state. [5] [15] [25] [58] In summary, there are a number
of mechanisms that may produce an ischemic injury, and the resultant ischemic injury may
contribute to other potential mechanisms of organ dysfunction/failure.
Another hypothesis proposes the occurrence of diffuse endothelial cell injury from elaborated
mediators of the SIRS response, such as TNF and other proinflammatory cytokines. [11] [20]
[22] [37] [39] [41] [53] This process has been proposed to explain the development of
acute lung injury and the acute respiratory distress syndrome (ARDS), which is frequently
seen in the setting of sepsis and SIRS. [20] The vascular endothelial cell injury could then
result in a permeability defect or compromise the integrity of the vascular endothelium,
leading to subsequent organ edema or compromise organ system function. [20] [22] [37]
Pinsky et al [49] have termed this process "malignant intravascular inflammation"; it may be a
common manifestation of the SIRS response.
Circulating humoral factors have been detected in some critically ill patients and may be
responsible for the development of organ system dysfunction. [20] [48] [59] One such
substance is the circulating depressant factor, called myocardial depressant factor; it has
been associated with the development of reversible biventricular failure in some patients with
septic shock. [48] [59] In this setting, there is an increase in end-diastolic volume and a
reduction in the ejection fraction, even though the stroke volume and the cardiac output may
be adequately maintained or even increased. Recent data support the involvement of TNF
and IL-1 as important contributors of myocardial depression; they likely function by causing
an increase in NO formation through the inducible form of nitric oxide synthase. [35] [48]
[59]
Critically ill patients are frequently catabolic and, thus, may be particularly at risk for the
development of protein calorie malnutrition. [1] [3] The malnutrition may compromise the
patient's immune function and the ability to mount an adequate inflammatory response
against the offending agent. Malnutrition and intestinal ischemia are both known causes of
bacterial-toxin translocation, at least in experimental animal models of injury. [1] [3] [17] It is
hypothesized that a loss of the intestinal mucosal barrier function may result from ischemia
or abnormal cell function related to mucosal cell death or injury. The terminal ileum and
cecum are large reservoirs for gram-negative bacteria and their toxic products, such as
endotoxin. These bacteria and their toxic products may then translocate through or between
the dysfunctional intestinal mucosal barrier cells and enter the mesenteric lymph system.
[17] [20] [27] [58] If they are not adequately neutralized by the mesenteric lymph nodes,
they may enter the systemic circulation or the portal circulation where they can trigger the
systemic inflammatory response and produce or amplify MODS/MOF. [17] [20] [27]
Recent reports have suggested that there are defective red blood cells with altered shapes or
rheologic properties that may predispose to plugging or obstruction of the microvasculature
and result in cellular or tissue ischemia. [20] [41] In the presence of the activated
coagulation system and endothelial abnormalities characteristic of the inflammatory state,
these altered red blood cells may further contribute to the perfusion abnormalities that may
result in MODS/MOF.
Finally, critically ill patients may have organ dysfunction that may be the result of some of the
treatments employed in the management of their illness. A frequent example is renal
dysfunction that results from use of aminoglycosides, amphotericin, or other nephrotoxic
agents. A large number of therapeutic agents and procedures have the potential to produce
undesirable adverse effects on a variety of organ systems. [16] The clinician must be aware
of these potential relationships, and the offending agents should be stopped or changed
whenever possible as part of the management strategy.
ASSESSMENT OF ORGAN FUNCTION
To date, there has been no uniform acceptance of an assessment tool for abnormal organ
function in patients with suspected MODS. A number of scoring systems and descriptive
tools have been used in clinical trials and descriptive reports, but there is no uniformity or
consistency in their assessment of organ dysfunction. [36] [40] [42] [44] [52] [61] Most of
the proposed tools use an assessment of seven major organ systems: respiratory, renal,
hepatic, central nervous system, gastrointestinal system, hematological system, and the
cardiovascular system. This variability in the assessment of specific organ function has
contributed to the confusion surrounding the terminology of MODS/MOF and to the
imprecision with which this topic is addressed in clinical trials and written reports (see
Display Box 2 ).
Some evaluation tools use aspects of severity of illness scoring systems, such as Acute
Physiology and Chronic Health Evaluation (APACHE) II. [40] [61] In other evaluation tools,
organ dysfunction is described according to the presence of a single physiologic or
biochemical abnormality, or as the need to use an organ support intervention, such as renal
replacement therapy or mechanical ventilatory support (see the article by Vincent et al
elsewhere in this issue).
MANAGEMENT OF MODS/MOF
The current management of patients with MODS/MOF is predominantly supportive. The
specific treatment is directed at identifying and treating the underlying disorder. Infection and
sepsis are common predisposing conditions for the development of MODS/MOF, and it is
imperative to investigate diligently for the presence of active infection. Frequently, it may be
necessary to use sophisticated imaging techniques and other diagnostic studies in addition to
obtaining adequate culture specimens from potential infective sources. Early administration of
appropriate, effective antibiotic therapy has been shown to be beneficial in the management
Box 2. Display Box 2. Common Clinical and Laboratory Methods to Evaluate Specific
Organ System Dysfunction
Respiratory Dysfunction has been described in a variety of ways. Among the most common
is the presence of altered oxygenation status, which may be reflected by a decreased Pa O2
/Fi O2 or the need for supplemental oxygen. The level of positive end-expiratory pressure
(PEEP) and/or the use of mechanical ventilatory support may also be used to define
respiratory dysfunction. The duration of the mechanical ventilatory support or the use of
nonconventional ventilatory support strategies may be used to distinguish the severity of the
respiratory abnormality.
Renal Dysfunction may be reflected by the serum creatinine, the urine output (especially the
presence of oliguria), or the need for renal replacement therapies (such as dialysis).
Hepatic Dysfunction may be reflected by the presence of jaundice or hyperbilirubinemia,
elevated serum transaminases, lactate dehydrogenase, or alkaline phosphatase.
Hypoalbuminemia and an elevated prothrombin time may also indicate hepatic dysfunction.
Cardiovascular Dysfunction may be manifested as hypotension, the presence of
arrhythmias, use of inotropic or vasopressor support, and elevated central venous pressure
or pulmonary capillary wedge pressure. Changes in heart rate, or cardiac arrest are also
considered to be evidence for cardiovascular dysfunction by some authors. A new concept
of the pressure adjusted heart rate has recently been introduced and is represented by the
ratio of the heart rate and mean arterial pressure.
Hematologic Dysfunction system may be reflected by thrombocytopenia, leukocytosis or
leukopenia, and the presence of a coagulopathy with an elevation of the prothrombin time,
partial thromboplastin time, fibrin degradation products, or other evidence of disseminated
intravascular coagulation. Excessive bleeding and ecchymoses are also considered in some
scoring systems as evidence of organ dysfunction.
Gastrointestinal Dysfunction may be manifest as gastrointestinal bleeding, acalculous
cholecystitis, pancreatitis, ileus, the intolerance of enteral nutritional support, intestinal
ischemia or infarction, and the development of a gastrointestinal perforation.
Neurologic Dysfunction is primarily reflected by alterations in level of consciousness and
cerebral function. Evidence of altered CNS function includes decreases in the Glascow Coma
Score, coma, obtundation, confusion, and psychosis.
Endocrine Dysfunction is less commonly included in the organ assessments. Manifestations
of endocrine dysfunction would include hyperglycemia from insulin resistance,
hypertriglyceridemia, hypoalbuminemia, weight loss, and hypercatabolism.
Immune System Dysfunction may be indicated by development of hospital-acquired
infections, pyrexia, increased leukocytosis, and alterations in immune activity.
of infected patients. [50] When necessary, effective drainage or surgical debridement should
be used.
Emphasis should be placed on prevention of MODS/MOF in the critically ill patient because
its onset has a dramatic effect on morbidity and mortality. Supportive measures for the
patient with MODS/MOF include those basic management provisions that are essential for all
critically ill patients. Pulmonary management is directed at supporting oxygenation and
ventilation. The value of early intubation and mechanical ventilatory support to reduce the
blood flow to the diaphragm and accessory muscles of respiration has been advocated by
some clinicians, but supporting data from human studies are lacking. The decision regarding
early intubation and ventilatory support needs to be weighed against the potential
complications associated with the procedure and the inability of the patients to protect their
own airways.
There is no disagreement on the importance of ensuring an adequate amount of tissue
oxygen delivery. Unfortunately, the definition of adequate has been a topic of debate and
controversy. [12] [32] [34] Whether there is an oxygen supply dependency in the setting of
critical illness has been debated and may depend on individual patient factors and the
methods used to quantify the oxygen use. Past studies performed primarily in a surgical
population demonstrated an improved survival in those patients who were managed with
strategies to increase tissue oxygen delivery. [55] Tissue oxygen delivery can be increased
using inotropic agents to increase the cardiac output or by increasing the hemoglobin with
red blood cell transfusions to increase the oxygen carrying capacity of the blood. [12] [55]
The use of inotropic and vasoactive agents may be associated with the development of
arrhythmias and even ischemia of some selected organ beds. [34] The use of packed red
blood cell transfusions to increase the oxygen carrying capacity of blood needs to be
counterbalanced by the potential risks, which include transmission of infectious agents,
immune suppression, and microcirculatory dysfunction. In blood that has been stored for
longer than 15 days in citrate phosphate dextrose adenine 1 (CPDA-1) there may be a loss of
normal red blood cell deformability with a potential for microcirculatory dysfunction. Recent
studies suggest that this previously demonstrated oxygen supply dependence may actually
reflect mathematical coupling, because this relationship was predominantly evident when the
oxygen delivery and the oxygen consumption were calculated using standard formulae. [34]
Potential toxicity has been demonstrated in some patients who were subjected to strategies
designed to greatly increase oxygen delivery by inotropic support of the cardiac output. [32]
[34] A large, prospective, randomized, controlled trial failed to demonstrate improved survival
using a therapeutic strategy designed to increase the tissue oxygen delivery to supranormal
levels. [32]
It is important to restore and maintain hemodynamic stability. The initial agent should be fluid
to ensure that the circulating intravascular volume is appropriate. There is controversy as to
which type of fluid is preferable, and a discussion of the pros and cons of crystalloid, colloid,
blood products, and volume expanders is beyond the scope of this article. If the use of
appropriate type and volume of fluid does not adequately resuscitate the patient, vasoactive
medications should be used to improve hemodynamic function and ensure adequate oxygen
delivery to the tissues. Some centers advocate the use of gastrointestinal tonometry to
assess the adequacy of mesenteric blood flow and intestinal perfusion. A persistently low
gastrointestinal intramucosal pH (pHi) and serum lactate concentration have been shown to
be associated with increased mortality and the development of MODS/MOF. [25]
The importance of early nutritional support, predominantly using the enteral route, as a
means to maintain the integrity of the intestinal mucosal barrier function and decrease the
likelihood of bacterial or toxin translocation has recently been emphasized. [27] Enteral
nutrition also supports the integrity of the upper gastrointestinal tract and may obviate the
need for other agents that are used to prevent stress-related gastrointestinal bleeding. Other
potential approaches to prevent stress-related gastrointestinal bleeding include the use of
histamine type 2 blockers and cytoprotective agents. Affected patients also are subject to all
of the potential complications that may befall the critically ill. Strategies to prevent deep vein
thrombosis and pulmonary emboli should be used unless there are specific contraindications.
The development of neuromuscular weakness recently has been recognized as a potential
complication in this group of patients and has been termed critical illness polyneuropathy or
polymyopathy. [11] The pathophysiology of critical illness polyneuropathy involves primary
axonal degeneration that likely results from proinflammatory mediators. [11] It may take up
to 3 to 6 months for the axons to sufficiently recover. These disorders may explain prolonged
ventilator dependency in some critically ill patients and may necessitate rehabilitation efforts
even after weaning or separation from ventilatory support before the patients are able to
return home and care for themselves.
PREVENTION OF MODS/MOF
Given that there is no specific therapeutic treatment, attention has turned toward the
development of strategies to prevent the development of MODS/MOF. Clinical investigations
have undertaken innovative trials aimed at blocking, neutralizing, or removing the potential
inflammatory mediators and at designing support strategies using increased tissue oxygen
delivery. [8] [9] [12] [18] [28] [32] [62] Unfortunately up to this point, none of these
approaches has been demonstrated in multicenter, prospective, randomized, controlled trials
to be effective in preventing or treating MODS/MOF in the critically ill patient. Early trials of
antiendotoxin therapy with the human and murine monoclonal antibodies against endotoxin
demonstrated a decrease in development of multiple organ dysfunction. [8] The murine
monoclonal antibody, E-5, also demonstrated increased resolution of established organ
dysfunction in the initial trials; however, a subsequent confirmatory trial failed to find a
statistical benefit to this form of treatment (Derek Angus, MD, personal communication,
1998). Some centers are investigating the use of continuous venovenous hemofiltration as a
means of removing circulating inflammatory mediators [18] ; however, recent concern has
emerged related to the potential for this technique to remove the inflammatory as well as the
anti-inflammatory mediators. Studies are ongoing in an attempt to define the role, if any, of
antimediator therapy in the management of patients with MODS/MOF.
Prevention has been investigated using the expensive technique of selective digestive
decontamination, which couples topical and systemic antimicrobial therapy in an attempt to
decrease the development of nosocomial infections and the complications associated with
their development. The true benefit of this technique remains to be established. Data have
demonstrated prevention of acute respiratory distress syndrome using the thromboxane
synthetase inhibitor, ketoconazole, in surgical patients who have increased risk for the
development of MODS/MOF. [56]
The activation of the coagulation system and the potential of microthrombi to obstruct the
blood flow to vital tissues is currently under evaluation using antithrombin III, activated
protein C, and tissue factor pathway inhibitor infusions. [23] Antithrombin III has been shown
to improve the oxygenation index (Pa O2 /Fi O2 ratio) in critically ill patients who were found
to have less than 70% antithrombin III activity at baseline. [38] Eisele et al [23] analyzed
several studies of critically ill patients with sepsis or after trauma and reported that there was
less organ dysfunction in the patients who had received antithrombin III infusions compared
with those treated with placebo. The beneficial value of this therapeutic approach awaits the
completion of prospective, randomized, placebo-controlled trials, which are currently
underway.
PROGNOSIS
The development of MODS/MOF in a critically ill patient has been associated with a high risk
for morbidity and mortality. [2] The onset of organ dysfunction has been heralded as a bad
prognostic sign and has been referred to as the major cause of death in most noncoronary
intensive care units. [2] The risk for death increases with the number of organ systems failing
and the duration of the failure. [39] Studies also have demonstrated that there is a higher risk
of mortality associated with some specific organ systems when they become dysfunctional or
fail. Included in the list of organs with a high rate of mortality when they fail are the brain,
liver, lung, and kidney. [9] [16] [54] [57] Specific scoring systems have been used to quantify
the level of organ dysfunction and have been primarily used in the evaluation of various
investigational agents. The use of a MODS score has been proposed as a prognostic index.
As demonstrated in Figure 1 (Figure Not Available) , there is an increase in mortality as the
MODS score increases. [43] Until we have the ability to provide specific therapy for the
treatment of organ dysfunction/failure, rather than just support, we must focus our attention
primarily on prevention. It is hoped that in the near future we will have specific forms of
therapy in our clinical armamentarium to allow for improved outcomes in these critically ill
patients.
Figure 1. (Figure Not Available) Aggregate multiple organ dysfunction score and mortality. (
From Marshall JC, Cook DJ, Christou NV, et al: Multiple Organ Dysfunction Score: A reliable
descriptor of a complex clinical outcome. Crit Care Med 23:1638-1652, 1995; with
permission.)