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8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 1
13 MULTIPLE ORGAN DYSFUNCTION
SYNDROME
John C. Marshall M.D., F.A.C.S., F.R.C.S.C.
Approach to Multiple Organ Dysfunction Syndrome
The multiple organ dysfunction syndrome (MODS)—also In general terms, the dysfunction of a given organ system can
known as progressive systems failure,1 multiple organ failure,2 be described in one of three ways:
and multiple system organ failure3—is characterized by progres-
1. As a physiologic derangement (e.g., an altered ratio of arteri-
sive but potentially reversible physiologic dysfunction of two or
al oxygen tension [PaO2] to fractional inspiration of oxygen
more organ systems that arises after resuscitation from an acute
[FIO2] or an altered platelet count).
life-threatening event. The term MODS was introduced by a
2. As the clinical intervention used to correct that derangement
1991 consensus conference of the American College of Chest
(e.g., mechanical ventilation or blood component replace-
Physicians (ACCP) and the Society of Critical Care Medicine
ment therapy).
(SCCM).4 The designation of MODS as a syndrome emphasizes
3. As a discrete clinical syndrome incorporating several descrip-
that dynamic alterations in physiologic function in critically ill
tive variables (e.g., acute respiratory distress syndrome
patients may have common pathophysiologic underpinnings.
[ARDS] or disseminated intravascular coagulation [DIC]).
However, MODS is as much a paradigm as a syndrome—that is,
it represents an approach to the care of the critically ill patient Whichever of these three perspectives is adopted, common
that emphasizes intensive monitoring and support of organ sys- pathogenetic mechanisms underlie MODS, and common prin-
tem function over specific therapies for isolated disease process- ciples direct its prevention and management.
es and that focuses on preventing or minimizing iatrogenic injury
RESPIRATORY DYSFUNCTION
resulting from ICU interventions.
MODS evolves in the wake of a profound disruption of sys- ARDS, initially described in the early 1960s,13,14 is the proto-
temic homeostasis.5,6 It was originally described in patients with typical expression of respiratory dysfunction in MODS.15 In its
overwhelming infection, multiple injuries, or tissue ischemia;
however, it has many overlapping risk factors [see Table 1]. Table 1 Risk Factors for MODS
Preexisting illness—in particular, chronic alcohol abuse7—pre-
disposes to the development of organ dysfunction in patients
Peritonitis and intra-abdominal infections
exposed to these risk factors.
Infection Pneumonia
Necrotizing soft tissue infections
Clinical Definitions of
Inflammation Pancreatitis
Organ Dysfunction
Although MODS is readily Injury
Multiple trauma
recognized by experienced Burn injury
clinicians, there is still no clear
Ruptured aneurysm
consensus on its description
Ischemia Hypovolemic shock
with respect to either the sys-
Mesenteric ischemia
tems whose function is
deranged, the descriptors that Autoimmune disease
best measure that derangement, or the degree of derangement Immune reactions Transplant rejection
that constitutes organ dysfunction or failure. Graft versus host disease
A systematic review of 30 published clinical studies evaluated
the organ systems and variables used to describe MODS.8 Seven Delayed or missed injury
organ systems—the respiratory system (all 30 reports), the renal Blood transfusion
Iatrogenic factors
system (29 reports), the hepatic system (27 reports), the cardio- Injurious mechanical ventilation
vascular system (25 reports), the hematologic system (23 Total parenteral nutrition
reports), the GI system (22 reports), and the CNS (18
Drug reactions
reports)—were included in at least half of the studies. Scoring
Intoxication Arsenic intoxication
systems from both North America9,10 and Europe11,12 define
Drug overdose
MODS using six of these seven organ systems, eliminating the
GI system because of the declining prevalence of stress-related Thrombotic thrombocytopenic purpura
upper GI bleeding and the lack of satisfactory measures of GI Idiopathic factors Hypoadrenalism
dysfunction. These scoring systems have many similarities [see Pheochromocytoma
Table 2].

2. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 2
Recognize susceptible patient
Patients at high risk for multiple organ dysfunction syndrome
(MODS) are those who have experienced a disruption of systemic
homeostasis resulting from one or more of the following:
Approach to Multiple Organ • Infection • Immune system activation
• Inflammation • Intoxication
Dysfunction Syndrome • Injury • Iatrogenic factors
• Ischemia
Minimal organ dysfunction
Prevent progression to MODS by optimizing support of hemodynamic,
metabolic, and immunologic function, taking care to minimize iatrogenic
injury during the provision of physiologic support.
Hemodynamic support
Maximize O2 delivery to tissues by the following measures:
• Fluid replacement therapy • Vasoactive agents
• Inotropic agents • Mechanical ventilation
Metabolic support
Reverse catabolic state with definitive intervention, including
the following:
• Debridement of devitalized tissue • Fixation of long bone
• Burn wound excision and grafting fractures
Provide early nutritional support by the enteral route. If gut function is
inadequate, parenteral nutrition should be employed.
Immunologic support
Prevent nosocomial infection, treat documented infection, and
minimize the consequences of injurious host defense responses by such
measures as the following:
• Timely and appropriate surgical intervention
• Limiting breaches of mucosal defenses
• Selective, targeted use of antibiotics
Organ function is preserved or restored Organ function deteriorates
Patient survives. Discharge patient from ICU.

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8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 3
Define prevalence, sites, and severity of organ dysfunction
Organ dysfunction involves essentially any organ system but is
classically identified in the respiratory, renal, cardiovascular, hepatic,
hematologic, GI, and neurologic systems. It can be defined as a
physiologic derangement, as the clinical support provided, or as a
clinical syndrome comprising several abnormalities. Aggregate
severity can be quantified by using readily available scores.
Significant organ dysfunction
Characterize physiologic derangement and institute supportive
therapy.
Single organ dysfunction Multiple organ dysfunction
Search for correctable causes, including the following: Search for correctable causes, including the following:
• Exacerbation of preexisting chronic disease • Occult infection • Adverse effects of medical therapy (e.g.,
• Complications from invasive devices and medications • Missed injuries transfusions, total parenteral nutrition)
• Local complications (e.g., fluid overload, pneumothorax,
biliary tract obstruction)
• Local pathology (e.g., myocardial infarction, pulmonary
embolism, pneumonia)
Modify supportive care
Minimize adverse consequences of supportive care through use of techniques
such as pressure-limited ventilation and continuous hemodialysis. Manage
infectious complications with local measures and sparing use of antimicrobial
agents. Evaluate need for antibiotic therapy or surgical intervention.
Antibiotic therapy Surgical intervention Adjuvant therapy
• Sparing use of empirical antibiotic therapy Prepare patient for operation: Consider use of adjuvant therapies
• Microbiologic diagnosis is usually possible • Preoperative optimization of physiologic function directed against coagulopathy
• If organism cannot be isolated, discontinue • Safe, well-organized transport to OR (activated protein C) or acute adrenal
antibiotics and repeat cultures • Surgical intervention in ICU when appropriate insufficiency (corticosteroids).
and feasible
Reevaluate clinical status
MODS resolves, and patient’s condition improves MODS persists, and patient’s condition deteriorates
or fails to improve despite support and in the absence
Transfer patient from ICU. of correctable underlying disease
Probability of death is high. Consider withdrawal of life
support.

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8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 4
Table 2 Multiple Organ Dysfunction (MOD) Score9
Degree of Dysfunction
Organ System Indicator of
Dysfunction None Minimal Mild Moderate Severe
(0) (1) (2) (3) (4)
Respiratory PaO2/FIO2 ratio > 300 226–300 151–225 76–150 ≤ 75
Renal Serum creatinine level ≤ 100 µmol/L 101–200 µmol/L 201–350 µmol/L 351–500 µmol/L > 500 µmol/L
Hepatic Serum bilirubin level ≤ 20 µmol/L 21–60 µmol/L 61–120 µmol/L 121–240 µmol/L > 240 µmol/L
Cardiovascular Pressure-adjusted HR* < 10.0 10.1–15.0 15.1–20.0 20.1–30.0 > 30.0
3
Hematologic Platelet count > 120,000/mm3 81,000–120,000/mm3 51,000–80,000/mm 21,000–50,000/mm3 ≤ 20,000/mm3
Glasgow Coma Scale 15 13–14 10–12 7–9 ≤6
Neurologic
score
*Calculated as the product of HR and central venous pressure (CVP), divided by mean arterial pressure (MAP): (HR · CVP)/MAP.
mildest form, respiratory dysfunction is characterized by tachyp- but supportive care, in the form of dialysis, did not become avail-
nea, hypocapnia, and hypoxemia. As lung injury evolves, a com- able until the 1950s.
bination of worsening hypoxemia and increased work of breath- Clinical or subclinical renal dysfunction is common in
ing necessitates mechanical ventilatory support [see 8:6 Me- MODS. Early-onset renal dysfunction typically results from
chanical Ventilator]. hypotension and decreased renal blood flow.The etiology of late-
Increased capillary permeability and neutrophil influx are the onset renal failure is multifactorial and includes both pre-
earliest pathologic events in ARDS. As the acute inflammatory renal factors (e.g., decreased cardiac output and hypovolemia)
process resolves, further lung injury results both from the and the cumulative renal effects of nephrotoxic agents (e.g.,
process of repair, which involves fibrosis and the deposition of medications and radiocontrast material).24 Intrarenal vasocon-
hyaline material, and from further lung trauma, resulting from striction results in a reduction in the glomerular filtration rate,
positive pressure mechanical ventilation.16 hypoxic or oxidative injury to tubular epithelial cells, and des-
Lung involvement in ARDS is inhomogeneous, with areas of quamation of injured cells into the tubules, causing leakage of fil-
functional and aerated alveoli interspersed with areas of non- trate back into the renal interstitium and evoking neutrophil-
functional alveoli.17 The distribution of injury reflects the seque- mediated inflammation that causes further local tissue injury.25
lae of care in the intensive care unit: consolidation occurs in the Intrarenal shunting of blood flow, coupled with occlusion of the
posterior dependent regions of the lung, and cystic changes renal microvasculature by thrombi or aggregated blood cells, fur-
develop from overdistention by the ventilator in the antidepen- ther contributes to ischemia and physiologic dysfunction. The
dent regions.18 situation may be further aggravated by renal circulatory changes
Impaired lung function is reflected in a reduced PaO2. To resulting from vasoactive agents administered to treat shock and
ensure adequate oxygen delivery to the tissues, mechanical ven- by increased intra-abdominal pressure consequent to massive
tilation must be instituted and FIO2 increased. The ratio of PaO2 fluid resuscitation. Histologic studies show acute tubular necro-
to FIO2, therefore, provides a sensitive and objective measure- sis with disruption of the basement membrane, patchy necrosis
ment of the degree to which oxygenation is impaired and so is a of the renal tubules, interstitial edema, and tubular casts; these
reliable measure of physiologic respiratory dysfunction.19 microscopic changes correlate poorly with functional impair-
Mechanical ventilation reflects the clinical intervention triggered ment.26 Activated neutrophils have also been implicated in the
by impaired oxygenation, and the additional criteria for ARDS— pathogenesis of ARF,27,28 as has the induction of apoptosis in
bilateral lung infiltrates and a normal pulmonary capillary wedge renal epithelial cells.29
pressure—serve to exclude such primary causes of acute hypox- Renal dysfunction in MODS is reflected physiologically in a
emia as pulmonary embolism, atelectasis, and congestive heart decreased urine output, biochemically in a rising serum creati-
failure. By consensus, ARDS is defined as a PaO2/ FIO2 ratio lower nine level, and therapeutically as the introduction of exogenous
than 200 mm Hg in association with bilateral fluffy pulmonary renal replacement therapy or dialysis.
infiltrates and a pulmonary capillary wedge pressure lower than
HEPATIC DYSFUNCTION
18 mm Hg.20
ARDS is a robust model for the complex interactions that Hepatic dysfunction after trauma, like ARF, was first
result in MODS. Lung injury in ARDS is the outcome of an described during World War II [see 8:9 Hepatic Failure].30 Two
interaction between an insult, a susceptible host, and the clinical clinical syndromes have been described. The first, ischemic
therapeutic response, and its severity reflects not only the degree hepatitis, or shock liver, characteristically follows an episode of
of the initial insult but also various poorly defined genetic influ- profound hypotension with splanchnic hypoperfusion. Early ele-
ences in the host21 and the inadvertent adverse consequences of vations of aminotransferase levels are striking and may be asso-
the mode of respiratory support employed.22 ciated with an increased international normalized ratio and
hypoglycemia; centrilobular necrosis is evident histologically.
RENAL DYSFUNCTION
Successful resuscitation of the shock state results in rapid nor-
Acute renal failure (ARF) [see 8:7 Renal Failure] was first malization of the biochemical abnormalities.31 The second syn-
described as a significant clinical problem during World War II,23 drome, ICU jaundice, is much more common than ischemic

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8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 5
HEMATOLOGIC DYSFUNCTION
hepatitis and typically evolves many days after the inciting phys-
iologic insult. Conjugated hyperbilirubinemia is a prominent The most common hematologic abnormality of critical illness
feature, whereas elevation of aminotransferase levels and alter- is thrombocytopenia, which occurs in approximately 20% of all
ations of hepatic synthetic function are less pronounced.32 ICU admissions.46,47 Causes include increased consumption,
Histologic features include intrahepatic cholestasis, steatosis, intravascular sequestration, and impaired thrombopoiesis sec-
and Kupffer cell hyperplasia. The pathogenesis is multifactorial ondary to suppression of bone marrow function. In addition,
and includes ongoing hepatic ischemia, total parenteral nutrition heparin-induced thrombocytopenia resulting from antibodies to
(TPN)–induced cholestasis, and drug toxicity. complexes of heparin and platelet factor 4 develops in as many
An increased serum bilirubin level is the most commonly rec- as 10% of patients receiving heparin.48 The most fulminant
ognized feature of the hepatic dysfunction of MODS. Although expression of hematologic dysfunction in MODS is DIC, which
extracorporeal support devices have been used for patients with is characterized by derangements in platelet numbers and clot-
end-stage liver disease, the hepatic dysfunction of critical illness ting times and the presence of fibrin degradation products in
is not considered to be life-threatening in itself, and no specific plasma.49 The coagulopathy of critical illness is complex, involv-
supportive therapy is indicated. ing multiple alterations in the biochemical mediators of coagu-
lation and resulting in a shift to a procoagulant state.50
CARDIOVASCULAR DYSFUNCTION
Mild anemia is common in critical illness, though the nature
Both peripheral vascular and myocardial function are altered of abnormalities in red cell production and removal are less well
in MODS. Characteristic changes in the peripheral vasculature characterized in this setting.51 Transient leukopenia may develop
include a reduction in vascular resistance and an increase in in response to an overwhelming inflammatory stimulus, but neu-
microvascular permeability, resulting in a hyperdynamic circula- trophilia is much more commonly encountered; total lympho-
tory profile and peripheral edema. Both alterations jeopardize tis- cyte counts are reduced. Abnormalities in white cell populations
sue oxygenation—reduced vascular resistance by facilitating reflect, at least in part, altered expression of apoptosis, which is
shunting in the microvasculature and edema by increasing the inhibited in the neutrophil52 but accelerated in lymphoid cells.53
distance across which oxygen carried in the blood must diffuse to
GASTROINTESTINAL DYSFUNCTION
reach the cell. Shunting also occurs as a result of occlusion of the
microvasculature by thrombi and aggregates of nondeformable Upper GI hemorrhage after burn injury was first described by
red cells33; it is signaled by a reduction in arteriovenous oxygen Curling in 1842.54 Stress bleeding was once a relatively common
extraction and an increase in mixed venous oxygen saturation complication, but improved techniques of resuscitation and
(SmvO2). Biventricular dilatation with a reduction in the right and hemodynamic support, earlier diagnosis of infection, and the
left ventricular ejection fractions has been described.34 Right ven- widespread use of stress ulcer prophylaxis have reduced the fre-
tricular dysfunction is particularly prominent, perhaps as a con- quency of this event, to the point where it now is seen in fewer
sequence of increased pulmonary vascular resistance secondary than 4% of ICU admissions.55 Other manifestations of GI dys-
to concomitant lung injury.35 Finally, a loss of normal heart rate function in MODS include ileus and intolerance of enteral feed-
variability characterizes advanced cardiovascular dysfunction.36 ing,56,57 pancreatitis,58 and acalculous cholecystitis.59
The cardiovascular dysfunction of MODS is apparent clini-
OTHER ORGAN SYSTEM DYSFUNCTION
cally as increased peripheral edema with hypotension that is
refractory to volume challenge and therapeutically in the use of MODS is associated with functional abnormalities of virtually
vasoactive agents to support the circulation. Nitric oxide (NO) every organ system. Endocrine abnormalities include impaired
has been implicated in both the peripheral vasodilatation37 and glucose regulation with hyperglycemia and insulin resistance60
the myocardial depression38 associated with critical illness. and hypercortisolemia with impaired responsiveness to adreno-
corticotropic hormone (ACTH) stimulation.61,62 The sick euthy-
NEUROLOGIC DYSFUNCTION
roid syndrome, characterized by reductions in serum T3, with or
Abnormalities of both central and peripheral nervous system without an increase in reverse T3 levels and a normal T4 level, is
function are common in critical illness. CNS dysfunction occurs in another manifestation of the endocrine dysfunction of MODS.63
as many as 70% of critically ill patients, typically presenting as a Numerous derangements of immune function have been
reduced level of consciousness without localizing signs. Its patho- described in MODS patients. Cell-mediated immunity is im-
physiology is incompletely understood. Postulated mechanisms paired, as reflected by anergy to delayed hypersensitivity recall
include the direct effects of proinflammatory mediators on cerebral skin testing64 and impaired in vitro lymphocyte proliferative re-
function, the development of vasogenic cerebral edema, areas of sponses.65 The development of ICU-acquired infections caused
cerebral infarction related to hypotension, and alterations in the by organisms of low intrinsic virulence can also be considered a
blood-brain barrier resulting in changes in the composition of the manifestation of impaired immunity in MODS.66
interstitial fluid.39 Electroencephalography typically shows one of Abnormal wound healing also occurs in MODS. Common
four patterns indicating increasingly abnormal activity: diffuse manifestations of impaired wound healing are the failure of an
theta wave rhythms, intermittent rhythmic delta waves, triphasic open wound to develop satisfactory granulation tissue and the
delta waves, and suppression or burst-suppression patterns.39 development of decubitus ulcers.67
Peripheral nervous system dysfunction, also known as critical
illness polyneuropathy, is also common in MODS, though its
clinical presentation tends to be more subtle than that of CNS Quantification of Organ Dysfunction
dysfunction.40-42 Peripheral nervous system dysfunction may pre- Physiologic instability is the major indication for ICU admis-
sent as failure of weaning from mechanical ventilation43 or as limb sion, and support of failing organ function is the ICU’s raison
weakness with relative sparing of the cranial nerves. Endoneural d’être. The degree of physiologic derangement present at the
edema and axonal hypoxia44 contribute to its pathogenesis, as do time of ICU admission is a potent determinant of ICU sur-
the iatrogenic sequelae of neuromuscular blockade.45 vival,68,69 and irreversible organ dysfunction is the preeminent

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8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 6
100
scores).77 Alternatively, the aggregate severity of organ dysfunc-
tion over time can be quantified by summing the worst values
over time in each of the component systems. Such an approach
80
permits quantitation of attributable ICU morbidity as the differ-
28-Day Mortality (%)
ence between the aggregate score and the score at baseline—thus
identifying that component of ICU morbidity that can be pre-
60
vented by an effective ICU intervention. Finally, morbidity and
mortality can be combined into a single value by using a mor-
40
tality-adjusted score that assigns a maximum number of points
plus 1 to any patient who dies [see Table 3].
20
Prevention of Organ
Dysfunction in Critically
Ill Patients
0
0 1–2 3–4 5–6 7–8 9–10 11–12 13–14 15–16 17–18 19–20 21+ Acute organ dysfunction is
Baseline MOD Score
the most common indication
for admission to an ICU, and
Figure 1 Increasing severity of organ dysfunction is directly any patient with significant
correlated with increasing ICU mortality. physiologic instability is at risk
for MODS. A number of risk
mode of ICU death.6,70 Formal quantification of the severity of factors for the development of organ dysfunction have been iden-
physiologic derangement or of the evolution of organ dysfunc- tified [see Table 1]: these reflect a common pathogenesis for the
tion over time is not generally incorporated into individual syndrome through the activation of an innate immune response to
patient care in the ICU. However, validated scoring systems have tissue injury.
proved invaluable in describing patient populations, stratifying The first priority for optimal ICU care is to halt the progression
patients for entry into clinical trials, and assessing ICU morbid- of existing organ dysfunction while preventing the development of
ity in patient groups. new organ dysfunction. Prevention of organ dysfunction is perhaps
There are a number of published systems for quantifying the best approached from the perspective of optimization of hemody-
severity of organ dysfunction in the critically ill.9,10,12.66,71-74 These namic, metabolic, and immune homeostasis. There are a number
systems are all structurally similar, evaluating dysfunction in each of interventions for which level 1 evidence of efficacy in reducing
of six or seven organ systems on a numerical scale in which more mortality or preventing organ dysfunction exists [see Table 4].
points are assigned for greater degrees of physiologic severity;
they vary primarily with respect to the variables used to describe OPTIMIZING HEMODYNAMIC HOMEOSTASIS
dysfunction. A representative example of such a scoring system is The ability of the heart to pump blood is determined by (1) the
the Multiple Organ Dysfunction (MOD) score [see Table 2].9 preload delivered to the right atrium, (2) the intrinsic contractility
The numerical scores can be obtained and applied in a vari- of the myocardium, and (3) the afterload against which the heart
ety of ways.75 Scores can be calculated on the day of ICU admis- must work—all of which may be deranged in critical illness. First,
sion or at the start of the institution of a novel therapy during the reduction of intravascular volume as a consequence of hemor-
ICU stay; such scores provide a measure of baseline illness sever- rhage, third-space loss, and increased microvascular permeability
ity and correlate in a graded manner with the risk of ICU mor- reduces preload. Second, circulating mediators and NO depress
tality [see Figure 1]. Scores can also be calculated daily, allowing myocardial contractility and thus impair the heart’s intrinsic
the clinician to track net clinical improvement or deterioration pumping ability. Third, reduced vascular tone, mediated by NO,
over time76 and to assess the progression or resolution of organ reduces afterload. The first two abnormalities reduce cardiac out-
dysfunction (expressed as the area under the curve for the daily put; the third increases it but may, by altering resistance gradients
Table 3 Approaches to Measuring Severity of MODS75
Objective Approach Uses
To quantify baseline severity of Calculate organ dysfunction score on day of admission To establish baseline severity (e.g., for entry criteria for a
organ dysfunction (admission MODS) clinical trial) or to ensure comparability of study groups
To quantify severity of organ To determine intensity of resource utilization or evolution or
Calculate score on particular ICU day (daily MODS)
dysfunction at point in time resolution of organ dysfunction at discrete point in time
To measure aggregate severity of Sum individual worst scores for each organ system over To determine severity of physiologic derangement over
organ dysfunction over ICU stay defined time interval (aggregate MODS) defined time interval (e.g., ICU stay)
To quantify new organ dysfunction Calculate difference between aggregate and admission To measure organ dysfunction attributable to events occur-
arising after ICU admission scores (delta MODS) ring after ICU admission
To provide combined measure of Adjust aggregate score so that all patients dying receive To create single measure that integrates impact of morbidity
morbidity and mortality maximal number of points (mortality-adjusted MODS) in survivors and mortality for nonsurvivors

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8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 7
Table 4 ICU Interventions That Reduce intrinsic myocardial dysfunction can all alter the pressure at
which optimal preload is obtained.
Mortality or Attenuate Organ Dysfunction In practice, resuscitation should be titrated to optimize the
balance between several parameters rather than targeting any one
Objective Intervention parameter. It is sobering to recognize that current sophisticated
approaches to resuscitation using the pulmonary arterial catheter
Resuscitation Early goal-directed resuscitation243
have not been shown to yield net clinical benefit and may, in fact,
Prophylaxis Selective digestive tract decontamination90 cause harm [see 8:4 Cardiopulmonary Monitoring].82
Hemodynamic resuscitation is most effective when it is early
Restrictive transfusion strategy107 and rapid. A randomized trial of goal-directed therapy for sep-
Low tidal volume ventilation22 sis, using a protocol comprising fluid administration, transfu-
ICU support Daily wakening144 sion, and vasoactive support titrated to SmvO2 as measured from
Tight glucose control60
the superior vena cava through a central venous catheter, found
Enteral feeding86
that mortality was reduced from 46.5% to 30.5% when patients
Activated protein C146 were resuscitated according to protocol in the emergency
Mediator-targeted therapy Corticosteroids148 department within hours of their initial presentation. On the
Antibody to TNF244 other hand, studies of goal-directed therapy initiated in the ICU
have generally failed to demonstrate any evidence of benefit.83,84
Optimization of oxygen delivery presupposes the ability to
in the microvasculature, alter nutrient flow to the tissues. oxygenate blood adequately in the lungs. Increased pulmonary
The first priority in supporting cardiovascular homeostasis, capillary permeability, atelectasis, altered consciousness, and
therefore, is to restore intravascular volume by administering flu- intrinsic lung disease can all reduce oxygen uptake in acutely ill
ids.There is no convincing evidence that any particular resuscita- patients. Support can be provided through the administration of
tion fluid is superior in all patients, though crystalloid is associat- oxygen to the spontaneously breathing patient, through the use
ed with a lower mortality in trauma patients.78 Either normal of positive pressure ventilation by mask, or through endotracheal
saline or lactated Ringer solution is an appropriate choice. The intubation and mechanical ventilation. Positive pressure ventila-
volume of fluid needed to restore optimal preload may be signifi- tion can cause further lung injury, however, particularly when
cant, reflecting not only acute losses but also the effective expan- the lung has been rendered vulnerable by early acute lung injury.
sion of the vascular compartment because of vasodilatation and Limiting tidal volume during mechanical ventilation to 6 ml/kg
the loss of fluids into the extravascular compartment because of has been shown to improve survival in patients with early
increased capillary permeability. Blood loss should be corrected ARDS.22
by transfusing red cells, preferably in fresh, leukocyte-depleted
OPTIMIZING METABOLIC
blood. When hypotension is refractory to fluid administration,
HOMEOSTASIS
vasoactive agents, including vasopressors (e.g., dopamine and
norepinephrine) and inotropes (e.g., dobutamine, epinephrine, The acute response to
and amrinone) may help increase blood flow to the tissues.79 stress and injury is a complex,
Given that the goal of hemodynamic stabilization is to sup- coordinated process charac-
port organ function rather than to restore physiologic or bio- terized by increases in levels
chemical normalcy, the best measures of the success of resusci- of catecholamines, glucocorti-
tation are those that reflect either return of function (in particu- coids, antidiuretic hormone,
lar, urine output) or adequate blood flow to the tissues (e.g., and hormones that regulate
SmvO2 or lactate concentration). Each of these measures, howev- intermediary metabolism, including insulin, glucagon, and
er, has shortcomings of which the clinician must be aware. Urine growth hormone [see 8:25 Metabolic Response to Critical Illness].6
output may be decreased because of intrinsic renal damage even The activation of this response results in a predictable series of
in the face of adequate renal flow. SmvO2 may be artefactually metabolic alterations, including retention of salt and water,
high because of shunting and abnormalities of oxygen uptake in increased production of glucose, enhanced lipolysis, increased
the microvasculature. Lactate concentration is relatively insensi- protein catabolism, and an altered pattern of hepatic protein syn-
tive to mild degrees of inadequate oxygen delivery and may be thesis known as the acute-phase response, characterized by
elevated in patients with liver disease. increased synthesis of C-reactive protein, alpha1-anti-trypsin, and
Gastric production of CO2 as measured with a gastric fibrinogen and reduced synthesis of albumin.
tonometer has been proposed as a means of evaluating splanch- Metabolic prophylaxis of MODS is directed toward reversal
nic blood flow, but the benefits of tonometry in improving out- of the stimuli responsible for the catabolic hormonal milieu and
come are unproven.80 Microvascular flow can also be directly toward the provision of adequate biochemical substrate at a time
visualized in the tongue or another exposed mucosal surface by of increased metabolic demand. Early definitive surgical therapy
using orthogonal polarization spectral imaging.81 Neither of in the form of debridement of devitalized tissue, burn wound
these approaches has been widely used to guide resuscitation. excision and grafting, and rigid fixation of long bone fractures
Blood pressure is widely used as an index of the initial ade- can attenuate the postinjury hypermetabolic state and minimize
quacy of resuscitation, but pressure measurements may not reli- the subsequent development of MODS, though the benefits of
ably reflect flow in the microvasculature, particularly when sys- early definitive therapy must be weighed against the additional
temic vascular resistance is low. Measurement of central venous stress of blood loss and hemodynamic instability. In the face of
or pulmonary capillary wedge pressures provides an estimate of overwhelming injury, a policy of damage control to permit sta-
the preload to the heart, though factors such as positive pressure bilization of the patient in the ICU is associated with an
ventilation, the extent of capillary leakage in the lungs, and improved clinical outcome.85

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8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 8
Nutritional support should be provided by the enteral route if Although nosocomial infections in critically ill patients usual-
possible [see 8:22 Nutritional Support]. Enteral nutrition is feasi- ly arise from endogenous reservoirs, pathogens may also spread
ble in most patients, particularly if feedings are initiated early. from patient to patient and from environment to patient. Certain
The administration of even small quantities of enteral nutrition organisms—in particular, Acinetobacter, Xanthomonas, and Le-
is considered advisable, even if it must be supplemented by some gionella—are transmitted through aqueous sources in the ICU,
degree of parenteral nutrition. There is increasing evidence that and the isolation of these organisms from a critically ill patient is
immunologically enhanced enteral formulas can yield better evidence of a potential problem in environmental infection con-
clinical outcomes than standard enteral formulas.86 trol. Hand washing is an important but underutilized mode of
Close regulation of glucose levels in accordance with an inten- infection prevention in the ICU [see 1:1 Prevention of Postopera-
sive policy of monitoring and insulin administration has been tive Infection]. There is no clear evidence that protective isolation
shown to improve clinical outcome.60 On the other hand, there of critically ill patients warrants the increased costs and
is no evidence that administration of growth hormone offers any increased demands on nursing staff.
significant benefit.87 The role of immunomodulation in the prophylaxis of MODS
remains undefined. At present, there is no defined role for
OPTIMIZING IMMUNOLOGIC
chemoprophylaxis of MODS beyond the specific effects of
HOMEOSTASIS
drugs such as heparin (prevention of deep vein thrombosis
Infection is an important [DVT]) and H2 receptor antagonists (prevention of upper GI
risk factor for MODS, but the bleeding).
converse is equally true:
patients with MODS are at
significantly increased risk for Evaluation of the Patient
infection. This risk arises as a with Organ Dysfunction
consequence both of impair-
SINGLE ORGAN DYSFUNCTION
ment of normal host defense mechanisms and of colonization
with potentially infectious nosocomial pathogens [see 8:16 Single organ dysfunction
Nosocomial Infection]. suggests local disease and
Of the numerous derangements of normal immune function should trigger a search for
with which critical illness is associated, impairment of mucosal potentially correctable causes
defenses is probably the most important (and certainly the most in the organ system involved. Isolated organ dysfunction may
preventable). Mucosal defenses are breached by surgical incisions reflect preexisting chronic disease or a local problem such as fluid
and by invasive devices, including intravascular catheters, urinary overload, atelectasis, biliary tract obstruction, or elevated intracra-
catheters, and endotracheal and nasogastric tubes. Limiting the nial pressure. Complications related to invasive devices or the
number of such devices in use and paying rigorous attention to adverse effects of medications are common causes of single organ
their insertion and maintenance are important for minimizing dysfunction; the diagnosis is often presumptive, established on the
nosocomial infection rates.88 Gastric acid plays a primary role in basis of clinical improvement after discontinuance of the agent or
maintaining the relative sterility of the stomach. Antacids ablate removal of the device. Finally, single organ dysfunction may indi-
this defense and are a recognized risk factor for nosocomial pneu- cate acute disease in the involved organ, such as myocardial infarc-
monia; they should not be used for stress ulcer prophylaxis. The tion, pulmonary embolism, or bone marrow suppression.
declining incidence of clinically significant stress bleeding in the Acute respiratory dysfunction, for example, may be caused by
contemporary ICU suggests that prophylaxis should be limited to pneumonia, atelectasis, pleural effusion, pneumothorax, or pul-
patients who are at increased risk for stress ulceration.55 monary embolism. Central venous and pulmonary arterial
Cytoprotective agents (e.g., sucralfate) appear to have no signifi- catheters may induce tachyarrhythmias as a result of mechanical
cant advantages over H2 receptor antagonists in reducing the risk irritation of the conducting system. Isolated renal dysfunction
of ventilator-associated pneumonia and are less efficacious in pre- may be a consequence of abdominal compartment syndrome or
venting bleeding89; accordingly, H2 receptor antagonists appear to of the nephrotoxic effects of medications (e.g., acute tubular
be the prophylactic agents of choice. necrosis caused by aminoglycosides and interstitial nephritis
An alternative strategy for preventing pathologic gut coloniza- caused by penicillins and cephalosporins). Occasionally, renal
tion and nosocomial infection involves prophylactic administra- dysfunction arises from a postrenal cause, such as blockage of a
tion of a combination of systemic antibiotics (e.g., cefotaxime) Foley catheter.
and topical nonabsorbed antibiotics (e.g., tobramycin, polymyx- Medications are important causes of liver dysfunction in the
in, and amphotericin B). This approach, known as selective critically ill patient. Erythromycin, ketoconazole, and haloperidol,
decontamination of the digestive tract (SDD), has proved effec- for example, can induce cholestatic liver injury. Thrombocyto-
tive in reducing nosocomial infection rates and even ICU mor- penia is an important adverse effect of a number of medications,
tality90; the effect is particularly evident in surgical patients who including heparin flushes to maintain the patency of arterial lines.
receive both systemic and topical therapy.91 A decreased level of consciousness is usually the result of the
Enteral feeding is beneficial in preventing nosocomial infec- poorly characterized metabolic encephalopathy of critical illness;
tion. Systemic antibiotics suppress the indigenous flora of however, it is necessary to rule out local causes such as meningi-
mucosal surfaces, promoting pathologic colonization with resis- tis, encephalitis, brain abscess, and subdural hematoma. Excessive
tant organisms.92 Therefore, use of antimicrobial agents in criti- or prolonged use of narcotics or sedative-hypnotics may lead to
cally ill patients must be selective and targeted, and the use of sustained alterations in level of consciousness, particularly when
broad-spectrum empirical therapy should be minimized by reg- hepatic or renal function is impaired. Nondepolarizing muscle
ular reviews of culture and sensitivity results and restrictions on relaxants (e.g., vecuronium) may cause prolonged neuromuscu-
antibiotic prescription practices. lar blockade and peripheral neuropathy.45

9. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 9
MULTIPLE ORGAN
DYSFUNCTION
aid in establishing or excluding the diagnosis.96,97
MODS is rarely caused by urinary tract infections or device-
Although it has been sug- related bacteremias, though these conditions are common in
gested that there is a charac- patients with significant organ dysfunction. Clostridium difficile
teristic temporal sequence in colitis or disseminated fungal infection may also present as dete-
the development of MODS riorating organ function in critically ill patients.98
[see Table 5],3,9 the clinical
course tends to be variable Iatrogenic factors MODS can be considered the quintes-
and depends in part on the sential iatrogenic disorder, reflecting both the successes and the
criteria used to define organ system dysfunction (see above).The failures of contemporary ICU practice. On one hand, the syn-
specific pattern of dysfunction is much less important than the drome arose only because the supportive care available today
course of the evolving syndrome. Resolution of dysfunction sug- permits the prolonged survival of critically ill patients who, in an
gests an appropriate response to specific and supportive therapy. earlier era, would have died rapidly; on the other hand, poten-
Worsening of dysfunction, on the other hand, should prompt a tially avoidable iatrogenic factors contribute prominently to the
search for potentially correctable causes and a reevaluation of evolution of MODS.
the methods of supportive care in use. Not infrequently, a treat- Technical or judgmental errors often set the stage for
able cause of evolving MODS is found; often, however, no cause MODS.99-101 Whenever a patient manifests unexplained organ
is evident. When no specific cause of the deterioration can be failure in the postoperative period, the surgeon must consider the
identified, therapy should focus on optimizing supportive mea- possibility of an iatrogenic complication—for example, a missed
sures to limit iatrogenic injury either until the patient recovers intestinal perforation in a trauma victim, a leak from a tenuous
or, alternatively, until a considered decision is made that contin- anastomosis, or left colon ischemia after aneurysmectomy.
uing active care is futile. Many of the therapeutic interventions that are the mainstay
Search for Correctable Causes of ICU care have the potential to cause local and remote organ
injury. In the experimental setting, mechanical ventilation with
Occult infection Uncontrolled infection, particularly infec- high tidal volumes and low levels of positive end-expiratory
tion arising within the abdomen, is an important risk factor for pressure (PEEP) can induce both pulmonary and remote
MODS.2,3,93 The development of otherwise unexplained organ organ injury.102,103 A multicenter, randomized, controlled trial
dysfunction should trigger a careful radiologic search for an confirmed that mechanical ventilation of patients with acute
occult intra-abdominal focus.94 However, MODS also develops lung injury in accordance with a lung-protective strategy (i.e.,
in patients with pneumonia58 and other life-threatening infec- a tidal volume of 6 ml/kg) significantly improves survival22 and
tions, and it sometimes evolves in patients in whom no infectious attenuates the local and systemic release of proinflammatory
focus can be identified.66,95 mediators [see 8:6 Mechanical Ventilator].16 Oxygen in
When MODS develops in the postoperative period, a careful high concentrations can produce pulmonary damage, probably
search for infection must be undertaken, concentrating in partic- as a result of the generation of toxic oxygen intermediates [see
ular on the operative site and on any invasive devices used. With 8:26 Molecular and Cellular Mediators of the Inflammatory
appropriate attention to the clinical possibilities, aided by ultra- Response].104
sonography and CT scanning, the presence or absence of signif- Blood transfusion has been implicated in the development of
icant intra-abdominal pathology can usually be established. Local organ dysfunction, an effect that occurs independent of the
wound exploration may suggest the possibility of occult intra- effects of shock, blood loss, and fluid resuscitation.105,106 A mul-
abdominal infection through the demonstration of impaired ticenter, randomized, controlled trial demonstrated a significant
wound healing or fascial dehiscence or through the isolation of reduction in the severity of new organ dysfunction in a heteroge-
typical intestinal microflora from a wound infection.The diagno- neous population of critically ill patients when transfusion was
sis of pneumonia in intubated ICU patients is notoriously diffi- withheld unless the hemoglobin concentration was less than 70
cult; however, the use of quantitative techniques (e.g., protected g/L (7 g/dl).107 The age of the blood administered may be an
specimen brush bronchoscopy and bronchoalveolar lavage) can underappreciated factor in defining optimal transfusion strate-
gies.The effects of blood transfusion on splanchnic blood flow as
Table 5 Temporal Evolution of MODS3,9 measured with a gastric tonometer are significantly dependent
on the age of the transfused blood. Transfusion of blood that is
more than 12 days old can have an adverse impact on oxygen
Time from ICU Admission to Onset of
System Significant Dysfunction (days) delivery.108
TPN can also contribute to the de novo development of organ
Respiratory 1–2 dysfunction.TPN-associated alterations in hepatic function with
intrahepatic cholestasis and fatty infiltration are relatively com-
Hematologic 3 mon and are manifested by elevated aminotransferase and alka-
line phosphatase levels.109 TPN may also give rise to glucose
Central nervous 4
intolerance and can aggravate ventilatory impairment through
Cardiovascular 4 increased CO2 production. In patients with borderline pul-
monary function, this additional CO2 production may prevent
Hepatic 5–6 weaning from ventilatory support.110 Parenteral nutrition is also
associated with higher rates of postoperative and nosocomial
Renal 4–11
infections after multiple trauma.111
Gastrointestinal 10–14 Medications—in particular, analgesics, sedatives, and antibi-
otics—have also been associated with evolving organ dysfunction.

10. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 10
Support of Patients with
ventilatory support, it may be necessary to accept an arterial oxy-
Established Organ
gen saturation (SaO2) as low as 80%.
Dysfunction
The fundamental challenge CARDIOVASCULAR SUPPORT
•
in providing intensive support- Tissue oxygen delivery (D O2) is a function of three variables—
ive care to patients with estab- cardiac output, hemoglobin concentration, and SaO2 (oxygen dis-
lished organ dysfunction is solved in the plasma makes • only a negligible contribution).
how to support physiologic Tissue oxygen consumption (VO2) is a function of cardiac out-
function while minimizing new put and oxygen extraction (defined as the difference between
iatrogenic organ dysfunction. As more is understood about the arterial and venous oxygen content). In practice, multiple factors
consequences of various treatment strategies, it is increasingly can impair oxygen delivery and consumption, and it is important
apparent that optimizing function is not synonymous with maxi- that the clinician recognize these.
mizing function and that the clinician must be acutely aware of the Oxygen uptake in the tissues is an entirely passive process,
potential for causing more harm than good. resulting from the diffusion of oxygen toward the relatively
hypoxic extravascular space along an oxygen saturation gradient
VENTILATORY SUPPORT
that is highest in the microvasculature and lowest at the cell.This
Although ventilatory support is generally provided by endo- passive diffusion can be reduced if there is interstitial edema,
tracheal intubation and mechanical ventilation, noninvasive pos- which makes the concentration gradient less steep, or if blood
itive pressure ventilation may be appropriate for patients with flow through the microvasculature is rapid. Alternatively, a
milder degrees of respiratory failure. A small randomized trial of reduction in the resistance of small arterioles may impede the
patients with cardiogenic pulmonary edema found that when diversion of blood into the microvasculature. Moreover, nutrient
compared with conventional administration of oxygen by mask, vessels in the microcirculation may be occluded by aggregates of
noninvasive positive pressure ventilation shortened the time to neutrophils, platelets, and aged (and thus less deformable) red
resolution of respiratory failure and reduced the need for subse- blood cells. The net result of these abnormalities is the shunting
quent endotracheal intubation.112 Whether this approach is use- of oxygenated blood from the arterial side of the circulation to
ful in patients with early ARDS is less clear, however; it may be the venous side. This phenomenon is readily detected through
associated with a higher risk of complications.113 measurement of SmvO2, which is about 70% in normal persons
Endotracheal intubation and positive pressure ventilation con- but typically is much higher in patients with sepsis and organ
stitute the mainstay of support for critically ill patients with res- dysfunction.
piratory failure. In unstable patients, it is best to use a controlled Paradoxically, each of the interventions commonly used to
ventilatory mode (e.g., pressure control ventilation) rather than a increase tissue oxygen delivery can also decrease it. Fluid resus-
spontaneous breathing mode (e.g., pressure support ventilation). citation can increase cardiac output by increasing preload, but in
Oxygenation can be optimized through the use of PEEP, a patients with altered capillary permeability, it can create edema,
maneuver that may also decrease the accumulation of interstitial thereby lengthening the distance across which oxygen must dif-
fluid and minimize ventilator-associated lung injury.114 Ventilation fuse.Vasopressors can raise cardiac output by increasing periph-
with large tidal volumes and high peak inspiratory pressures con- eral vascular resistance, but at the cost of reducing flow through
tributes to lung injury, and it has been shown that the survival of nutrient vessels in the microcirculation. Inotropes, on the other
ARDS patients can be improved by using low tidal volumes (~ 6 hand, directly increase cardiac output, albeit at the cost of
ml/kg).22 Pressure-controlled ventilatory techniques limit peak increased myocardial oxygen consumption, but agents such as
airway pressures to a maximum predetermined level, optimizing dobutamine may lead to further shunting by decreasing periph-
gas exchange by inverting the inspiration-to-expiration ratio (I/E) eral vascular resistance.
from its normal value of 1:2 to 1:1 or higher and by changing the Currently, intensive invasive monitoring of critically ill
shape of the inspiratory flow curve (normally square) to one in patients with organ dysfunction is employed less frequently than
which flow initially is rapid, then decelerates [see 8:6 it once was. The benefits of such monitoring remain somewhat
Mechanical Ventilator].115 Although oxygenation can be main- uncertain. For example, a 1996 study suggested that the use of a
tained with low tidal volumes, ventilation is jeopardized, with the pulmonary arterial catheter was associated with a 24% increase
result that CO2 levels rise (so-called permissive hypercapnia).116 in mortality—not, presumably, because of complications of the
Hypercapnia per se does not appear to be deleterious117; indeed, catheter itself but rather because the decisions made on the basis
animal studies suggest that increased levels of CO2 may be inde- of the data provided led to greater harm than benefit.125
pendently beneficial to critically ill patients.118 For patients with Although this estimate of harm may be exaggerated, there is lit-
refractory hypoxemia, high-frequency oscillation appears to be a tle countervailing evidence of benefit to justify routine use of
promising ventilatory mode.119,120 pulmonary arterial catheters. A 2003 study of 1,994 high-risk
Inhaled NO is selectively delivered to ventilated lung seg- patients undergoing major elective surgery found that Swan-
ments and may effect early improvement of oxygenation in Ganz catheterization and preoperative optimization did not
ARDS patients121; whether this early physiologic effect translates reduce mortality but was associated with a significant increase in
into an improved clinical outcome is unknown. Extracorporeal the risk of pulmonary embolism.84
lung support by means of extracorporeal membrane oxygenation
RENAL SUPPORT
or extracorporeal CO2 removal can be lifesaving in patients with
isolated severe respiratory failure that is refractory to other forms Renal replacement therapy in critically ill patients with
of respiratory support.122,123 These techniques are resource MODS serves three functions:
intensive, however, and have not been convincingly shown to 1. Regulation of fluid and electrolytes in patients in whom nor-
yield better outcomes than conventional mechanical ventila- mal renal function is compromised and altered capillary per-
tion.124 If the patient remains hypoxemic despite optimization of meability has led to total body fluid overload with edema.

11. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 11
2. Removal of products of metabolism, medications, and other seen in patients with underlying cardiovascular disease.143
toxins that the failing kidneys are unable to clear. Thrombocytopenia is corrected by transfusion of platelet con-
3. Removal of circulating mediators of inflammation. centrates, but this generally is done only if the platelet count
drops below 20,000/mm3. Coagulation factors can be replaced
The first two are classic indications for dialysis, though the by giving fresh frozen plasma or cryoprecipitate.
therapeutic objectives may differ; the third lies more in the realm Adequate analgesia and sedation are essential components of
of promising experimental therapy. the care of MODS patients; however, the natural desire to allevi-
Fluid overload is a common consequence of hemodynamic ate pain and discomfort can lead to oversedation. A policy of daily
resuscitation during the early stages of acute illness. It results awakening can reduce morbidity and shorten the ICU stay.144
from increased capillary permeability, peripheral vasodilatation
with expansion of the intravascular compartment, and impaired PHARMACOLOGIC THERAPY TARGETING HOST RESPONSE
renal function. The use of continuous renal replacement thera- Experimental studies implicate an activated inflammatory
pies to titrate fluid balance and reduce uremia is conceptually response in the pathogenesis of MODS. Despite extensive eval-
appealing, but the benefits remain unproven. Both individual uation of a variety of novel strategies to target the host response
randomized trials126,127 and a systematic review128 failed to show in sepsis, to date, only two approaches have demonstrated an
that early and aggressive continuous renal replacement improved ability to improve survival.
clinical outcome. On the other hand, a multicenter randomized Activated protein C is an endogenous anticoagulant molecule
trial of more than 400 ICU patients with ARF showed that high- that inhibits factors V and VIII; in addition to its anticoagulant
flow ultrafiltration (at a rate of 35 ml/kg/hr or higher) increased activities, it exerts significant anti-inflammatory activity [see 8:26
survival,129 and a prospective study demonstrated that daily (as Molecular and Cellular Mediators of the Inflammatory Response].145
opposed to alternate-day) intermittent hemodialysis improved Activated protein C has been produced as a recombinant protein
survival and hastened the resolution of ARF.130 Another system- (drotrecogin alfa activated) and has been evaluated in a multicen-
atic review suggested that imbalances between study groups ter randomized trial involving 1,690 patients with severe sepsis. In
might have masked a potential benefit of therapy associated with this trial, treatment resulted in a 6.1% improvement in 28-day
early continuous hemodialysis.131 survival146 and a more rapid resolution of cardiovascular, respira-
Whether it significantly improves outcome or not, early con- tory, and hematologic dysfunction.147 The benefit appears to be
tinuous renal replacement therapy does facilitate early manage- greatest in patients who have more severe illness (reflected in an
ment of the patient with MODS by permitting the removal of elevated APACHE II [Acute Physiology and Chronic Health
fluid, and it is generally better tolerated by hemodynamically Evaluation II] score or a greater number of dysfunctional organs),
unstable patients than is intermittent hemodialysis. Evidence community-acquired infection, or coagulopathy.
that dialytic therapy can accelerate the clearance of circulating Critical illness is associated with multiple abnormalities of
mediators of sepsis is scant.132 endocrine function, including reduced responsiveness to endoge-
nous glucocorticoids,62 a state that predicts an increased risk of
SUPPORT OF OTHER ORGANS
ICU mortality.61 In a 2002 study, administration of pharmaco-
Enteral nutritional support has been shown to reduce the rate logic doses of corticosteroids (50 mg of hydrocortisone every 6
of infectious complications in patients with multiple trau- hours and 50 µg of fludrocortisone) to patients with refractory
ma111,133 and in those with pancreatitis.134 A systematic review of septic shock and an impaired response to a short-course ACTH
15 randomized trials found that early enteral feeding reduced stimulation test reduced mortality by 10%.148 In contrast, earlier
the infectious complication rate and shortened the ICU stay studies of high-dose corticosteroids in more heterogeneous
without affecting mortality.135 The use of immunologically groups of patients with sepsis found no evidence of benefit.149
enhanced enteral formulas appears to be associated with a fur- Systematic reviews have suggested that neutralization of tumor
ther reduction in infectious complications, ventilator days, and necrosis factor (TNF) or interleukin-1 (IL-1) can improve out-
length of hospital stay.136 Paralytic ileus makes the provision of come in sepsis,150 but neither of these approaches is clinically
enteral feeding more difficult. Erythromycin, which is a motilin available at present. Other anticoagulant or anti-inflammatory
secretagogue, can facilitate bedside placement of enteral feeding strategies have been suggested but remain unproven.
tubes137 and accelerate gastric emptying.138
Techniques for extracorporeal support of the failing liver have MODS AND ICU-ACQUIRED INFECTION
been described, but their use is generally limited to a few centers Infection is a risk factor for organ dysfunction, but the con-
with a particular interest in liver failure and organ transplanta- verse is equally true: organ dysfunction is a risk factor for noso-
tion.139,140 Unlike primary liver failure, the hepatic dysfunction of comial infection, with the risk increasing as the severity of organ
MODS does not lead to life-threatening organ system insuffi- dysfunction increases.66 The typical isolates are microbes of low
ciency and rarely calls for specific support. Hypoalbuminemia is intrinsic pathogenicity, including coagulase-negative Staphy-
common in MODS, occurring as a consequence of increased lococcus, Enterococcus, and Candida species and gram-negative
vascular permeability, loss through the GI tract, and reduced organisms such as Pseudomonas and Enterobacter.151 These organ-
hepatic synthesis from the activation of an acute-phase response. isms commonly colonize the upper GI tract of the critically ill
Although hypoalbuminemia is associated with increased ICU patient,152 they emerge under antibiotic pressures, and they form
morbidity and mortality, there is no convincing evidence that colonies on invasive devices—all of which may explain why they
albumin supplementation improves clinical outcome.141 emerge as predominant infecting species in this setting. Studies
A randomized trial of transfusion strategies in the ICU of SDD have demonstrated that preventing such infections
demonstrated that organ function was improved by a restrictive reduces ICU morbidity and mortality,90,153 but there is scant evi-
transfusion policy that withheld transfusion unless the hemoglo- dence that aggressive antimicrobial therapy to treat suspected
bin level dropped below 70 g/L,107 a conclusion supported by a nosocomial infection improves outcome. In fact, two reports
large European multicenter observational study.142 Benefit is also from 2000 suggested that a more restrictive approach to the pre-

12. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 12
scription of antimicrobial agents reduced mortality and morbid- Table 6 Prognosis in MODS
ity.97,154 Worsening organ dysfunction should prompt a careful
search for untreated foci of infection, but empirical therapy Number of Failing Systems Mortality (%)
should be used cautiously; if such therapy is started, it should be
discontinued promptly as culture data are obtained. Often, mere 0 3
removal of a colonized device (e.g., a central line or a urinary 1 15–30
2 50–60
catheter) amounts to definitive therapy for these infections. 3 60–100
The association of organ dysfunction with occult intra-abdom- 4 70–100
5 100
inal infection3,94 stimulated a period of enthusiasm for the prac-
tice of so-called blind laparotomy—that is, laparotomy undertak-
en to identify and treat an intra-abdominal infectious focus with- positive indicators according to those criteria had a mortality of
out radiographic evidence that infection is present.155,156 The uni- close to 100%; today, a majority of such patients survive.93
formly disappointing results of such intervention,157 coupled with Organ dysfunction is potentially recoverable when the factors
improvements in diagnostic imaging techniques, led to abandon- responsible for the persistence or progression of MODS can be
ment of this approach except in certain unusual circumstances reversed. Identifying these factors, treating them appropriately,
(e.g., clinically compelling evidence of a surgically correctable and providing optimal physiologic support can prove a daunting
problem, suspicion of visceral ischemia, or the absence of the challenge, and it is often advisable to consider seeking indepen-
appropriate imaging facilities). It goes without saying that the dent advice or transporting the patient to a center with the clin-
classic physical findings of peritonitis—particularly when no ical expertise and facilities to manage the multidisciplinary prob-
abdominal operation has been done—may be the sole indication lems faced by MODS patients. Given that MODS often evolves
for surgical exploration. Moreover, in a complicated postopera- as a consequence of medical misadventure, early consultation or
tive patient transferred from another institution because of wors- referral may be a sound approach from a medicolegal perspec-
ening organ dysfunction, repeat laparotomy may legitimately be tive as well. On the other hand, it is a common contemporary
considered a component of the admission physical examination. ICU scenario that MODS evolves and worsens despite optimal
care, necessitating a decision whether to continue or discontinue
active care.
Outcome
WITHDRAWAL OF LIFE SUPPORT
PROGNOSTIC INDICATORS
The most common mode of death for a patient with advanced
The prognosis of MODS is MODS is limitation or withdrawal of life support in the face of
directly related to the severity a persistent failure to respond to full, aggressive ICU care.160 The
of the underlying organ dys- decision to withdraw or withhold life support is a complex one,
function, which can be and there are considerable differences of professional opinion
expressed in terms of either and practice regarding how best to make it.161 Factors that must
the number of failing sys- be taken into consideration include the nature of the underlying
tems3,73,158 [see Table 6] or the global severity of dysfunction as disease, the patient’s premorbid health status, the wishes of the
determined by an organ dysfunction score [see Figure 1]. It must patient and the family regarding long-term ICU care, the
be emphasized, however, that prognostic indicators reflect the patient’s ultimate prospects for an independent existence, and
expected outcome of a group of patients and are of limited use the presence of active problems amenable to medical therapy.
in making decisions about the care of an individual patient. Although end-of-life deliberations may be difficult for medical
Moreover, the prognostic weight of these scales reflects stan- staff and family alike, careful and realistic consideration of the
dards of care prevalent at a particular time and in a particular expectations of all involved can facilitate a decision to discontin-
clinical setting. For example, at the time when Ranson’s criteria ue active therapy in a manner that is dignified and humane
were developed,159 patients with pancreatitis and six or more rather than adversarial.
Discussion
MODS: Evolution of a Syndrome
MODS.4 MODS is perhaps the classic instance of the new dis-
The first ICU was established in Baltimore in the late ease paradigm, in that it develops only in patients who would
1950s.162 Its development marked much more than a simple have died without medical intervention and evolves because of
advance in medical technology. The improvements in fluid the inadvertent consequences of that intervention.
resuscitation achieved during World War II, followed by the Earlier reports had described the physiologic failure of dis-
development of techniques of positive pressure mechanical ven- crete organ systems after trauma or acute illness. Stress-related
tilation, hemodialysis, and central venous catheterization over upper GI bleeding was described in 184254 and trauma-related
the subsequent decade, had set the stage for an entirely new dis- renal23 and hepatic30 dysfunction during World War II.
ease paradigm—that of a disease that arose only in patients who Description of respiratory failure awaited the widespread use of
would have died in the absence of resuscitation and exogenous mechanical ventilators, but a process termed high-output respi-
support. The need for that support to sustain life became the ratory failure was described in patients with peritonitis in
metaphor that described this new disorder, originally described 1963,13 anticipating the classic description of ARDS 4 years
as sequential systems failure163 and now generally known as later.14 In each of these reports, however, the physiologic organ

13. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 13 MULTIPLE ORGAN DYSFUNCTION SYNDROME — 13
abnormality was viewed as an isolated problem of a single organ, lipopolysaccharide (LPS), derived from the cell wall of gram-neg-
albeit one that could have broader secondary consequences. The ative bacteria reproduces the physiologic features of sepsis in
suggestion by Baue1 in 1975 that each organ abnormality was human volunteers,169 with larger doses producing life-threatening
simply the local manifestation of a systemic process set the stage organ dysfunction.170 Moreover, endotoxin can be detected in the
for attempts to identify common systemic pathologic processes circulation of patients at risk for MODS—not only patients with
and hence to develop therapies that were not merely supportive sepsis,171,172 but also those who have experienced traumatic173 or
but also targeted fundamental mechanisms in the pathogenesis thermal injury174 and those who are undergoing cardiopulmonary
of MODS.The search for such therapies is, admittedly, still in its bypass or repair of an abdominal aortic aneurysm.175
infancy. Not only is the disease process complex, but our ability Animal studies, however, have shown that the sequelae of
to describe and characterize it is limited as well. endotoxemia are an indirect consequence of the activation of
MODS is invariably preceded by evidence of systemic activa- host innate immunity rather than a direct cytopathic effect of the
tion of an adaptive host stress response to infection or tissue endotoxin molecule.The C3h HeJ strain of mice arose through a
injury. This response, which includes changes in cardiorespirato- spontaneous mutation of the parental C3h HeN strain, involving
ry function, increased microvascular permeability, evidence of an alteration in a single gene product. This defect, later recog-
activation of innate immune mechanisms, and alterations in nized as a point mutation in the gene encoding Toll-like receptor
intermediary metabolism, is termed sepsis when caused by infec- 4 (TLR4),176 conferred complete resistance to endotoxin lethal-
tion and the systemic inflammatory response syndrome (SIRS) ity in C3h HeJ mice. Studies involving bone marrow irradiation
when considered independent of cause.4,164 SIRS is mediated and crossover transplants of bone marrow cells between C3h
through the release of a complicated network of host-derived HeN and C3h HeJ mice showed that endotoxin sensitivity was
mediator molecules (see below).The name notwithstanding, des- transferred with bone marrow cells177 and confirmed that the
ignation of SIRS as a syndrome may be somewhat presumptu- sequelae of endotoxin challenge arose indirectly, through the
ous. There is no discrete or invariant pattern of clinical manifes- activity of marrow-derived cells from the host. Microarray stud-
tations that identifies patients with activation of this complex ies have demonstrated that literally hundreds of genes are
response, nor is there convincing evidence that the response is expressed in macrophages, endothelial cells, and neutrophils
common to all patients who meet the clinical criteria for SIRS. after stimulation by LPS.178,179 The importance of this enor-
It has been suggested that it is also possible to define a com- mously complex response is underlined by the observation that
pensatory anti-inflammatory response syndrome (CARS) or a the lethality of murine endotoxemia can be prevented by neu-
mixed acute response syndrome (MARS)165; however, these tralizing any one of several dozen of these gene expressions
“syndromes” are more conceptual entities than they are diseases before endotoxin challenge.145
that can be diagnosed and treated.166 Endotoxin interacts with cells of the host innate immune sys-
tem through TLR4.TLR4 is one of a family of 10 TLRs that have
evolved to recognize danger signals in the extracellular environ-
Theories of Pathogenesis ment and to activate cells to mount an appropriate response to a
Organ dysfunction must ultimately be the consequence of the threat.180 TLRs recognize not only microbial products (e.g.,
malfunctioning or death of cells in that organ. Although cellular endotoxin) and components of the wall of gram-positive bacteria
derangements are readily documented under experimental con- (e.g., lipoteichoic acid and peptidoglycan) (TLR2) but also bac-
ditions, it remains largely unknown how these derangements terial DNA (TLR9) and even heat-shock proteins and structural
translate into the physiologic changes that define the clinical syn- components of damaged cells (TLR2) [see Table 7]. Thus, the
drome. Cellular dysfunction may reflect altered patterns of syn- response evoked appears not to be specific for the stimulus that
thetic function, either because of activation of alternate patterns elicited it, just as the clinical syndrome of systemic inflammation
of gene expression or because of relative cellular oxygen defi- and organ dysfunction is not unique to patients with infection
ciency from defective cellular respiration (so-called cytopathic but can also be seen in association with other causes of tissue
hypoxia).167 Mechanisms of fibrosis and repair may alter the nor- injury.164,181
mal cellular anatomic relationships and thereby impair function. The binding of endotoxin to TLR4 triggers a cascade of intra-
Finally, cell death may result from mechanical or biochemical cellular signaling pathways leading to the expression of hundreds
injury of sufficient severity to prevent oxidative metabolism and of genes whose products mediate innate immunity [see Figure 2].
produce anatomic disruption of the cell or necrosis, but it may The resulting alterations in normal patterns of cellular protein
also occur through the activation of apoptosis (programmed cell synthesis are profound: not only does the initial stimulus trigger
death). Each of these abnormalities has been described in a complex response, but the newly synthesized protein products
patients with sepsis, and each has multiple overlapping causes. of this response also, in turn, are capable of acting on the cell to
induce a further cascade of mediator molecules. Any attempt to
INFECTION AND HOST SEPTIC RESPONSE
classify the mediators involved is inevitably arbitrary and sim-
The earliest descriptions of MODS emphasized its association plistic. It is useful, however, to consider the response as involving
with occult infection,58,94 prompting the hypothesis that organ (1) early inflammatory mediators (e.g., TNF and IL-1), (2) late
dysfunction arises through the direct effects of one or more inflammatory mediators (e.g., macrophage inhibitory factor and
microbial toxins. However, the observations that MODS could high-mobility group box [HMGB]–1), (3) counterinflammatory
also develop in patients with no identifiable focus of infection95 and tissue repair mediators (e.g., IL-10 and transforming growth
and that treatment of infection did not necessarily reverse the factor [TGF]–β), (4) enzymes involved in the regulation of non-
syndrome168 suggested that infection may be a cause of organ protein inflammatory mediators (e.g., inducible NO synthase,
dysfunction in critical illness but is not necessarily the funda- phospholipase A2, and platelet-activating factor acetylhydro-
mental mechanism. lase), (5) acute-phase reactants, and (6) cell surface adhesion or
Microbial products, independent of bacterial viability, can signaling molecules (e.g., intercellular adhesion molecule
evoke the clinical features of sepsis. Injection of endotoxin, or [ICAM]–1 and tissue factor).