Rudolf M.

Tan MODS Page 1 of 9

MULTIPLE ORGAN DYSFUNCTION SYNDROME

MULTIPLE ORGAN DYSFUNCTION SYNDROME

Multiple organ dysfunction syndrome (MODS), previously known as multiple organ failure (MOF) or
multisystem organ failure (MSOF), is altered organ function in an acutely ill patient requiring medical
intervention to achieve homeostasis. The use of "multiple organ failure" or "multisystem organ failure"
should be avoided since that phrase was based upon physiological parameters to determine whether or
not a particular organ was failing.

The most common cause of death for patients admitted to a contemporary intensive care unit (ICU) is a
clinical condition that owes its existence to the development of the ICU. Variously known as the multiple
organ dysfunction syndrome (MODS), multi-organ failure, multiple systems organ failure, or through
some of its more prominent manifestations, as the acute respiratory distress syndrome (ARDS) or
disseminated intravascular coagulation (DIC), MODS is as poorly understood as it is prevalent. Even its
terminology merits comment. Although originally described as multiple organ failure, it is evident that
normal physiologic function of the failing organ systems can be restored in survivors. Thus,
characterization of the process as multiple organ dysfunctions is more appropriate. And although the
syndrome involves the dysfunction of many organs, it also affects physiologic systems not classically
thought of as organs, including the hematologic system, immune system, or the endocrine system.
Finally, although it is described as a syndrome, its clinical course and causes are highly variable, and
there is only the most general form of consensus regarding the organs whose dysfunction comprises the
syndrome, or the criteria that should be used to describe this dysfunction.

History

The historical origin of the concept of MODS is as follows. For many years, some patients were loosely
classified as having sepsis or the sepsis syndrome. In more recent years, these concepts have been
refined, so that there are specific definitions of sepsis, and two new concepts have also been developed:
the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS).

Definition

Dysfunction or failure of multiple organ or system happened simultaneously or sequentially due to

various etiological factors.

Multiple organ dysfunction syndrome is the presence of altered organ function in acutely ill patients
such that homeostasis cannot be maintained without intervention. It usually involves two or more organ
systems.

The Multiple Organ Dysfunction Syndrome (MODS) can be defined as the development of potentially
reversible physiologic derangement involving two or more organ systems not involved in the disorder
that resulted in ICU admission, and arising in the wake of a potentially life-threatening physiologic insult.
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Etiology

The condition usually results from infection, injury (accident, surgery), hypoperfusion and
hypermetabolism. The primary cause triggers an uncontrolled inflammatory response. In operative and
non-operative patients’ sepsis is the most common cause. Sepsis may result in septic shock. In the
absence of infection, a sepsis-like disorder is termed systemic inflammatory response syndrome (SIRS).
Both SIRS and sepsis could ultimately progress to multiple organ dysfunction syndrome. However, in
one-third of the patients no primary focus can be found. Multiple organ dysfunction syndrome is well
established as the final stage of a continuum Systemic inflammatory response syndrome + infection
sepsis severe sepsis Multiple organ dysfunction syndrome. Currently, investigators are looking into
genetic targets for possible gene therapy to prevent the progression to Multiple organ dysfunction
syndrome. Some authors have conjectured that the inactivation of the transcription factors NF-κB and
AP-1 would be appropriate targets in preventing sepsis and Systemic inflammatory response syndrome.
These two genes are pro-inflammatory. However, they are essential components of a normal healthy
immune response, so there is risk of increasing vulnerability to infection, which can also cause clinical
deterioration. The following are considered as the most common cause of MODS:
 Infection: Gram positive/negative bacteria, fungal, Virus
 Shock, hemorrhage, etc.
 Allergy
 Burns
 Trauma
 Severe acute pancreatitis

Some have developed a mouse model sepsis via cecal ligation and puncture (CLP). Male Balb/c mice
subjected to CLP were given an IL-10-carrying vector or an empty control vector. Lung, Liver and kidney
tissue destruction were measured by assessing myeloperoxidase and malondialdehyde activity. These
last two are endogenous oxidizing compounds produced during tissue inflammation. The authors
assessed the level neutrophil infiltration in lung and liver tissue. IL-10 protein expression was measured
using immunohistochemistry. The expression of Tumor necrosis factor-alpha mRNA was measured at
3,8, and 24 hours after CLP using reverse transcription polymerase chain reaction. Their results show
significantly reduced organ damage by IL-10 gene transfer, as quantified by reduced myeloperoxidase
activity in the lung, liver, and kidney. The malondialdehyde level was not affected by the transfer into
the liver. The livers of the mice infected with the adenoviral vector showed reduced neutrophil activity.
The lung and kidney samples in mice carrying the gene showed lower expression of Tumor necrosis
factor-alpha mRNA. The investigators concluded that increased IL-10 expression significantly reduced
sepsis-induced Multiple organ injury.

Pathophysiology

A definite explanation has not been found. Local and systemic responses are initiated by tissue damage.
Respiratory failure is common in the first 72 hours after the original insult. Following this one might see
hepatic failure (5–7 days), gastrointestinal bleeding (10–15 days), and renal failure (11–17 days)
Gut hypothesis

The most popular hypothesis by Deitch to explain MODS in critically ill patients is the gut hypothesis.
Due to splanchnic hypoperfusion and the subsequent mucosal ischemia there are structural changes and
alterations in cellular function. This results in increased gut permeability, changed immune function of
the gut and increased translocation of bacteria. Hepatic dysfunction leads to toxins escaping into the
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systemic circulation and activating an immune response. This results in tissue injury and organ
dysfunction.

Classification of MODS

 Immediate Type (Primary) ：Dysfunction is happened simultaneously in two or more organs due to
primary disease.
 Delayed type (Secondary ） ： Dysfunction happened in an organ, other organs sequentially
happened dysfunction or failure.
 Accumulation type：Dysfunction leaded by chronic disease.

Mechanism

 Common Manifestations of MODS

 Diagnosis of Criteria
 Organ/ system dysfunction and failure
 GLASGOW SCORE

Management Summary of Treatments of MODS

Combined therapy
 Correction of ischemia: fluid resuscitation, mechanical, ventilation
 Prevention of infection：drainage, antibiotics
 Interruption of pathological reaction：hemofiltration
 Stabilization of internal environment：water, electrolyte, acid-base imbalance
 Regulation of immunity：cellular and humor

Support of organ function

 Ventilator
 Artificial kidney
 Artificial liver
 Protection of enteral mucosa
 Drugs of protection of heart

MODS: Clinical and Pathologic Description

Organ dysfunction in a critically ill patient can be described in one of two ways
 as the clinical intervention that was employed to support the failing organ system (mechanical
ventilation, hemodialysis, inotropic or vasopressor agents, parenteral nutrition etc.),
 or as the acute physiologic derangement that made such support necessary. The first descriptions of
the syndrome generally counted the number of failing systems, using as descriptors, and the need
for clinical intervention.
More recently several similar descriptive scales have been developed, based on the quantification of
organ dysfunction as a numeric scale. Each uses the same six organ systems to characterize MODS - the
respiratory, cardiovascular, renal, hepatic, neurologic, and hematologic systems. They differ in minor
ways with respect to the selected parameters to describe cardiovascular dysfunction, and in the timing
and weighting of the variables selected.
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The Multiple Organ Dysfunction (MOD) score, a scale that uses physiologic variables exclusively is
presented in the preceding table.

The multiple organ dysfunction (MOD) score

Organ system 0 1 2 3 4
a
Respiratory
(PO2/FIO2 Ratio) > 300 226–300 151–225 76–150 ≤ 75
Renalb
(Serum Creatinine) ≤ 100 101–200 201–350 351–500 > 500
c
Hepatic
(Serum Bilirubin) ≤ 20 21–60 61–120 121–240 > 240
Cardiovasculard
(R/P Ratio) ≤ 10.0 10.1–15.0 15.1–20.0 20.1–30.0 > 30.0
e
Hematologic
(Platelet count) > 120 81–120 51–80 21–50 ≤ 20
Neurologicf
(Glasgow Coma Score) 15 13–14 10–12 7–9 ≤6

a. The PO2/FIO2 ratio is calculated without reference to the use or mode of mechanical
ventilation, and without reference to the use or level of PEEP
b. The serum creatinine level is measured in μmol/liter, without reference to the use of
dialysis.
c. The serum bilirubin level is measured in μmol/liter.
d. The R/P ratio is calculated as the product of the heart rate and right atrial (central venous)
pressure, divided by the mean arterial pressure:

r/ p

e. The platelet count is measured in platelets/mL 10-3

The Glasgow Coma Score is preferably calculated by the patient's nurse, and is scored conservatively (for
the patient receiving sedation or muscle relaxants, normal function is assumed unless there is evidence
of intrinsically altered mentation).

Regardless of how MODS is characterized, it is apparent that the risk of ICU death increases as the
severity of organ dysfunction - whether the number of failing organs (table II), or the overall degree of
dysfunction increases.

Table II
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Number of failing systems Mortality (%)

0 < 10
1 0–30
2 20–50
3 40–80
4 60–100
5 or more > 80

Endotoxin macrophage hypothesis

Gram-negative infections in MODS patients are relatively common; hence endotoxins have been
advanced as principal mediator in this disorder. It is thought that following the initial event cytokines are
produced and released. The pro-inflammatory mediators are: tumor necrosis factor-alpha (TNF-α),
interleukin-1, interleukin-6, thromboxane A2, prostacyclin, platelet activating factor, and nitric oxide.
Tissue hypoxia-microvascular hypothesis
As a result of macro- and microvascular changes insufficient supply of oxygen occurs. Hypoxemia causes
organ dysfunction and cell death.

Integrated hypothesis

Since in most cases no primary cause is found, the condition could be part of a compromised
homeostasis involving the previous mechanisms.

Diagnosis

The European Society of Intensive Care organized a consensus meeting in 1994 to create the "Sepsis-
Related Organ Failure Assessment (SOFA)" score to describe and quantitate the degree of organ
dysfunction in six organ systems. Using similar physiologic variables, the Multiple Organ Dysfunction
Score was developed.

Four clinical phases have been suggested:

 Stage 1 the patient has increased volume requirements and mild respiratory alkalosis which is
accompanied by oliguria, hyperglycemia and increased insulin requirements.
 Stage 2 the patient is tachypneic, hypocapnic and hypoxemic. Moderate liver dysfunction and
possible hematologic abnormalities.
 Stage 3 the patient develops shock with azotemia and acid-base disturbances. Significant
coagulation abnormalities.
 Stage 4 the patient is vasopressor dependent and oliguric or anuric. Ischemic colitis and lactic
acidosis follow.

Management
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At present there is no agent that can reverse the established organ failure. Therapy therefore is limited
to supportive care, i.e. safeguarding hemodynamics, and respiration. Maintaining adequate tissue
oxygenation is a principal target. Starting enteral nutrition within 36 hours of admission to an Intensive
care unit has reduced infectious complications.
Human recombinant activated protein C (activated drotrecogin alfa) can reduce 28-day mortality among
patients with multiple organ dysfunction syndrome according to a randomized controlled trial. The
relative risk reduction was 21.8%. For patients at similar risk to those in this study (33.9% had 28-day
mortality), this leads to an absolute risk reduction of 7.4%. 13.5 patients must be treated for one to
benefit.

Prognosis

Mortality varies from 30% to 100% where the chance of survival is diminished as the number of organs
involved increases. Since the 1980s the mortality rate has not changed.

Disorders which may progress to MODS

Acute renal failure

Acute respiratory distress syndrome
Heart failure
Intensive care
Liver failure
Respiratory insufficiency
Shock
Systemic inflammatory response syndrome

The histologic features of the organs involved in MODS are less well characterized, but generally include
evidence of edema, inflammation, tissue ischemia or necrosis, and variable degrees of fibrosis and
repair. These alterations, in turn, are responsible for the clinical features of MODS in each of its
component systems.
Lung
The characteristic abnormality of the lung in MODS is a failure of normal gas exchange, reflected
predominantly in arterial hypoxemia. Multiple pathologic factors contribute to impaired gas exchange.
Early in the course of lung injury, atelectasis and intravascular thrombosis or altered regional flow
contribute to ventilation/perfusion mismatch, while increased capillary permeability leads to alveolar
flooding and an increased diffusion distance for oxygen. Regional injury resulting from infection or
trauma contributes to compromised lung function. With the institution of ventilatory support, lung
injury can be aggravated through what has been termed volutrauma and barotrauma, leading to further
atelectasis in dependent lung zones, and cyst formation in the anti-dependent zones. Finally, the process
of tissue repair, initiated with the influx of inflammatory cells into the injured lung, results in fibrosis and
hyaline membrane formation, the cardinal pathologic features of late ARDS.
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Kidney
Renal dysfunction in MODS is reflected in impairment of normal selective excretory function, initially in
oliguria despite adequate intravascular volume, but later in a rising creatinine level, and fluid and
electrolyte derangements of sufficient magnitude that dialysis is required. Its causes are both pre-renal
and renal. Reduced renal blood flow secondary to systemic hypotension, altered regional perfusion, or
increased intra-abdominal pressure is an early risk factor; evolution of the disorder is compounded by
pre-existing physiologic deficit and the effects of nephrotoxic drugs. Obstructive causes must be
considered and ruled out. As is the case for lung injury, ICU interventions contribute to the evolution of
the syndrome: vasopressor agents cause further reductions in renal blood flow, while potentially
nephrotoxic drugs are a key part of the anti-infective arsenal used in the ICU.
Heart and cardiovascular system
The acute cardiovascular derangements of MODS consist of five features:
1. a generalized reduction in peripheral vascular tone, mediated largely through the local
vasodilator’s activity of nitric oxide
2. a generalized increase in capillary permeability producing diffuse capillary leak and edema,
and contributing to further dysfunction in other organ systems
3. alterations in regional blood flow to specific organ beds
4. microvascular plugging and stasis, resulting from occlusion of the microvasculature by
abnormally rigid erythrocytes and leukocytes, and resulting in arteriovenous shunting that
contributes to a high mixed venous saturation
5. myocardial depression, affecting the right side of the heart in particular
It is readily apparent that these abnormalities predispose to impaired oxygen delivery, and therefore
contribute to the injury of other organ systems. Since their net physiologic consequence is hypotension
that is refractory to increased preload, we have used a measure called the pressure-adjusted heart rate
(PAR) to quantify cardiovascular dysfunction in the MOD score. Calculated as the product of the heart
rate and the ratio of central venous to mean arterial pressure (HR × CVP/MAP), it is, like the PO2/FIO2
ratio, a reflection of physiology, corrected for therapy; increasing values reflect worsening
cardiovascular dysfunction.
Gastrointestinal/hepatic
Gastrointestinal dysfunction in critical illness likely results from the interacting effects of reduced
regional blood flow, impaired motility, and alterations in the normal microbial flora. In the past, upper
gastrointestinal bleeding or stress ulceration was the most common manifestation of gut dysfunction;
this complication has become uncommon with improvements in hemodynamic support, earlier
diagnosis of infection, and the appropriate use of effective prophylaxis. Intolerance of enteral feeding,
reflected in bloating and diarrhea is another manifestation of gut dysfunction. However, in contrast to
other organ systems, simple clinical measures of gut dysfunction are not readily available.
Hepatic dysfunction in MODS is reflected in hyperbilirubinemia and cholestasis, rather than in
biochemical evidence of hepatocellular injury or synthetic dysfunction. A stereotypical pattern of altered
hepatic protein synthesis - the acute phase response - typically accompanies MODS as a non-specific
manifestation of systemic inflammation. Serum levels of C reactive protein and alpha-1 anti-trypsin are
elevated as part of the acute phase response, whereas levels of albumin, a negative acute phase
reactant, are depressed.
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Neurologic
An altered level of consciousness, reflected in a reduction in the Glasgow Coma Score, is the most
readily recognizable manifestation of the neurologic dysfunction of MODS. Its causes are multiple,
including the iatrogenic effects of sedatives and analgesics, metabolic alterations, subclinical cerebral
edema and reduced cerebral perfusion pressure, and, perhaps, micro-abscesses in the brain. A
peripheral neuropathy - the so-called ‘critical illness polyneuropathy’ - is commonly present, though
harder to measure.
Hematologic
Leukocytosis is an adaptive response to a variety of acute stresses and therefore commonly present,
although not truly a manifestation of organ dysfunction. Similarly, a mild anemia resulting from both
bone marrow suppression and iatrogenic blood-taking is common. However, the most widely cited
manifestation of dysfunction of the hematologic system in MODS is thrombocytopenia, in its most
extreme form resulting in disseminated intravascular coagulation (DIC). Like other manifestations of
MODS, the causes of thrombocytopenia in critical illness are many - heparin-induced thrombocytopenia,
intravascular consumption, and reduced production to name a few.
Immunologic
Multiple abnormalities of non-specific and specific immune function are described in the critically ill
patient, including impaired delayed type hypersensitivity responsiveness, altered production of
antibodies, and a complex spectrum of abnormalities in the regulation of lymphocyte responses. The
most readily evident, and clinically relevant manifestation of altered immunity in MODS is the
development of nosocomial ICU-acquired infection, caused by relatively avirulent organisms. The
characteristic flora of ICU-acquired infection in MODS includes coagulase-negative Staphylococci,
Enterococci, Candida, and Pseudomonas.
Endocrine/metabolic
Multiple metabolic and endocrine abnormalities are evident during MODS, although they are less well-
characterized, Hyperglycemia and relative insulin resistance is both common and readily detected. Less
accessible abnormalities include the sick euthyroid syndrome, and relative adrenal insufficiency. The
latter has recently gained prominence as a promising therapeutic target for the patient with prolonged
inflammation and organ dysfunction.
Prevention of MODS
MODS are less a syndrome to be treated than a complication to be prevented. Iatrogenic factors, or
processes amenable to prophylactic intervention figure prominently in the expression of the syndrome.
Because the syndrome almost invariably arises following the activation of a host inflammatory response,
MODS can be considered to be the maladaptive consequence of acute inflammation, the systemic
equivalent of function lease, or loss of function, a cardinal sign of acute localized inflammation. To date,
however, interventions targeted at the host inflammatory response have not proven effective in
preventing MODS or minimizing its evolution. Other simpler approaches are more promising. Table III
summarizes ICU interventions for which there is evidence of significant benefit, reflected in reduced
organ dysfunction, or improved ICU survival. The list is a sampling that is of necessity inadequate. Any
intervention that can prevent death or bring physiologic benefit to critically ill patients might reasonably
be included; on the other hand, rigorous evaluation of most commonly accepted ICU interventions has
not been undertaken.
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Conclusion
The multiple organ dysfunction syndrome is both a syndrome and a form of clinical shorthand for the
approach to patient care that is exemplified by contemporary ICU practice. As a syndrome, it is
intimately linked to the adaptive host response to injury or infection, and it is to be expected that
interventions that can modulate the expression of this response will ultimately prove effective in
improving clinical outcome. As a clinical shorthand, it categorizes the range of interventions available to
support critically ill patients, and underlines the prime importance of recognizing the potential for
iatrogenic harm implicit in the increasingly complex and technological repertoire we use to care for
them.