Multi -Organ Failure

Multi -Organ Failure: Pathophysiology and Clinical Manifestations .

Name: Naveed Saleem
Student Number: 180804229
Module: W HR7010
Date: December 3 rd, 2018
Word Count: 2000

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Background :
From the last few decades , due to advancements within acute care settings the chances of
survival of severely ill and injured patients have eventually improved , a part from that medical
specialists have come across with heinous and life -threatening complications that have
surpassed the mortality and morbidity rates within intensive care system and manifested as
Multi -Organ Dysfunction Syndrome (MODS ) (1) . As the name indicate s, it is a syndrome
associated with failure of more than one system which may or may not is associated with
initial injury or a ctual disease for which the patient has admitted within Intensive care unit
(2) . This problem had come into consideration for the first time during World War II, where
majority of individuals developed Respiratory and Renal failure despite adequate blood and
fluids resuscitation therapy , because hemorrhagic shock was contemplated as one of the
leading causes of death during world wa r I , so a new root cause of mortality and morbidity
was identified at that period (1) . This essay will illustrate the pathophysiology of this ailment
and the chain of events ultimately responsible for activation of several intrinsic metabolic
pathways which initially have cytoprotective effects but later erupt lethal inflammatory
responses and lead to the development of failure in distinct organs.
Definition of M ODS :
As stated earlier , it is progressi ve or sequential systems organ failure associated with
potentially life -threatening physiological assaults caused by both infectious and non –
infectious causative agents and finally resul ted in ICU admission (1) . The term MODS was
suggested firstly by a Consensus Conference in 1991 as ” the development of potentially
reversible physiological disarrangement involving either two or more organ systems in acutely
ill patients which homeostasis cannot be maintained without doing possible concilia tions ”(3) .
In order to predict the severity, risk s of development of MODS , patient’s response to
treatment and its final consequences several p rognostic methods are used to quantify organ
dysfunction and patient outcome by considering different scoring systems which use only one
parameter f or each organ system and standardise the reporting of MODS and also provide
quantitative measure of severity and changes in organ function with time (2) . The table

demonstrates the MODS scoring system, which uses following six different variables to access
outcomes (2) .
Table 1: Multiple Organ Dysfunction Syndrome (MODS) Score (2)
.
Organ System 0 1 2 3 4
Respiratory System (PO 2/FIO 2
Ratio) ; 300 226 -300
151 –
225 76 -150 ?75
Renal System (Serum Creatinine) ?100 101 -200
201 –
350 351 -500 ; 500
Hepatic System (Serum Bilirubin) ? 20 21 -60 61 -120 121 -240 ; 240
Cardiovascular System (R/P
Ratio) ? 10
10.1 –
15.0 15.1 -20 20.1 -30 ; 30
Hematologic System (Platelet
Count) ; 120 81 -120 51 -80 21 -50 ? 20

Epidemiology of MOD S:
Due to limited availability of information related to demographic incidences of MODS, still, it
is considered as one of the leading causes of morbidity and mortality within Intensive care
setting s and develops in approximately 15% of medical and surgical a cute care units (2) .
Although various studies have been conducted across the globe from last few decades to
figure out possible causes and outcomes (9) .A study conducted in the US for more than two
decades and i t showed the incidence has surpassed from 1.3 % to 13.7 % with an annual death
rate of about 8.7 % and several variables were considered t o find out causative agents (9) . The
incidence of mortality due to MODS tends to vary accordi ng to the number of organ
involvement while single organ failure approaches up to 48% within cases (2) .
Risk factors :
Even though MODS is validated as a common cause of death in medical and surgical care units
and accounts for 50 % of deaths within intensive care setting s, its severity strongly correlates
with mortality and length of hospital stay, so the commonest risk factor is either
hypoperfusion without shock or sepsis without shock and any kind of shock irrespective of its
etiology (3) . Pri marily it is caused either by infection or secondary to some disease process

(2) . Moreover, it is also influenced by pre -existing chronic ailments such as chronic liver and
kidneys disease, carcinomas and complicated diabetes (3) . Few diseases are mentioned
below (3) .
Tab le 2: Diseases that can progress to MODS (3) .
Infectious Non -Infectiou s
1. Pneumonia.
2. Peritonitis and intra -abdominal
infection.
3. Necrotizing soft tissues infections.
4. Tropical infection (malaria, typhoid,
dengue)
1. Major trauma.
2. Burns.
3. Pancreatitis.
4. Aspiration syndrome.
5. Multiple blood transfusions.
6. Autoimmune disease.
7. Poisoning / Toxicity.
Clinical manifestations :
Patient with MODS shows contradicted clinical presentation, firstly the organs which are
frequently fail ed are not responsible for the initial presentation for which the patient is
admitted within ICU, seco ndly there is some lag period between the initial insult and the
actual initiation of systemic organ s failure because it demonstrates systemic manifestation s
of infection which exacerbates the actual disease process (1) . In addition to this, MODS is als o
influenced by both host and genetic factors which consider playing a key role in aggravating
the initial illness (3) . S ome precipitating factors are enlisted as below (3) .
Host factors Genetic factors
. Advanced age
. Pre -existing comorbidities
. Malignancy
. Immunosuppressive drugs
. Malnutrition
. Genetic var iations in pro -inflammatory
cytokines
. Genetic polymorphism in anti –
inflammatory mediators.
. Modifications within TLR receptors
There is no typical time course of organ dysfunction that describes MODS, some may develop
mild organ dysfunction which can be reversed by supportive treatment whereas others can
present with fulminant MODS rapidly le ading to death (2) . Furthermore, the clinical course is
subdivided into four different stages. Stage 1 is an acute phase and associated with a slightly
variable period of hypotension, while stage 2 is active resuscitation phase which lasts only for
24 hour s and stage 3 is an active hypermetabolic phase that may persist for 7 to 10 days (3) .
During this whole course, the patient can appear as clinically stable but later may develop
systematic organs dysfunction. Identification of MODS as a distinct clinical syndrome is quite
difficult because of unavailability of agreement which depicts an organ dysfunction and each

organ system can reveal disorientation in many ways, for example, lung is the most common
primary organ of insult and exhibits as pulmonary dysfunction before any other organ
involvement , subsequently liver, kidneys, and intestines are involved whereas neurological
sequelae such as confusion, coma and collapse may present early or late in this disease
progress. Several physiological and biochemical parameters are used in combination with
clinical features to explain the full spectrum of this syndrom e(1) .
Pathophysiology :
MODS is a systemic process conceptualized as a complex dynamic nonlinear system involving
a large number of variables which are highly interconnected, several key factors play a central
role in this pathophysiological process (1) . Initially, there is a dysregulated immune response
to critical illness due to disruption of host -derived inflammatory mediators which result in
acute physiological impairment and dysfunction in distant organs (4) . Furthermore, this
iatrogenic insult also exaggerates immune response s that can lead to systemic organs
dysfunction (2) .

Figure 1 : MODS results from a complex interaction of different pathogenic processes (2) .
Disordered Immune Response :
The most important pathogenic mechanism responsible for MODS is immune dysregulation
which ascribes organ failure secondary to the toxic effects of extensive systematic
inflammatory responses because homeostasis fails to keep a balance between systemic
inflammation and counterbalancing anti -inflammatory response (3) . Because of availability of
pathogenic microorganisms’ immun e system is activated, microbial infection is detected by

several mononuclear phagocytes ( monocytes, macrophages) and mast cells due to the
presence of Toll -Like Receptors on their cell surfaces which helps host defense mechanism
for early recognition of i nvading organisms and activation of natural immune response (4) .TLR
interacts with intracellular molecules and results in translocation of pro -inflammatory
transcription factor s such as NF -kB , which are responsible for upregulation of pro and anti –
inflammatory cytoki nes and chemical mediators, apoptotic signaling pathways and nitric
oxide production (3) . All these factors are collectively responsible for systemic inflammatory
immune responses ultimately leading to MODS (3) .

Figure 2: Overview of cellular and molecular mechanisms ultimately leading to MODS (3) .
Coagulation defects :
The mechanisms which are resp onsible for the activation of immunological processes are
highly interlinked to those that can control and regulate coagulation cascades, therefore, any
disturbance within this system leads to disseminated intravascular coagulation which favors
widespread macro and microvascular thrombi formations within different organs alongside it
also causes profuse bleeding due to reducing circulating platelets counts (5) . During critical
ailment levels of anticoagulants such as antithrombin III, protein C and S are disproportionally
low which are strongly correlated with disease pathogenesis and severity (2) .
Neurohumoral Changes during MODS :

The autonomic nervous system is highly interlaced with the inflammatory response, as
various lymphoid organs have both sympathetic and parasympathetic innervations and
release neurohormones which inhibit the release of cytokines and chemical mediators
therefore responsible for downre gulation of immunological processes during severe diseases
(2) . In addition to that, stress response to critical illness is a ssociated with activation of HPA
system, which encourages the release of stress hormones such as adrenal hormones,
vasopressin whic h is controlled by hypothalamic secretion of CRH under direct neural control
and affected by circulating cytokines, therefore under unfavorable body conditions pituitary –
adrenal response is suppressed which may contribute to MODS (6) .
Hepatic dysfunction :
Hypoperfusion results in acute disorientation of hepatic functions and tissue hypoxia which
is a reversible condition and can overcome with sup portive measures while syst emic
inflammation results in activation of TNF alpha, IL and other mediators within hepatosplenic
area, all these contributory factors play a pivotal role in pathophysiology of diffuse hepatic
dysfunction by enhancing portal pressure which increase the possibility of developing variceal
bleeding while portal -systemic shunting in combination with excessive a mmonia production
intensifies the chances of having hepatic encephalopathy (7) . Additionally, there is reduced
hepa tic microcircul ation du e to splanchnic vasodilation (3) .Endothelial dysfunction within
hepatocytes and macrophages affiliated with uncontrolled production of inflammatory
mediators while biogenetic failure is caused by hepatic mitochondrial dysfunction due to
excessive free radical production leading to oxidative stress condition within mitochondria (3) .
Respiratory dysfunction :
The lung is typically the first organ which is involved in MODS and acute lung injury is triggered
by either direct (pneumonia, aspiration) or indirect (massive transfusion, pancreatitis)
assaults. During initial phase, release of pro -inflammatory mediators (cytokines, leukotrienes,
complements) by pulmonary macrophages and endothelial cells initiate sequestration of
ne utrophils within pulmonary circulation and release proteolytic enzymes and reactive
oxygen species which mediate acute lung injury by damaging basement membranes resulting
into surfactant dysfunction and alveolar pooling i.e. non -cardiogenic pulmonary oede ma
responsible for impaired gaseous exchange resulting in tissue hypoxemia (3) . Furthermore,
abnormal coagulation cascades are associated with deposition of platelet -fibrin thrombi

within microcirculation and impair fibrinolysis leading to pulmonary coagulopathy and
defective ventilation -perf usion ratios (2) .
Cardiovascular dysfunction :
Sequential organ failure is initially manifested as hypoperfusion with dramatically decreased
systematic vascular resistance which can overhaul by baroreceptor reflex mechanisms which
initiate autonomic sympathetic outflow to both heart and peripheral circulation to
compensate hypote nsion , later inflammatory mediator particularly NO causes mitochondrial
oxidative injury which is linked with decreased myocardial contractility due to
downregulation of beta -adrenergic receptors activity, therefore, leads to circulatory collapse
and depressed myocardial activity (8) .On top of that sepsis also impairs autonomic
sympathetic activity which is m anifested as peripheral vasodilation that gradually worsens
MODS and ultimately leading to death because of unresponsive to exogenous
vasoconstrictors (3) .
Renal dysfunction :
Posttraumatic injury or hypovolemic shock results in acute kidney injury which is reversible
condition and can be corr ected by fluid resuscitation and supportive therapy (1) .However,
sepsis results in serious insults despite having adequate renal perfusion which results in the
reduction of glomerular filtration rate characterized as defective urea and creatinine
excretion due to vasodilation of efferent arterioles (2) . Moreover, inflammatory mediators
have direct lethal effects on renal tubules and cause acute tubular necrosis by inducing
apoptosis of normal renal cells and the patient experiences oligu ria (3) . Administration of
vasopresso rs and nephrotoxic drugs can also contribute to insufficient renal perfusion and
cellular injury (2) .
Neurological dysfunction :
Systemic inflammatory responses activate cellular and humoral mechanisms to produce
changes within microcirculation throughout the body (2) . Due to profound disturbances of
microcirculation and impaired delivery of oxygen and other substrates, the neurological
system is more commonly affected first and presents as alter ed sensorium (3) . When infection
is accompanying with acute alteration in consciousness it demonstr ates ‘'septic
encephalopathy” because of increased permeability of blood -brain barrier , circulatory

inflammatory and chemical mediators can easily cross this barrier and enter into central
nervous system to induce cerebral edema, encephalopathy, apoptotic cell death and
myopathies (3) .
In a nutshell, this essay demonstrates the basic principl e of MODS and how human’s body
response to overcome the devastating effects of this syndrome, which results in severe
dysfunction of at least two or more body systems especially among critically ill pat ients
which present with sepsis, shock, and trauma. Furthermore, it also explains the
epidemiological incidences, precipitating factors, pathophysiological influences, and clinical
outcomes. So, by keeping in consider ation of body variables, several preven tive measures
must be taken at the beginning to counterbalance this disease process which can reduce the
burden of mortality within acute settings.

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