Multiple Organ Disfunction

Syndrome

Ariandi Setiawan
 HISTORY
• 1914, Schottmueller -"Septicemia is a state of
microbial invasion from a portal of entry into the
blood stream which causes sign of illness.“
• late 1960s, several reports describing remote organ
failure (eg, pulmonary failure, liver failure) as a
complication of severe sepsis.
• 1975, a classic editorial by Baue-"Multiple,
progressive or sequential systems failure, a
syndrome of the 1970s."
• More recently, the term multiple organ dysfunction
syndrome (MODS) has been proposed as a more
appropriate description.
 DEFINITION
• Multiple organ dysfunction syndrome
(MODS), previously known as multiple organ
failure (MOF), is altered organ function in an
acutely ill patient requiring medical
intervention to achieve homeostasis.
• Multiple Organ Dysfunction Syndrome
(MODS) is dysfunction of two or more
organs initially uninvolved developing
within a short period of time.
• The use of "multiple organ failure" should be
avoided since that term was based upon
physiologic parameters to determine whether
or not a particular organ was failing.
ORIGIN

Originally patients were

classified as having sepsis or
the sepsis syndrome.
This resulted in two concepts:

 Systemic inflammatory
response syndrome (SIRS)
and
Multiple organ dysfunction
syndrome (MODS).
 Intra-abdominal Shock
infection

Multiple trauma

Pancreatitis

Biliary tract
infection MODS
MODS Burn

Infective diseases Non-infective diseases

 INTRODUCTION
• Multiple Organ Dysfunction Syndrome (MODS)
describes the progressive dysfunction and ultimate
failure of organs in response to a noxious stimulus.
 This may be infection, trauma or inflammation, or
some combination of these. MODS is common in the
Intensive Care Unit (ICU), and carries a high
mortality. It is easy to recognise when fully
established, but more difficult to appreciate whilst it
is developing, which is the time when prompt action
may prevent further progression.
 Crucially, MODS is a syndrome not a diagnosis.
 AETIOLOGY

 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 seen which is
termed as 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.
07/09/2025 9
 ROLE OF INFECTION
Since infection has such a pivotal role in the development of MODS,
it is important to consider possible sources. Primary infective
causes that may lead to MODS include:

 primary pneumonia (community acquired).

 intra-abdominal surgical emergency (e.g. faecal peritonitis).
 meningococcal disease.
 gram positive toxic shock (Streptococcal or Staphylococcal).
 severe forms of food poisoning (e.g. Salmonella, E. coli 0157).
Secondary infective causes (especially after surgery)
that may lead to MODS include:

• postoperative pneumonia.

• direct surgical complication (e.g. anastomotic leak,

abscess).

• other new infection (e.g. acalculous cholecystitis,

urinary tract infection [UTI]).
 Hospital-acquired (nosocomial) infections, especially in the ICU,
have a different pattern from those acquired in the community.
 Today, about 40% of ICU-acquired infections are Gram-positive
and a similar number are Gram-negative, with fungal infections
comprising the next largest group.
 Staphylococcus aureus is the most common Gram-positive
organism, followed by Coagulase Negative Staphylococci and
Enterococci.
 The most common Gram-negative is still Pseudomonas
aeruginosa, with various coliforms also being seen frequently.
 All intubated patients suffer chronic low-grade aspiration of
pharyngeal secretions, which become contaminated with
bacteria from the GI tract and nasal sinuses.
 Mechanism

Uncontrolled inflammatory response

Microcirculatory hypo-perfusion

Ischemia/reperfusion
injury
 Inflammation

Inflammatory cells
Inflammatory
cytokines
MODS is the failure of the
balance
Uncontrolled inflammatory response
 Anti-inflammatory reaction
IL-10, IL-4, TGF-β
IL-1ra ,Lipoxin
Cell elimination

Pro-inflammatory reaction
TNF-a, IL-1, IL-6, IFN
TXA2, PAF
Cell activation
Systemic Inflammatory Response Syndrome
(SIRS)
【 Definition
】
An uncontrolled inflammation process
Pro-inflammatory signals exceed its normal
domain or degree

Result in end-organ damage and multi-system

failure.
 CLASSIFICATION
 Primary MODS describes a situation in which multiple organ
dysfunction is directly attributable to the initiating insult, as in
the case of multiple trauma.
 Secondary MODS describes a situation where the organ
dysfunction is not a direct result of the initial injury, but is a
consequence of the host response, characterised by a
generalised activation of the inflammatory response in organs
remote from the initial insult.
 .

• Of course, both primary and secondary aspects of

MODS may exist in the same patient, but it is
secondary MODS which has become such a familiar
sight in modern ICUs.
 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)
 There are various theories such as:-
Gut hypothesis:-
 The most popular theory to explain MODS in critically ill
patients is the gut hypothesis.
 Due to splanchnic hypoperfusion and the subsequent
mucosal ischaemia 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 systemic
circulation and activating an immune response.
 This results in tissue injury and organ dysfunction.
• The gut also has the largest aggregation of lymphoid tissue in the
body (gut-associated lymphoid tissue, GALT), and may be a
source of cytokine release even without translocation.
 Surface mucosal immunity, which is mediated by IgA, seems to
operate in a common fashion in both the gut and the respiratory
tree.
 Failure to protect the gut by failing to provide enteral feeding
and ensuring adequate gut perfusion diminishes the effectiveness
of the GALT and the gastrointestinal IgA, and also of the
respiratory mucosal IgA, so potentially predisposing to respiratory
infection.
Endotoxin macrophage theory:-

 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.
Infection/ injury Inflammatory stimulato

Local inflammatory
Pro-inflammatory cell activated
mediators released (M,PMN,VEC,)
Systemic inflammatory
cell activated
(M,PMN,VEC,)

Tissue injury
Systemic Inflammatory Response Syndrome
(SIRS) Anti-inflammatory reaction
IL-10, IL-4, TGF-β
【 Definition IL-1ra ,Lipoxin
Cell eliminate
】
An uncontrolled inflammation process
Pro-inflammatory signals exceed its normal
domain or degree
Pro-inflammatory reaction
TNF-a, IL-1, IL-6, IFN
TXA2, PAF
ResultCell
in activation
end-organ damage and multi-system
failure.
 【 SIRS Clinical manifestations 】

Body temperature above 38℃ or less

than 36℃.
Heart rate >90 beat/min.
Respiration rate >20/min or PaCO2 <32
mmHg.
WBC >12,000/mm3 or <4000 cells/mm3, or
>10% immature cells.
pensatory Anti-inflammatory Response Syndrome( CA
Anti-inflammatory reaction
【 Definition IL-10, IL-4, TGF-β
IL-1ra ,Lipoxin
】
An uncontrolled anti-inflammation Cell eliminate
process
Anti-inflammatory signals exceed its normal
domain or degree
Result in end-organ damage and multi-system
failure.
Pro-inflammatory reaction
TNF-a, IL-1, IL-6, IFN
TXA2, PAF
Cell activation
Immune paralysis
 Infection/Injury

Uncontrolled Controlled
inflammatory response inflammatory response

SIRS CARS

Infection/
injury
MODS
controlled
 DIAGNOSIS

• The European Society of Intensive Care in 1994 has

devised SOFA:
"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.
 CLINICAL MARKERS
• Brachial systolic blood pressure: < 90mmHg
• Sinus tachycardia: >90 beats/min
• Respiratory rate: <7 or >29 breaths/min
• Urine Output: <0.5cc/kg/hr
• Metabolic acidemia: [HCO3]<31mEq/L or
base deficit>3mEq/L
• Hypoxemia: 0-50yr: <90mmHg; 51-70yr:
<80mmHg; >71yo<70mmHg;
• Cutaneous vasoconstriction vs. vasodilation.
• Mental Changes: anxiousness, agitation,
indifference, lethargy
 SYMPTOMS

• Anxiety /Nervousness
• Dizziness
• Weakness
• Faintness
• Nausea & Vomiting
• Thirst
• Confusion
• Decreased urine output
 SIGNS

• Pale
• Cold an clammy
• Sweating
• Cyanosis
• Tachycardia
• Tachypnoea
• Confused / agitated
• Unconscious
• Stridor
• Hypotensive
 COMPENSATORY MECHANISM

• Baroreceptor reflexes
• Circulating vasoconstrictors
• Chemoreceptor reflexes
• Reabsorption of tissue fluids
• Renal reabsorption of sodium and water
• Activation of thirst mechanisms
• Cerebral ischemia
• Hemopoiesis
There are various systems involves such as:-

1) Cardiovascular dysfunction:-
Cardiovascular dysfunction is a key component of MODS, and
can be both a cause and a consequence. The key components
of cardiovascular function are:

 cardiac function
 vascular tone
 vascular permeability.
The pattern of cardiac dysfunction typically seen in sepsis and
MODS is:

Pathological vasodilatation
Leading to hypotension and reduced cardiac filling, and a relative
reduction in cardiac output.
 The reduced vascular tone also tends to increase cardiac output
by reducing resistance to forward blood flow (afterload).
 The net effect of these opposing phenomena depends on the
overall volume status. The mechanism for the vasodilatation is
an increased production of nitric oxide by the vascular
endothelium, resulting in vascular relaxation.
 Increased permeability, resulting in leakage of fluid into the
interstitium, oedema formation and hypovolaemia.
 In the lung the oedema contributes to impaired gas exchange.
The hypovolaemia contributes to a fall in cardiac output.
 Many cytokines have direct myocardial depressing effects,
resulting in impaired contractility and reduced stroke volume, so
limiting the compensatory increase in cardiac output in response
to a fall in vascular resistance.
 Heart rate is generally increased in response to the inflammatory
mediators and increased sympathetic drive, resulting in an
increase in cardiac output.
If blood pressure is inadequate there will be reduced
perfusion of vital organs, manifested by:

• confusion
• a falling urine output
• reduced myocardial perfusion – dependent
predominantly upon systemic diastolic blood
pressure.
• If cardiac output is inadequate there will be signs of
tissue hypoxia due to reduced oxygen delivery
 Oxygen consumption (VO2) is the difference between the amount
of oxygen being despatched by the arterial supply and returning
via the venous system.

If oxygen delivery is inadequate and tissue hypoxia develops, the

signs of anaerobic metabolism will be present:

 worsening metabolic acidosis, with an increasingly negative base

excess
 rising blood lactate level
 splanchnic ischaemia measured with a gastric tonometer (which
measures CO2 production by the gastric mucosa, which increases
as perfusion worsens).
2) Respiratory dysfunction :-Respiratory dysfunction
is a key feature of MODS and arises for a number of
reasons. Lung damage may be primary or secondary.
Primary lung damage include:

• pneumonia
• pulmonary contusion
• aspiration
• smoke inhalation.
Secondary lung damage occurs through the action of
inflammatory cytokines and activated white blood
cells from a distant source. Triggering events
include:

• pancreatitis
• abdominal sepsis
• massive blood transfusion.
 A key feature of lung dysfunction in MODS is that it
is acute, although there may be pre-existing lung
disease.
 The term Acute Respiratory Distress Syndrome
(ARDS) is used in this context but, just as with the
terms relating to sepsis.
 Less severe damage would be known as Acute Lung
Injury (ALI) and more severe damage as Acute
Respiratory Distress Syndrome (ARDS).
The definitions of Acute Lung Injury and Adult (Acute)
Respiratory Distress syndrome have several
features in common:

• an appropriate clinical setting with one or more

recognised risk factors
• bilateral diffuse fluffy infiltrates on the chest X-ray
• no clinical evidence of heart failure or fluid overload
(pulmonary artery occlusion pressure <18 mmHg),
or chronic lung disease
Diffuse mottling of the lung fields characteristic of
ARDS
 Apart from occurring as part of the end-organ damage seen in
MODS, ALI and ARDS may be triggered or exacerbated by
overenthusiastic fluid resuscitation in patients where there is
already pulmonary capillary damage with increased permeability
and therefore a tendency to develop pulmonary oedema.

Recently, there have been two more important conceptual

advances. The first is that a considerable proportion of the lung
injury seen in MODS patients with ALI or ARDS is probably caused
by the sheer stresses imposed upon the lung by the mechanical
ventilator.

 This has led to the term ventilator-induced lung injury (VILI). New
ventilatory strategies and techniques are under development to
address this problem.
 The second advance, briefly mentioned earlier, is the realisation
that the injured lung can contribute to the development or
progression of MODS through the release of cytokines, even in
the absence of pulmonary infection.
 A severe lung injury also has haemodynamic consequences.
Pulmonary hypertension develops acutely and can be very
severe, leading ultimately to right heart failure, with a rising
central venous pressure and liver congestion. Forward blood flow
through the injured lung also becomes impaired, and left
ventricular filling and systemic blood flow fall. The combination
of a falling cardiac output and a high venous pressure results in
impaired arterio-venous perfusion gradients across various organ
beds, so further contributing to end-organ damage and the
progression of MODS.
 Finally, severe hypoxaemia due to ARDS also contributes to the
development of MODS by exacerbating tissue hypoxia.
3) Acute renal dysfunction:-

Acute renal dysfunction and failure is a common

feature of MODS. As with other organs, the kidney is
a ‘victim’ of the systemic process, but the pattern of
renal impairment and subsequent failure and
recovery owes much to the specific anatomical and
physiological characteristics of the kidney.
• Traditionally, acute renal failure is considered under
the headings ‘pre-renal’, ‘renal’ and ‘post-renal’.
 Pre-renal failure implies inadequate blood flow, usually due to
hypovolaemia or hypotension.
 Renal renal failure implies direct renal damage.
 Post-renal failure implies obstruction to urine outflow.

 In the context of MODS there are numbers of insults to the

kidney occurring at the same time rather than a single injury, and
this classification is less useful.
 The haemodynamic changes contribute to reduced perfusion and
local hypoxia, which is exacerbated by hypoxaemia secondary to
the lung injury.
 Conditions of borderline hypoxia already exist in the renal
medulla, due to the countercurrent anatomy of the kidney,
making it particularly vulnerable to further insult.
 The generalised inflammatory response also results in direct
kidney damage by cytokines and activated white blood cells.
The renal response to injury consists of three phases:
 Oliguria - conservation of salt and water by a reduction in urine
output. Urea and creatinine levels rise. At this stage, urine output
can still be restored if the patient is resuscitated successfully.
 Anuria - renal failure becomes established, urine output becomes
minimal or ceases for a period of days or weeks even if renal
blood flow is restored and the initiating insult resolved. During
this period renal support techniques are required.
 Recovery - urine output returns, but initial quality is poor and
there is often a period of polyuria before full recovery of function
occurs. Occasionally, there is no anuric period, and the patient
suffers polyuric renal failure only. This may still be associated with
marked metabolic and biochemical abnormalities, but
management of fluid balance remains possible with appropriate
fluid replacement regimens.
The major pathological consequences of acute renal
failure are:

• rising urea and creatinine.

• rising potassium.

• worsening metabolic acidosis, usually associated

with a normal lactate.

• fluid balance abnormalities (depending upon the

cause of the renal failure), followed by a tendency to
become fluid overloaded easily if anuric, and fluid
depleted if polyuric.
• The impact of acute renal failure upon the outcome
of patients with MODS is often debated, since the
mortality of this group of patients is so high; of the
order of 50–70%.

• With modern approaches to continuous renal support

(haemofiltration and haemodiafiltration), the
mortality is significantly reduced.

• In fact, the patients have MODS, and the outcome

relates to the degree of overall organ dysfunction
which reflects the severity of illness, and the
underlying cause.
4) Acute liver dysfunction:- The liver is fundamental to many
metabolic and immune functions, and has a rich blood supply via
the hepatic artery and the portal vein.
Not surprisingly, it may well have a pivotal role in the development
of MODS, although research into the liver in this context has
been relatively lacking.
Traditional liver function tests (liver enzymes, bilirubin, albumin
and clotting) are often non-specifically deranged in critically-ill
patients, and give little information about acute changes in liver
function.
Transaminases may be dramatically increased after episodes of
severe ischaemia or shock; so called ‘shock liver’.
 More specific tests of dynamic liver function are
available for research purposes, and these include:

• measurements of liver blood flow using a hepatic

vein catheter
• indocyanine green clearance, which measures liver
blood flow and secretory function
• arterial ketone body ratio, which gives a marker of
the redox state of the liver
• metabolism of an injection of lignocaine to
monoethylglycinexylidide (MEGX), which gives a
measure of liver blood flow and cytochrome P450
system function.
• If bacteria, endotoxin or cytokines are released into
the portal blood from a leaky gut, an immune
response in the liver results.

• What subsequent role this might have in causing the

systemic response seen in MODS is still unclear, but
this mechanism has often been suggested as one
possible stimulus for the development of MODS as
part of the ‘gut-origin of MODS’ theory.
• 5) Gastrointestinal dysfunction :-
Apart from a possible role in the genesis of MODS, the
gut is directly involved in two more straightforward
ways, both of which might be regarded as being ‘gut-
failure’.

• failure to tolerate enteral feeding.

• stress ulceration and gastrointestinal bleeding.

• Critically-ill patients all require tube feeding when

they are intubated and ventilated, and may be
difficult to feed enterally.
Total parenteral nutrition (TPN) is often used in the ICU since it
provides a sure way of delivering nutrition to patients
immediately.

 Unfortunately, however the use of TPN does not appear

beneficial compared with no feeding at all for at least 10 days
rather has a number of harmful effects, and is very expensive.

TPN is associated with:

 increased infection rate, because of direct immunosuppressive

effects due to the fat preparations used, and due to the
requirement for central venous access.
 gut atrophy leading to increased gut permeability, since
enterocytes receive much of their nutrition from the contents
of the gut lumen and villi atrophy with disuse.
The complications of enteral feeding?

• Diarrhoea
• Aspiration pneumonia
• Nasopharyngeal injury .

Whether TPN actually contributes to translocation of

toxins or bacteria and leads to MODS is far less clear
but, from the physiological perspective as well as for
preventing stress ulceration and on cost grounds,
enteral nutrition should be preferred whenever
possible. In good centres, an enteral feeding success
rate of 80-90% would be expected, with only a few
patients genuinely needing TPN.
 Stress ulceration and gastrointestinal bleeding

 Blood supply to the gut is reduced as part of the stress response,

potentially leading to ischaemia, particularly at the mucosal level,
and subsequent stress ulceration and gastrointestinal bleeding.
 Severe gastrointestinal bleeding was once common place in
critically-ill patients, but now occurs in only 2-3% of patients.
 This reduction has been paralleled by the introduction of stress
ulcer prophylaxis with H2 antagonists such as ranitidine.
 Nevertheless, the use of such agents is controversial, since
stomach acidification may fail in patients who are very sick,
raising doubts about their value.

 Conversely, prevention of stomach acidification may lead to
colonisation of the upper gastrointestinal tract with bacteria,
contributing to the development of nosocomial pneumonia.
 To minimise this latter effect, stress ulcer prophylaxis is often
provided with sucralfate, which has a barrier rather than an
antacid effect.
 Debate still continues as to the better approach, and the
latest studies suggest that ranitidine is slightly better at
preventing bleeding in patients at risk than sucralfate, but
that sucralfate is probably associated with a lower incidence
of pneumonia.
6) Haematological dysfunction:-
• Haematological dysfunction is an area that is readily
overlooked, but abnormalities are commonplace in
the patient with MODS.
• The patterns seen are usually due to systemic
consumption of blood components or bone marrow
depression.
• Peripheral consumption (disseminated intravascular
coagulation, DIC) due to activation of the
coagulation pathways as part of the inflammatory
response seen in MODS – features include prolonged
clotting, low platelets, low fibrinogen, low
antithrombin III and low protein C, with bleeding and
anaemia in severe cases.
• Bone marrow depression – features include anaemia,
a very low white cell count in the face of severe
infection, and a low platelet count.
• Both syndromes, which often occur at the same
time, require support with blood products if severe.
• Moreover, microvascular coagulation in DIC impairs
perfusion at the capillary level and contributes to
organ hypoxia and dysfunction seen with MODS
7) Cerebral dysfunction:-

 Cerebral dysfunction is very difficult to quantify and assess in

critically-ill patients.
 In the acute phases of severe illness patients become obtunded,
often for a variety of reasons. Most common are the global
effects of hypoxia and hypotension, but there may be more
subtle changes affecting extra-mitochondrial enzyme systems
and nerve conduction.
 Any patient who has depressed consciousness in this context is
severely unwell, and should have his/her airway protected as
soon as possible.
 Once intubated and sedated, patients with MODS become much
more difficult to assess, but non-specific encephalopathy as well
as drug effects are commonplace, and may take considerable
time to resolve.
8) Peripheral neuropathy :-
Patients with prolonged MODS also exhibit peripheral
neuropathies and myopathies.
These may be subclinical, detectable only on
neurophysiological testing, or profound, resulting in
severe and prolonged weakness or even complete
paralysis. The clinical picture is very similar to that of
the Guillian-Barré Syndrome, and peripheral
demyelination and axonal damage are sometimes
seen, as well as muscle wasting and necrosis. The
exact cause is unclear, but immunological factors,
microvascular occlusion and effects of drugs,
especially non-depolarising neuromuscular blockers
(and denervation in the case of muscle damage)
have all been implica
 INVESTIGATIONS
ABG
– Measurement of serum lactate provides an assessment of tissue
hypoperfusion.
Normal In Shock
pH 7.35 to < 7.35 -
7.45 7.45 >
PaCO2 35 – 45 >
mmHg 45mmHg
PaO2 86 – 100 < 80
mmHg mmHg
HCO3 22 – 26 < 31
mmol/L mmol/L
Base 0 mmol/L >3
Excess mmol/L
SPO2 94 – < 92%
100%
• Serum lactate: Higher serum lactate indicates a
worse degree of shock and a higher mortality.
• Prothrombin time (PT) and activated partial
thromboplastin time (aPTT):
• Assess coagulation status with prothrombin time
(PT) and activated partial thromboplastin time
(aPTT).
• Blood cultures: Indiscriminate use of blood cultures
has low utility.
– Blood culture is the primary modality for aiding in the
diagnosis for intravascular infections (eg, endocarditis) and
infections of indwelling intravascular devices.
– Two populations, people who abuse IV drugs and patients
with prosthetic heart valves, are at high risk for
endocarditis.
– Patients at risk for bacteremia include adults who are
febrile with an elevated WBC or neutrophil band counts,
elderly patients who are febrile, and patients who are
febrile and neutropenic. These populations have a 20-30%
incidence of bacteremia.
– The incidence of bacteremia is at least 50% in patients
with sepsis and evidence of end-organ dysfunction.
• Urinalysis and urine culture: Urinary infection is a
common source for sepsis, especially in elderly
individuals. Adults who are febrile without
localizing symptoms or signs have a 10-15%
incidence of occult urinary tract infection (UTI).
• Tissue staining and culture: Obtain secretions or
tissue for Gram stain and culture from sites of
potential infection. Generally, the Gram stain is
the only available test to immediately document
the presence of bacterial infection and guide the
choice of initial antibiotic therapy.
 IMAGING STUDIES
– Obtain a chest radiograph in patients with severe sepsis
because the clinical examination is unreliable for
pneumonia. Clinically occult infiltrates have been detected
by routine use of chest radiography in adults who are
febrile without localizing symptoms or signs and in
patients who are febrile and neutropenic without
pulmonary symptoms.
– Supine and upright or lateral decubitus abdominal films
may be useful when an intraabdominal source is
suspected.
– Ultrasound is the imaging modality of choice when a biliary
tract source is suspected to be the source of sepsis
– CT scan is the imaging modality of choice for excluding
intraabdominal abscess or a retroperitoneal source of
infection.
– Obtain a CT scan of the head in patients with evidence of
increased intracranial pressure (papilledema) or suggestion
of focal mass lesions (eg, focal defects, previous sinusitis or
otitis, recent intracranial surgery) or prior to lumbar
puncture (LP) when meningitis is suspected.
– When there is clinical evidence of a deep, soft tissue
infection, such as, crepitus, bullae, hemorrhage, or foul
smelling exudate, obtain a plain radiograph. The presence
of soft tissue gas and the spread of infection beyond
clinically detectable disease may require surgical
exploration
 PROCEDURES
◦ Procedures, such as cardiac monitoring, noninvasive BP monitoring, and
pulse oximetry, are necessary because patients often require ICU admission
for invasive monitoring and support.
◦ Supplemental oxygen is provided during initial stabilization and
resuscitation.

 All patients in septic shock should have adequate venous access for volume
resuscitation. A central venous line also can be used to monitor central
venous pressure to assess intravascular volume status.
• The most commonly used veins are the internal
jugular vein, the subclavian vein and the femoral
vein.
• The Seldinger technique is generally employed to
gain central venous access.
• Drugs that are prone to cause phlebitis in peripheral
veins (caustic), such as:
– Calcium chloride
– Chemotherapy
– Potassium chloride
– Amiodarone
• Need for intravenous therapy when peripheral
venous access is impossible
– Blood
– Medication
– Rehydration\
 An indwelling urinary catheter used to monitor urinary
output is used as a marker for adequate renal perfusion and
cardiac output.

 Patients who have developed septic shock require right heart

catheterization with a pulmonary artery (Swan-Ganz)
catheter. This catheter provides an accurate assessment of
the volume status of a patient who is septic. The cardiac
output measurement can be obtained. Furthermore,
determination of mixed venous oxygenation is helpful in
determining the status of tissue oxygenation.

 Most patients who are septic develop respiratory distress

secondary to severe sepsis or as a manifestation of septic
shock. Pulmonary dysfunction of sepsis (ARDS) also may
occur. These patients need intubation and mechanical
ventilation for optimum respiratory support.
 STAGING
Two well-defined forms of multiorgan dysfunction syndrome exist.
In both, the development of acute lung injury or ARDS is of key
importance to the natural history.
ARDS is the earliest manifestation in all cases.

 In the more common form of multiorgan dysfunction syndrome,

the lungs are the predominant, and often the only, organ system
affected until very late in the disease.
 These patients most often present with primary pulmonary
disorder, such as pneumonia, aspiration, contusion, near
drowning, exacerbation of chronic obstructive pulmonary disease
(COPD), hemorrhage, or pulmonary embolism
• Lung disease progresses to meet ARDS criteria.

• Encephalopathy or mild coagulopathy may

accompany pulmonary dysfunction, which
persists for 2-3 weeks.

• At this time, the patient either begins to recover

or progresses to develop fulminant dysfunction in
another organ system.

• Once another major organ dysfunction occurs,

these patients frequently do not survive.
 The second form of multiorgan dysfunction syndrome presents
quite differently.
 These patients often have an inciting source of sepsis in organs
other than the lungs, the most common being intraabdominal
sepsis, extensive blood loss, pancreatitis, or vascular
catastrophes.
 Acute lung injury or ARDS develops early, and dysfunction in
other organ systems also develops much sooner than in the more
common form of multiorgan dysfunction syndrome.
 The organ systems affected are hepatic, hematological,
cardiovascular, and renal. Patients remain in a pattern of
compensated dysfunction for several weeks, at which time they
either recover or deteriorate further and die.
Organ System Mild Criteria Severe Criteria

Hypoxia/hypercarbia requiring ARDS requiring PEEP* >10 cm H2O

Pulmonary
assisted ventilation for 3-5 days and FiO2† <0.5

Bilirubin 2-3 mg/dL or other liver

function tests more than twice
Hepatic Jaundice with bilirubin 8-10 mg/dL
normal, PT elevated to twice
normal

Oliguria ( <500 mL/d or increasing

Renal Dialysis
creatinine) 2-3 mg/dL

Stress ulceration with need for

Intolerance of gastric feeding for
Gastrointestinal transfusion, acalculous
more than 5 days
cholecystitis

aPTT >125% of normal, platelets Disseminated intravascular

Hematologic
<50-80,000 coagulation

Decreased ejection fraction with Hyperdynamic state not responsive

Cardiovascular
persistent capillary leak to pressors
CNS Confusion Coma
Combined motor and sensory
Peripheral nervous system Mild sensory neuropathy
deficit
 SCORING SYSTEMS IN ICU

• APACHE II ("Acute Physiology and Chronic Health

Evaluation II") is a severity of disease classification
system, one of several ICU scoring systems.

• After admission of a patient to an intensive care

unit, an integer score from 0 to 71 is computed
based on several measurements; higher scores
imply a more severe disease and a higher risk of
death
• APACHE II was designed to measure the severity of
disease for adult patients admitted to Intensive care
units.
• The lower age is not specified in the original article,
but a good limit is to use Apache II only for patients
age 15 or older.
• This scoring systems is used in many ways:
Some procedures and some medicine is only given to
patients with certain APACHE II score
• APACHE II score can be used to describe the
morbidity of a patient when comparing the outcome
with other patients.
• Predicted mortalities are averaged for groups of
patients in order to specify the group's morbidity.
 The point score is calculated from 12 routine physiological
measurements (such as blood pressure, body temperature, heart
rate etc.) during the first 24 hours after admission, information
about previous health status and some information obtained at
admission (such as age).
 The calculation method is optimized for paper schemas. The
resulting point score should always be interpreted in relation to
the illness of the patient.
 After the initial score has been determined within 24 hours of
admission, no new score can be calculated during the hospital
stay.
 If a patient is discharged from the ICU and readmitted, a new
APACHE II score can be calculated
 TREATMENT
The principles in the management of MODS based on current
literature include the following components:

 Early recognition
 Early and adequate antibiotic therapy
 Source control
 Early hemodynamic resuscitation and continued support
 Corticosteroids (refractory vasopressor-dependent shock)
 Drotrecogin Alpha (severely ill if APACHE II score > 25)
 Tight glycemic control
 Proper ventilator management with low tidal volume in patients
with ARDS
General supportive care
– Initial treatment includes support of respiratory and
circulatory function, supplemental oxygen, mechanical
ventilation, and volume infusion.
– Treatment beyond these supportive measures includes
a combination of several parenteral antibiotics, removal
or drainage of infected foci, treatment of complications,
and pharmacologic interventions to prevent further
harmful host responses.
– Administer supplemental oxygen to any patient who is
septic with hypoxia or respiratory distress.
– If the patient's airway is not secure or respirations are
inadequate, perform endotracheal intubation and
mechanical ventilation.
 GOAL DIRECTED THERAPY
• GDT is a bundle of care that includes intensive
care unit (ICU) monitoring, fluids, blood
transfusion and inotropes, and it is difficult to
know if the benefits of GDT are due to all or just
some of these components.

• Of note for practitioners, the safety of the

pulmonary artery (PA) catheter has been
questioned and this was a core technology to
measure cardiac output in earlier GDT studies.
 OBJECTIVES OF GDT
 Goal-directed therapy has been used for severe sepsis and
septic shock in the intensive care unit.

 This approach involves adjustments of cardiac preload,

afterload, and contractility to balance oxygen delivery with
oxygen demand.

 The purpose of this study was to evaluate the efficacy of early

goal-directed therapy before admission to the intensive care
unit
 The systemic inflammatory response syndrome can be self-
limited or can progress to severe sepsis and septic shock.
 Along this continuum, circulatory abnormalities (intravascular
volume depletion, peripheral vasodilatation, myocardial
depression, and increased metabolism) lead to an imbalance
between systemic oxygen delivery and oxygen demand,
resulting in global tissue hypoxia or shock.
 An indicator of serious illness, global tissue hypoxia is a key
development preceding multiorgan failure and death.
 The transition to serious illness occurs during the critical
"golden hours," when definitive recognition and treatment
provide maximal benefit in terms of outcome.
 These golden hours may elapse in the emergency
department,hospital ward,or the intensive care unit.
 A more definitive resuscitation strategy involves goal-
oriented manipulation of cardiac preload, afterload, and
contractility to achieve a balance between systemic oxygen
delivery and oxygen demand.
 End points used to confirm the achievement of such a
balance (hereafter called resuscitation end points) include
normalized values for mixed venous oxygen saturation,
arterial lactate concentration, base deficit, and pH.
 Mixed venous oxygen saturation has been shown to be a
surrogate for the cardiac index as a target for hemodynamic
therapy.
 In cases in which the insertion of a pulmonary-artery catheter
is impractical, venous oxygen saturation can be measured in
the central circulation.
 PROTOCOL FOR GDT
• The protocol was as follows. A 500-ml bolus of
crystalloid was given every 30 minutes to achieve a
central venous pressure of 8 to 12 mm Hg.
• If the mean arterial pressure was less than 65 mm
Hg, vasopressors were given to maintain a mean
arterial pressure of at least 65 mm Hg.
• If the mean arterial pressure was greater than 90
mm Hg, vasodilators were given until it was 90 mm
Hg or below.
• If the central venous oxygen saturation was less than
70 percent, red cells were transfused to achieve a
hematocrit of at least 30 percent.
 After the central venous pressure, mean arterial pressure, and
hematocrit were thus optimized, if the central venous oxygen
saturation was less than 70 percent, dobutamine administration
was started at a dose of 2.5 µg per kilogram of body weight per
minute, a dose that was increased by 2.5 µg per kilogram per
minute every 30 minutes until the central venous oxygen
saturation was 70 percent or higher or until a maximal dose of 20
µg per kilogram per minute was given.

 Dobutamine was decreased in dose or discontinued if the mean

arterial pressure was less than 65 mm Hg or if the heart rate was
above 120 beats per minute.
 To decrease oxygen consumption, patients in whom
hemodynamic optimization could not be achieved received
mechanical ventilation and sedatives.
Extracellular fluid replacement

• Crystalloids should be given first

• Monitoring of these is must;

BP, pulse, urine output(>0.5 ml/kg/hr), CVP,
Laboratory tests

• If severe blood loss, should be replaced by

blood; not only with fluids or even blood
substitutes
 CRYSTALLOIDS

• Ringer's Lactated solution is the most widely

used
• equilibrates rapidly throughout the
extracellular compartment, restoring the
extracellular fluid deficit associated with
blood loss.
• Because of the rapid equilibration of
balanced salt solutions into the extracellular
space, larger volumes may be required for
adequate resuscitation, resulting in
decreased intravascular oncotic pressure.
• It was observed by Rhee et al. that lactated Ringer's
solution exacerbated neutrophil superoxide burst
activity and increased neutrophil adherence.

• Also, it has been shown that aggressive crystalloid

resuscitation was followed by increased cytokine
activation including IL-1, IL-6, and TNF.

• It provides a source of bicarbonate as a result of the

metabolism of lactate to CO2 and H2O; and unlike
bicarbonate.

• It does not precipitate calcium when it is added to

intravenous fluids.
 COLLOIDS SOLUTION
 In the intravascular compartment has been advocated
for treatment of hemorrhagic shock.

 human albumin, hydroxyl ethyl starch (HES), and

dextran.

 It remains briefly in the intravascular compartment, a

lower total volume of resuscitative fluid is required to
attain hemodynamic stability compared to crystalloid
solutions. However, colloid solutions are more
expensive, may bind and decrease serum ionized
calcium, decrease circulating levels of
immunoglobulines, and may further compromise the
extracellular fluid volume deficit rather than restoring
it.
• No protective effect of colloid solutions on post-
resuscitation pulmonary function was
demonstrated, even though colloid solutions do
produce transiently greater intravascular expansion
per unit compared to crystalloid solutions.

• Colloid solutions are recommended in military

scenarios because of a major concern with regard to
resuscitation of hemorrhage in the military setting
where considerable weight and volume of
crystalloid solutions must be transported in the field
sometimes on the back of the medical
professionals.

• Causes Raullex Formation as difficulty occurs in

cross mating
 HYPERTONIC SOLUTIONS
 hypertonic saline (5 ml/kg NaCl 7.5%) with or without
dextran can be an effective initial resuscitation solution.
 Hypertonic solutions improve microvascular flow,
control intracranial pressure, stabilize arterial pressure
and cardiac output with small-volume infusion, with no
deleterious effects on immune functions.
 the Committee on Fluid Resuscitation for Combat
Casualties of the Institute of Medicine concluded that
the initial fluid resuscitation of the hemorrhaging
battlefield casualty should be a 250 ml bolus of 7.5%
saline delivered by a rapid infusion system.
 Systemic access would be achieved via an intraosseous
needle or by intravenous access.
 In hemorrhagic shock showed an increase in blood
pressure and cardiac output but there was no
significant improvement in survival.
 OXYGEN CARRYING SUBSTITUTES
 Two types: fluorocarbon-based synthetic oxygen carriers

Stroma-free cross linked human or non-human hemoglobin

products.

 The fluorocarbon emulsions are easy to

produce, have a long shelf life, and have minimal infectious or
immunogenic effects.
Disadvantages : requirement of a high FiO2 and rapid plasma
clearance.

 Hemoglobin-based oxygen carriers are notable for high

oxygen carrying capacity, an appreciable oncotic effect, and
prolonged shelf life.
Disadvantages : short plasma half life, potential renal
toxicity, hypertensive effects, and the potential of
immunogenic effects.
 Vital signs, mental status, urinary output, and capillary refill
should be assessed regularly throughout the resuscitation.
Initiation of central monitoring may be indicated at this time.

 Blood components may also be used at this stage to replace

identified deficiencies.

 Most cases of unresponsive hemorrhagic shock to fluid

management in the trauma patient are due to ongoing losses
of blood volume or myocardial dysfunction.

 Mild to moderate hypotension allows for clot formation and

slows bleeding from injured blood
 Empirical antimicrobial therapy
◦ Administer initial antibiotics. Selection of particular agents is empirical
and is based on an assessment of the patient's underlying host
defenses, the potential sources of infection, and the most likely
responsible organisms.

◦ Antibiotics must be broad spectrum and cover gram-positive, gram-

negative, and anaerobic bacteria because all classes of these
organisms produce identical clinical pictures.

◦ Administer antibiotics parenterally in doses adequate to achieve

bactericidal serum levels.

◦ Many studies have found that clinical improvement correlates with the
achievement of serum bactericidal levels rather than the number of
antibiotics administered.
 Include coverage directed against anaerobes in the therapy of patients
with intraabdominal or perineal infections.

 Antipseudomonal coverage is indicated in patients with neutropenia or

burns.

 Patients who are immunocompetent usually can be treated with a single

drug with broad-spectrum coverage, such as a third-generation
cephalosporin.

 Patients who are immunocompromised usually require dual antibiotic

coverage with broad-spectrum antibiotics with overlapping coverage.

 Within these general guidelines, no single combination of antibiotics is

clearly superior to others.
 Vasopressor supportive therapy

◦ When proper fluid resuscitation fails to restore hemodynamic stability

and tissue perfusion, initiate therapy with vasopressor agents.

◦ These agents are dopamine, norepinephrine, epinephrine, and

phenylephrine.

◦ These vasoconstricting drugs maintain adequate BP during life-

threatening hypotension and preserve perfusion pressure for
optimizing flow in various organs.

◦ Maintain the mean BP required for adequate splanchnic and renal

perfusion (mean arterial pressure [MAP] of 60 or 65 mm Hg) based on
clinical indices for organ perfusion.
 If the patient remains hypotensive despite volume infusion
and moderate dose dopamine, start a direct
vasoconstrictor (eg, norepinephrine) at a dose of 0.5
mcg/kg/min in and titrated to support a systolic BP of 90
mm Hg.
 While potent vasoconstrictors (eg, norepinephrine)
traditionally have been avoided because of their adverse
events on cardiac output and renal perfusion, human data
has shown that norepinephrine can reverse septic shock in
patients unresponsive to volume and dopamine.
 These patients require invasive hemodynamic monitoring
with arterial lines and pulmonary artery catheters.
 A brief discussion of the hemodynamic drugs used to
support patients who are critically ill and septic follows:
◦ Vasopressor therapy
 Dopamine: A precursor of norepinephrine and epinephrine, dopamine has
varying effects based on the doses. A dose of less than 5 mcg/kg/min results
in vasodilation of renal, mesenteric, and coronary beds.
 At a dose of 5-10 mcg/kg/min, beta-1-adrenergic effects induce an increase
in cardiac contractility and heart rate. At doses about 10 mcg/kg/min, alpha-
adrenergic effects lead to arterial vasoconstriction and an increase in BP.
 Dopamine is effective in increasing MAP in patients who are hypotensive
with septic shock after volume resuscitation.
 The BP increases primarily as a result of an inotropic effect and, thus, is
useful in patients who have concomitant reduced cardiac function.
 The undesirable effects are tachycardia, increased pulmonary shunting,
potential to decrease splanchnic perfusion, and increased pulmonary
arterial wedge pressure.
 Epinephrine: Epinephrine can increase MAP by increasing the
cardiac index, stroke volume, systemic vascular resistance,
and heart rate.
 Epinephrine may increase oxygen delivery and consumption
and decreases splanchnic blood flow.
 Epinephrine administration is associated with an elevation of
systemic and regional lactate concentrations.
 The use of epinephrine is recommended in patients who are
unresponsive to traditional agents.
 The undesirable effects are an increase in lactate
concentration, a potential to produce myocardial ischemia
and arrhythmias, and a reduction in splanchnic flow
 Norepinephrine: Norepinephrine is a potent alpha-adrenergic
agonist with minimal beta-adrenergic agonist effects.
 Norepinephrine can successfully increase BP in patients who
are septic and remain hypotensive following fluid
resuscitation and dopamine.
 The dose of norepinephrine may vary from 0.2-1.35
mcg/kg/min; doses as large as 3.3 mcg/kg/min have been
used because alpha-receptor down regulation may occur in
sepsis.
 In patients who are septic, indices of regional perfusion, such
as urine flow and lactate concentration, have improved
following norepinephrine infusion.
 Renal-dose dopamine: The use of renal-dose dopamine in sepsis is
a controversial issue. In the past, low-dose dopamine was
routinely used in many units because of the presumed renal
protective effects.

 Dopamine at a dose of 2-3 mcg/kg/min is known to initiate

diuresis by increasing renal blood flow in healthy animals and
volunteers.

 Multiple studies have not demonstrated a beneficial effect with

prophylactic or therapeutic low-dose dopamine administration in
patients who are critically ill. Low-dose dopamine does not protect
the patient from developing acute renal failure, and there is no
data stating that it preserves mesenteric profusion; the routine
use of this practice is not recommended.
• Recombinant human-activated protein C
– The inflammatory mediators are known to cause
activation of coagulation inhibitors of fibrinolysis,
thereby causing diffuse endovascular injury, multiorgan
dysfunction, and death.
– Activated protein C is an endogenous protein that not
only promotes fibrinolysis and inhibits thrombosis and
inflammation but also may modulate the coagulation
and inflammation of severe sepsis.
– Sepsis reduces the level of protein C and inhibits
conversion of protein C to activated protein C.
– Administration of recombinant activated protein C
inhibits thrombosis and inflammation, promotes
fibrinolysis, and modulates coagulation and
inflammation.
 MEDICAL/LEGAL PITFALLS
 Sepsis is the most common cause of shock leading to multiorgan
failure in most ICUs and is a leading cause of death.
 Recognition of septic shock requires features of SIRS (mental
changes; hyperventilation; distributive hemodynamics;
hyperthermia; hypothermia; and reduced, elevated, or left-shift on
WBC) and existence of a potential source of infection.
 Patients in septic shock require immediate cardiorespiratory
stabilization with large volume of fluids intravenously, infusion of
vasoactive drugs, and often, endotracheal intubation and
mechanical ventilation.
 Immediately direct intravenous empirical antibiotic therapy at all
potential infectious sources.
 Infectious processes require drainage or debridement surgically
and expeditiously, even if the patient does not appear stable
because the patient may not improve without emergent surgical
 The effects of drugs used to support the hemodynamics of
patients who are septic have adverse effects on splanchnic
circulation.

 Therefore, the ideal hemodynamic therapy in these patients is

not known. Following adequate fluid resuscitation, therapy
with dopamine may be initiated, followed by norepinephrine
when dopamine fails.

 The alternate approach is initiating therapy with

norepinephrine and using dobutamine if inotropic support is
needed.

 Manipulation of oxygen delivery by increasing cardiac index

has either shown no improvement or has worsened morbidity
and mortality. Routine use of hemodynamic drugs to improve
cardiac output to supranormal is not recommended.
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• Schwartz’s; Principles of surgery; 8th ed

• Harrison’s Principles of Medicine, 16th ed

• Textbook of Critical Care; 5th ed

• Hamilton Bailey’s Emergency Medicine; 13th ed

• Text Book of Surgery, S. Das; 4th ed

• Love & Bailey’s Short Practice of Surgery, 24th ed

• The New England Journal of Medicine Volume

345:1368-1377 November 8, 2001 Number 19.
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