Multiple Organ Dysfunction Syndrome

Definition Diagnosis Management

 Definitions
• Multiple Organ Dysfunction Syndrome “MODS”
– 1991 Consensus conference of the American College
of Chest Physicians (ACCP) and the Society of
Critical Care Medicine (SCCM)
• Dysfunction replaced failure to accentuate the
reversible nature of the condition
• Underlying concept
– Sepsis, systemic inflammatory response syndrome
(SIRS), acute respiratory distress syndrome (ARDS),
and MODS are closely related phenomena
 Definition of systemic inflammatory response
syndrome (SIRS) and multiple organ dysfunction
syndrome (MODS)
Systemic inflammatory response syndrome
• The systemic inflammatory response to a variety of severe clinical
insults is manifest by two or more of the following conditions:
• Temperature > 38°C or < 36°C
• Heart rate > 90 beats/min
• Respiratory rate > 20 breaths/min or Paco2 < 32 mmHg (or
ventilator dependence)
• White blood cell count > 12 000 cells/mm3, < 4000 cells/mm3 or >
10% band forms

Multiple organ dysfunction syndrome

• The presence of altered function involving at least two or more
organ systems in an acutely ill patient such that homeostasis cannot
be maintained without intervention
• MODS is the most common cause of late
trauma deaths
• Approximately 50% of ICU patients will
develop MODS (estimates 25-80+%)
• Estimates of 20% to up to 75% mortality in
patients having at least two-organ failure
• As each organ fails the average risk of
death increased 11 to 23 percent

Ulvik A, Kvale R, Wentzel-Larsen T, et al. Multiple organ failure after trauma

affects even long-term survival and functional status. Crit Care 2007;11:R95.
Mortality in intensive care unit black
Mortality to hospital discharge black + dark grey
Mortality to 1 year black + dark grey + light grey.
Mayr VD et al Causes of death and determinants of outcome in critically ill
patients Crit Care 10:R154, 2006.
 Definitions

Most organ failure assessment systems assign values

to six organ systems
• Respiratory
• Cardiovascular
• Renal
• Hematology,
• Hepatic
• Central nervous system.
 General Definitions

Most commonly Respiratory Failure followed by the cardiovascular,

renal, and hematologic systems.

• Respiratory failure
– Hypoxemia, reduced P/F, require mechanical ventilation
• Cardiovascular failure
– Hypotension that is unresponsive to adequate fluid resuscitation and
requires vasopressors.
• Renal dysfunction
– Diminished urine output, increased serum creatinine,
• Hematologic failure
– Anemia, thrombocytopenia, and disseminated intravascular coagulation.
Pathogenesis of multiple organ dysfunction Crit Care Clin 2000;16:337-
352
 Multiple System Organ Failure
Score

Afessa et. Al, Severity of Illness and Organ Failure Assessment in Adult Intensive Care
Units Crit Care Clin 23 (2007) 639–658
 Sequential Organ Failure Assessment
(SOFA) score

Afessa et. Al, Severity of Illness and Organ Failure Assessment in Adult Intensive Care
Units Crit Care Clin 23 (2007) 639–658
 Definitions and grading of organ
dysfunction (MODS score)

Mayr VD et al Causes of death and determinants of outcome in critically ill patients Crit Care 10:R154,
2006.
 Denver Postinjury MOF Score

Ciesla et al, The role of the lung in postinjury multiple organ failure Surgery 01-OCT-2005; 138(4): 749-
57
 Diagnosis by Definition

• Syndrome
– wide spectrum of pathophysiology under one term
believed to be related by common cascade of events
culminating in organ dysfunction
• Heterogeneous collection
– Approximately 50%–70% of patients with MODS do
not have an identifiable focus of infection
– Approximately 1/3 do not have lung involvement
– Trauma patients may form a distinct subset
 The role of the lung in postinjury multiple
organ failure
• 1,344 Trauma patients
– (age greater than 16 years, trauma intensive care unit admission, Injury
Severity Score greater than 15, and survival longer than 48 hours)
• 75% developed Organ dysfunction 25% MODS
• MODS Morality 26% (80% of total mortality of 112)
• The onset of MOF occurred an average of 3.4 ± 0.2 days postinjury
• Lung dysfunction established within 72 hours in 89% patients
followed by
– cardiac dysfunction at 0.6 +/- 0.2 days
– hepatic dysfunction at 4.8 +/- 0.2 days
– kidney dysfunction at 5.5 +/- 0.5 days
• Lung dysfunction was noted in :
– 94% with with1 or more organ dysfunctional
– 99% with 2 or more organ dysfunctional

Ciesla DJ - Surgery - 01-OCT-2005; 138(4): 749-57

 Potential Pathophysiologic
Mechanisms Producing MODS
• Circulating immune/inflammatory mediators
• Primary cellular injury
• Mitochondrial Injury/ down-regulation
• Inadequate tissue/organ perfusion
– Hypoperfusion
– Ischemia/reperfusion
– Microaggregation and/or DIC
• Diffuse endothelial cell injury
• Circulating humoral factors
• Protein calorie malnutrition
• Bacterial-toxin translocation
• Adverse effect of directed treatment or medication
 Models
Meakins “two-hit” model of postinjury MOF.
• The first hit (trauma / shock ) primes
neutrophils and macrophages
• The second hit (nosocomial
infection/complication) results in
detrimental inflammatory response
 Inflammatory Model

• MODS is caused by an overwhelming imbalance

between systemic inflammatory response and counter
regulation (anti-inflammatory) response.
• May be activated by a number of external and internal
factors, including pro-inflammatory (e.g., infection,
sepsis, shock, and trauma) and immunosuppression
(e.g., Blood transfusion, infection, and steroids) .
• The imbalance in favor of inflammatory response causes
loss of the host's ability to localize the inflammation to
ijnitial inciting factor, leading to systemic inflammation
and tissue damage.
 Bioenergetics Model

• Multiple organ dysfunction is the results of

the dysregulation of mitochondria
• Mitochondrial activity is down-regulated as
a protective reflex to inciting factors
• Failure to recover mitochondrial function
results in self perpetuating cycle of cell
damage furthering shutdown of
mitochondria
•Mervyn Singer, Mitochondrial function in sepsis: Acute phase versus multiple
organ failure (Crit Care Med 2007; 35[Suppl.]:S441–S448)
 Bioenergetics and Sepsis

Mervyn Singer, Cellular Dysfunction in Sepsis Clin Chest Med 29 (2008)

655–660
 Progression of Bioenergetics Dysfunction

Mervyn Singer, Mitochondrial function in sepsis: Acute phase versus multiple organ failure (Crit
Care Med 2007; 35[Suppl.]:S441–S448)
• Shock Model

• Hypoperfusion
causes dysfunction
due to hypoxia and
secondary injury

Pathophysiology of multiple organ dysfunction syndrome (MODS).

 Multifactor Models

• Gut-liver-lung axis
• Initiation of the inflammatory state can occur in any of
these organs following trauma or shock.
• The gut can leak inflammatory mediators into the portal
circulation, causing a response in the liver.
• Inflammatory mediators then travel in the hepatic vein to
the inferior vena cava and to the lungs.
• The lungs may become injured and release inflammatory
substances themselves, which travel systemically to
distant organs (including the gut).

Martinez-Mier G, Toledo-Pereyra LH, Ward PA: J Trauma 51:408, 2001

LPS, Lipopolysaccharide.
Gut-liver-lung axis in response to shock and hemorrhage Martinez-Mier G, Toledo-Pereyra LH,
Ward PA: J Trauma 51:408, 2001.
All In Models

Abraham 2007, Crit Care Med

 Composite model

Current Therapy of Trauma and Surgical Critical Care Asensio and Trunkey 2008
Therapy
Targeted therapy

• Activated Protein C
– Modulating the systemic inflammatory,
procoagulant, and fibrinolytic host responses
• Vasopressin Therapy
– Replacing falling plasma levels of vasopressin
seen in shock
• Steriods
– Replacement reversible failure of the
hypothalamic-pituitary-Adrenal (HPA) axis
 Activated Protein C for Severe
Sepsis
• The properties of activated protein C include
• (1) Antithrombotic activity
– inhibition of thrombin formation
– inhibition of factors V and VIII
• (2) Profibrinolytic activity
– inhibition of PAI-1 (plasminogen-activator inhibitor 1)
• (3) Anti-inflammatory activity
– Direct effect inhibitory effect monocytes, neutrophils,
and endothelial cells
– indirectly through reduced thrombin resulting in less
tumor necrosis factor and interleukin-1 production,

Bernard et al, N Engl J Med, Vol. 344, No. 10 March 8, 2001

James A Russell MD. Management of Sepsis. N Engl J Med 2006; 355:1699-1713

Yong Lee, Pharm.D. Jackson Memorial Hospital Trauma Critical Care Pharmacist
Bernard et al, N Engl J Med, Vol. 344, No. 10 March 8, 2001
RCT: PROWESS
EFFICACY AND SAFETY OF RECOMBINANT
HUMAN ACTIVATED PROTEIN C
FOR SEVERE SEPSIS
• 1690 randomized patients with a known or suspected
infection on the basis of clinical data who meet the
following criteria within a 24-hour period:
– 1) three or more signs of the Systemic Inflammatory
Syndrome
– 2) the sepsis-induced dysfunction of at least one
organ or system that has lasted no longer than 24
hours
• Study group received drotrecogin alfa (activated)
– 24 μg per kilogram of body weight per hour for a total duration of
96 hours

Bernard et al, N Engl J Med, Vol. 344, No. 10 March 8, 2001

RCT: PROWESS

Findings

• Absolute reduction in the risk of death of

6.1 percent
• Mortality rate
– 30.8 percent in the placebo
– 24.7 percent in the drotrecogin alfa activated
group

Bernard et al, N Engl J Med, Vol. 344, No. 10 March 8, 2001

RCT: ADDRESS

Drotrecogin Alfa (Activated) for Adults with Severe

Sepsis and a Low Risk of Death

• 2640 adults patients with severe sepsis and a low risk of

death
– (defined by an Acute Physiology and Chronic Health Evaluation
[APACHE II] score <25 or single organ failure)
– Randomized intravenous infusion DrotAA (24 Μg per kilogram
of body weight per hour) for 96 hours or placebo
• Trial was terminated early
– No benefit from treatment
– Increased incidence of serious bleeding complications,
• Conclusion DrotAA should not be used in patients with
severe sepsis who are at low risk for death

Abraham, et al N Engl J Med 353;13 Sept 29,2005

 Activated Protein C Here

• APACHE II score > 25

– No benefit seen in patients w/ APACHE II score < 25
• More than 1 organ system affected
– Drotrecogin had no benefit in patients with single organ
dysfunction
• Must start Drotrecogin w/in 48 hrs of 1st sign of
organ dysfunction
– To achieve benefit seen in PROWESS drotrecogin
should be started w/in 24hrs
• Consider continuing prophylactic heparin when
starting drotrecogin

Yong Lee, Pharm.D. Jackson Memorial Hospital Trauma Critical Care Pharmacist
 Exclusion Criteria

• Anyone of the following:

– Active bleed
– Recent CVA (w/in 3 months)
– Recent head trauma or intracranial/spinal
surgery (w/in 2 months)
– Intracranial mass lesion or aneurysm < 12 hrs
post surgery req. general or spinal anesthesia
– Epidural catheter
– Trauma patient w/ increased risk of bleeding
– Patient is moribund
Yong Lee, Pharm.D.Jackson Memorial Hospital Trauma Critical Care Pharmacist
 Inclusion Criteria

• Must be in an ICU or consulted by an ICU team

• Patient has known or suspected infection
– 1 of the following:
• Positive culture
• White cells in a sterile body fluid
• Perforated viscus
• CXR evident of PNA with purulent sputum production
• Patient has signs of SIRS ( >3 of the following):
– 360 < Temp > 380
– HR > 90
– RR > 20 or PaCO2 < 32 or mech vent
– 4000 < WBC > 12000 or > 10% immature neutraphils
Yong Lee, Pharm.D.Jackson Memorial Hospital Trauma Critical Care Pharmacist
 Inclusion Criteria

• Patient has organ system dysfunction

– At least 2 of the following:
• Cardiovascular dysfunction: MAP < 70 or arterial SBP
< 90 or vasopressor support
• Renal dysfunction: UOP < 0.5ml/kg/hr for > 1 hr
• Respiratory dysfunction: PaO2 /FiO2 < 250 or < 200 if
the lung is the only dysfunction
• Hematologic dysfunction: plt < 80000 or 50% decline in
3 dys
• Unexplained metabolic acidosis: pH < 7.3 or BE > 5 w/
lactate > 1.5 X normal
Yong Lee, Pharm.D. Jackson Memorial Hospital Trauma Critical Care Pharmacist
 Vasopressin Therapy for Septic
Shock
In early shock, appropriately high levels of
vasopressin are produced to support organ
perfusion.
• As the shock state progresses, plasma
vasopressin levels fall from:
– depletion of pituitary stores of vasopressin exhaustive
release in early septic shock
– central inhibition from elevated norepinephrine levels
(endogenous or exogenous)
– central inhibition from increased nitric oxide release
by vascular endothelium within the posterior pituitary
during sepsis
 Vasopressin
and Septic Shock Trial (VASST)
• Randomization trial of 778 patients with shock
• 396 patients received vasopressin, and 382
norepinephrine
• There was no significant difference :
– 28-day mortality rate (35.4% and 39.3%, respectively;
P = 0.26)
– in 90-day mortality (43.9% and 49.6%, respectively; P
= 0.11).
– Overall rates of serious adverse events (10.3% and
10.5%, respectively;P = 1.00).

Russell et al, Vasopressin versus Norepinephrine Infusion in Patients with

Septic Shock N Engl J Med 2008;358:877-87
 Hydrocortisone Therapy for
Patients with Septic Shock
• 499 patients multicenter
• Randomized, double-blind, placebo-controlled trial
• Concluded
– Hydrocortisone did not improve survival or reversal of
shock in patients with septic shock, either overall or in
patients who did not have a response to corticotropin,
although hydrocortisone hastened reversal of shock
in patients in whom shock was reversed.

Sprung et. Al N Engl J Med 358;2 January 10, 2008

 International task force by the American
College of Critical Care Medicine

• Review published literature concluded most of the

research supports treatment with moderate-dose
corticosteroids in patients with septic shock who have
responded poorly to volume resuscitation and
vasopressor agents
• Tests of adrenal function are not routinely required in
these patients.

•Recommendations for the diagnosis and management of corticosteroid

insufficiency in critically ill adult patients: Consensus statements from an
international task force by the American College of Critical Care Medicine Crit Care
Med 2008 Vol. 36, No. 6
 Management

• Prevention
• Removal of inciting factors
• Support Recovery
 Algorithm for preventing and managing MODS

Current Therapy of Trauma and Surgical Critical Care eds Asensio and Trunkey 2008
 Surviving Sepsis Campaign Guidelines

ALI, acute lung injury; DA, dopamine; DVT, deep vein thrombosis; NE, norepinephrine;
PUD, peptic ulcer disease.
Dellinger RP, Carlet JM, Masur H, et al: Surviving Sepsis Campaign guidelines for
management of severe sepsis and septic shock. Crit Care Med 2004;32:858-873.)
 Hemodynamic Support

• Early Goal directed therapy

• 1. Preload
– Monitor/Support central venous pressure 8 - 12 mm
Hg 12 - 15 mm Hg in mechanically ventilated patients
• 2. After-load
– Monitor/Support Mean arterial pressure >65 mm Hg
– Urine output >0.5 mL/Kg/h
• 4. Balance oxygen delivery and oxygen demand
– Monitor/Support Oxygen balance
– Central venous or mixed venous oxygen saturation
>70%
 Hemodynamic Support

• Low-dose steroids administered for

nonresponders to fluid and vasopressors
– Hydrocortisone dose should be < 300 mg/day
– Steroid therapy may be weaned once
vasopressors are no longer required
• Activated Protein C administered in
accordance policy here
 Infection Control
Source Control
• Early Identification abscess, infection with imaging/studies
– ID treatable causes e.g., necrotizing fasciitis, diffuse peritonitis,
cholangitis,intestinal infarction
• Early intervention
– Drainage of infected fluid collection
– Surgery to control /eliminate source if appropriate
– Debridement of infected solid tissue
– Removal of devices or foreign bodies
• Monitor/Address abdominal compartment syndrome
• Remove intravascular access devices if potentially infected

Systemic Antibiotics
• Broad-spectrum antibiotic therapy started within the first hour
• Cultures (blood, urine, sputum,tissue) preferable prior,
• Therapy adapted to most appropriate single drug as soon as antibiogram
available.
• Combination therapy for patients with known or suspected Pseudomonas
infections and neutropenic patients with severe sepsis
 Sepsis Resuscitation Bundle

• 1. Serum lactate measured at clinical presentation

• 2. Blood cultures obtained before antibiotics
administered
• 3. Broad-spectrum antibiotics within 3 hours
• 4. In the event of hypotension or lactate >4 mmol/L (36
mg/dL)
– a. deliver an initial minimum of 20 mL/kg of crystalloid (or colloid
equivalent)
– b. apply vasopressors for ongoing hypotension
• 5. In the event of persistent hypotension despite fluid
resuscitation or lactate >4 mmol/L (36 mg/dL)
– a. achieve central venous pressure of >8 mm Hg
– b. Achieve central venous oxygen saturation > 70%

The Role of Bundles in Sepsis Care Crit Care Clin 22 (2006) 521–529
 On Going Intensive Care Support

• DVT/PE prevention
• Ulcer Prevention
• Nutritional Support
• Glucose Control/Insulin therapy as needed
• Specific organ Support
• Minimize Blood Transfusion
• Infection control
– Avoidance of Ventilator Associated Pneumonia
– Avoidance of Catheter (any type) Related
Infection
 Long-term Outcome
• Follow up 322 patients Trauma related organ failure
• 47% had multiple organ failure (MOF), 28% had single
organ failure.
• Long-term survival and functional status were the same
for patients suffering single organ failure and no organ
failure.
• MOF increased the overall risk of death 6.0 times.
• Complete recovery occurred in 52% of survivors 87%
were able to look after themselves
• MOF had 3.9 times greater odds for requiring personal
assistance in activities of daily living

Ulvik A, Kvale R, Wentzel-Larsen T, et al. Multiple organ failure after trauma

affects even long-term survival and functional status. Crit Care 2007;11:R95.