Download SIRS, Sepsis, and MODS

SIRS, Sepsis and MODS: Pathophysiology and Diagnosis
Jonathan Sevransky, MD, MHS
Associate Professor Of Medicine
Emory University School of Medicine
Atlanta GA
[email protected]
SIRS, Sepsis and MODS: Definitions and Diagnosis
The inflammatory and coagulation cascades can be triggered by infection, trauma, medications, heat
exposure , toxins, and a host of other insults. Infection is the most common etiology. To standardize the
nomenclature, a consensus conference in 1984 defined the relationships between the systemic
inflammatory response syndrome, sepsis, and multiorgan dysfunction syndrome1. The systemic
inflammatory response syndrome consists of 2 of the 4 following parameters1
T> 38 <36
Pulse >90
RR > 20 or PCO2 <32 or need for positive pressure ventilation
Wbc >12 < 4 or > 10% immature “band forms”
In conjunction with the evidence of an infection, a patient with SIRS would meet sepsis criteria. Of note,
evidence of infection includes signs and symptoms of infections ( purulent sputum, cloudy urine) or
positive gram stains or cultures: it does not require microbiologic proof. Severe sepsis is defined as
sepsis with an organ failure, and septic shock as sepsis with hypotension refractory to volume
resuscitation. Septic shock represents with most severe form of sepsis, and is associated with higher
mortality rates than for sepsis or severe sepsis1.
Increasing severity of illness is also associated with increasing incidence of organ failure1,2. While some
patients with sepsis die of acute cardiac arrest, the most common cause for death in patients with sepsis
is multiorgan dysfuction and failure3. Respiratory failure is the most common and severe sequalae of
severe sepsis and sepsis shock, and is often accompanied by the development of the acute respiratory
distress syndrome ( ARDS)2,4. Renal failure , disseminated intravascular coagulation( DIC),
encephalopathy and delirium, and hypotension and shock are other important sequalea of sepsis. In
order to meet the criteria of multiorgan dysfunction, more than one organ needs to fail. Of note, while
individual organ dysfunction and failure is usually reversible, with an increasing number of organ failures
comes an increasing risk of mortality5,6.
Multiorgan dysfunction can be triggered in the absence of infection, with trauma a common
precipitant1. Pancreatitis, burns, surgery are other frequent triggers. An activator event, which can
include tissue injury, ischemia or reperfusion injury, or severe infection can lead to a cascade of
activation of pathways such as the alarmin, pathogen associated molecular pathways ( PAMP) which
can initiate microcirculatory changes as well as activation of monocytes and macrophages leading to
multiorgan dysfunction7. Since the clinical picture seen in non infectious insults is often
indistinguishable from that caused by sepsis, it is important to use both history and the response to
therapy to help distinguish between the two. For example, it would be rare for a patient to develop an
infection immediately after a sterile trauma or operation.
Sepsis, SIRS, and multiorgan dysnfuction all lack defined biomarkers1,2. Thus, they are syndromes rather
than diseases. Unlike other defined illness such as myocardial infarction or cerebrovascular accident,
there is no clear diagnostic test, and clinicians are forced to rely on clinical suspicion to make the
diagnosis. Of note, SIRS lacks specificity- other illnesses such as myocardial infarction, alcohol
withdrawal can lead to SIRS. In addition, standard cultures lack sensitivity- as few as 50% of patients
with severe infections leading to ICU admission will have positive cultures2. While newer diagnostic
testing modes that depend upon rapid DNA amplification of bacterial products may improve sensitivity,
these tests have not yet either been validated in patients, or entered routine clinical practice
Pathophysiology of SIRS and Multiorgan dysfunction
Both infection, inflammation and trauma can lead to activation of the host defense system , and
similarly to the activation of the coagulation cascade. Multiple complementary pathways can be
initiated by an activator event- leading to damage associated molecular patterns ( DAMP’s), which can
lead by several pathways to multiorgan dysfunction. A recent review summarizing these pathways is
listed here7. In preclinical models, this activation of multiple pathways produces a state clinically similar
to sepsis, and can lead to multiorgan dysfunction and death. Blocking inflammation prior to delivering
the insult can prevent the escalation of this pro-inflammatory cascade and coagulation dysregulation.
Unfortunately, this paradigm of blocking inflammation prior to an insult is rarely clinically feasible and
the use of either specific and non- specific anti-inflammatory therapies have not proven successful in
human clinical trials8.
Infection is the most common etiology of multi organ dysfunction, and activation of the host defense
system is an integral part of the process that leads clinical deterioration8. While the host defense
system is an important part of the development of multiorgan dysfunction, patients with impaired host
defense – for example with neutropenia are both at increased risk of developing sepsis and remain at
high risk for developing complications of sepsis such as sepsis- induced ARDS4. Thus, treatment designed
to block the host defense system may not be useful in treatment or prevention of multiorgan
dysnfuction and death2,8.
Multi-organ dysfunction is defined usually by the presence of several organ dysfunctions. The precise
limits of what is considered an organ dysfunction may vary: there are a number of validated organ
failure and dysfunction scores, including the Sequential Organ Failure Assessment Score ( SOFA) ,and
the Multiple Organ Dysfunction Score ( MODS)5,6. Most of these are centered upon laboratory values or
supportive treatment requirements; it is rare that tissue is available to confirm a diagnosis5,6,9.
Treatment of sepsis
Sepsis is by definition triggered by an infection. Thus, the treatment of sepsis centers around 1) proper
identification of the patient with sepsis 2) proper and prompt selection and delivery or antibiotics
effective against the causative pathogen and 3) source control of the infection in selected patients.
While these are relatively straightforward goals, the absence of a biomarker for sepsis may at times
complicate the delivery of appropriate treatment for patients with sepsis. An appropriate index of
suspicion for an infection is often necessary to begin treatment2.
Since culture results are rarely available when treatment is initiated, the treating clinician needs to
select empiric antibiotics directed at the most likely organisms. Several factors drive the choice of
antibiotics10. First, the site of infection is important – the epidemiology of lung, gut, bloodstream,
urinary, and CNS infections all vary. Second, the location of the patient will determine which organisms
may be prevalent: the organisms causing disease in West Africa differ from those in East Asia, which
may differ from those in the Eastern US. Third, whether the patient has had exposure to medical care
recently will also drive the epidemiology of organisms causing sepsis. Initially, especially in the setting of
severe sepsis and septic shock most clinicians will start with broad spectrum antibiotics and will narrow
therapy based on culture results2. The length of antibiotic therapy is often driven by the type of
organism, and the severity of illness of the patient. Some clinicians use biomarkers such as procalcitonin
the help with length of therapy2,11.
The importance of early appropriate antibiotic therapy in patients with severe sepsis and septic shock
has been highlighted in recent studies and consensus recommendations10,12. Delivery of antibiotics (
hypotension to antibiotics infusion ) within an hour of hypotension has been shown to improve patient
mortality rates in several studies, with incremental additional mortality of 6-7% for every additional
hour it takes to deliver appropriate antibiotics10. Streamlining the mechanism to antibiotic delivery
remains an essential part of performance improvement plans for patients with severe sepsis13. Of note,
while sending cultures prior to antibiotics will be helpful for antibiotic de-escalation strategies, the
clinician must guard against excessive delay caused by the need to send cultures prior. If sending
cultures will prevent the timely administration of antibiotics, the treating clinician may need to give
antibiotics first2.
Infection source control is also an essential part of sepsis therapy2. Patients with closed space infections,
or invasive supportive devices that become infection require removal of those devices and drainage of
the closed space infections. When a patient is sick enough to come to the intensive care unit, it is
unusual to be able to treat through an infected device or to successfully cure a closed space infection
without source control.
Supportive therapies are an essential adjunct to antibiotic therapy, and should commence with the
identification of the patient with sepsis. Fluid resuscitation is a cornerstone of severe sepsis treatment
and should commence immediately after diagnosis of severe sepsis or septic shock. A standard initial
dose of crystalloid fluid , such as lactated ringers or normal saline, is 30/cc/kg, but many patients require
additional fluids both initially and over the course of the first 6 hours of treatment. While colloid therapy
such as albumin has theoretical advantages over crystalloid, there is no proven clinical advantage and
substantial additional cost to use14. Similarly, while blood transfusion may have theoretical benefits of
increasing oxygen delivery, there is no proven benefit for its use in severe sepsis or septic shock15.
Some patients remain hypotensive despite volume resuscitation, and need consideration for the
addition of vasopressor support. There is some evidence supporting the use of norepinephrine over
dopamine for septic shock2,16. Additionally, other supportive therapies are commonly needed to treat
patients with severe sepsis and septic shock such as mechanical ventilator support, renal and nutritional
support. More details about these supportive therapies may be found in a recent consensus statement.
Most patients with severe sepsis and septic shock will respond to therapy. For patients who do not
initially respond to therapy, it is reasonable to conduct a search for undrained foci of infection, to
consider whether the patient may be infected with an organism that is not responsive to the
antimicrobial therapy being used. In addition, it may be reasonable to consider whether the patient may
have an alternate diagnosis that is not related to an infection. While many patients will respond to
therapy, some patients will have host defense systems that are not able to fight off an infection, or may
have underlying diseases that will not allow effective clearance of an infection.
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