Chapter 24
SIRS, Sepsis, and MODS
G. BERLOT, A. TOMASINI, M. VIVIANI
For decades, a number of different terms, such as sepsis and septicaemia,
derived from the ancient Greek term indicating putrefaction, have been used to
indicate the clinical conditions associated with severe infections [1]. This lack
of uniformity was due to extreme heterogeneity of the infection-related systemic signs and symptoms, ranging from mild fever to severe cardiovascular
collapse. As a consequence, although every minimally experienced physician
could distinguish between a moderately sick patient with pneumonia and a
critically ill patient dying in septic shock, the intermediate degrees of severity
were much less well defined. Further confusion was added by the suffix
“-aemia”, derived from the Greek word indicating the blood; it was generally
held that the presence of germs in the bloodstream was the only factor responsible for the disturbances involving the whole organism; only recently has it
become clear that (1) these are primarily related to the interaction between the
germs and the host’s immune system, leading to the production and the release
of a host of mediators with either pro- or anti-inflammatory properties, and
that (2) this process can occur everywhere in the body, and the resulting systemic disturbances are related to the spillover of these substances from the initial site of reaction [2].
In the late 1980s and in the early 1990s the interest of intensivists was captured by two remarkable developments. First, the basic mechanisms underlying
the septic process were elucidated, and a number of endogenous molecules
responsible for the related symptoms were isolated; moreover, it became clear
that the very same symptoms associated with the most-severe infections could
be present in a number of non-infectious conditions, including acute pancreatitis, postoperative status, etc. A systemic inflammatory reaction involving the
whole organism appeared as a final common pathway linking both conditions.
Second, a number of different molecules aimed at inhibiting the putative mediators of this process became available. Preliminary experimental results in dif-
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G. Berlot, M. Viviani, A. Tomasini
ferent models of sepsis, as well as in a small number of patients, were encouraging, and large, internationals trials with different molecules were initiated.
Consequently, more-precise definitions of the degrees of severity of the infection-related conditions were needed, in order to compare and to track the clinical course of patients enrolled in clinical trials running in different countries
and treated with these novel substances. Under the auspices of the American
Society of Chest Physicians (ACCM) and of the Society of Critical Care
Medicine (SCCM), a consensus conference was then held which ultimately
established a number of definitions to describe different clinical settings (Table
1) [2, 3]. At the same time, the definition of multipe organ dysfunction syndrome (MODS) replaced the multiple organ failure (MOF) to indicate that the
derangement of two or more organs cannot be considered an all-or-nothing
phenomenon, but rather a progressive (and hopefully reversible) loss of function occurring along a continuum.
The proposed definitions were not uniformly accepted and were challenged
primarily on the basis of their low diagnostic specificity, as the same symptoms
can occur both following severe infections and in non-inflammatory conditions, such as strenuous exercise, drug intoxication, heat stroke, etc [4-6]. Other
authors, albeit recognizing their limitations, considered them valuable as they
set some standards, thus allowing intensivists from all over the world to use a
common language [7, 8].
Recently, several North American and European intensive care societies
agreed to revisit the definitions for sepsis and related conditions in a conference including 29 participants. The published document reflected a process
whereby a group of experts and opinion leaders revisited the 1992 sepsis guidelines and found that apart from expanding the list of sign and symptoms of
sepsis to reflect clinical bedside experience, no evidence exited to support a
change to the definitions [9].
In this chapter, the advantages as well as the shortcomings of these definitions will be reviewed and discussed, on the basis of the following questions:
- Do these definitions describe clinical settings with different courses and
outcomes?
- Do these definitions reflect different physiopathological conditions?
- Can the diagnostic tools available 10 years ago still be considered valuable
to differentiate between infectious and non-infectious conditions?
Put in other words, is it wise to choose among different treatments only relying upon the ACCP- SCCM definitions?
539
SIRS, Sepsis, and MODS
Table 1. ACCP/SCCM Consensus Conference definitions of sepsis, severe sepsis, and septic
shock. Modified from reference [3]
Definitions
Features
Possible clinical settings
Systemic
inflammatory
response syndrome
(SIRS)
The systemic inflammatory response
to a wide variety of severe clinical
insults, manifested by 2 or more of
the following conditions:
1. Temperature> 38°C or < 36°C
2. Heart rate> 90 bpm
3. Respiratory rate> 20 breaths/min
or PaCO2 < 32 mmHg
4. White blood cell count> l2,000/ml
or < 4,000/ml or> 10% immature forms
Acute pancreatitis
Status post repair of
ruptured aortic
aneurysm
Acute vasculitis
Postoperative status
Burns
Trauma
Sepsis
The systemic inflammatory response to
a documented infection. The clinical
manifestations should include 2 or more
of the following signs as a result of
a clinical infection:
1. Temperature> 38°C or < 36°C
2. Heart rate> 90 bpm
3. Respiratory rate> 20 breaths/min
or PaCO2 < 32 mmHg
4. White blood cell count> l2,000/ml
or < 4,000/ml or> 10% immature forms
Uncomplicated pneumonia
Urinary infections
Uncomplicated
appendicitis
Severe sepsis
SIRS or sepsis associated with signs of
organ dysfunction or hypoperfusion,
including, but not limited, to lactic
acidosis, hypotension, oliguria or acute
deterioration of the mental status
Complicated pneumonia
or abdominal infection
Septic shock
Sepsis-induced hypotension unresponsive Peritonitis
to fluid resuscitation, along with signs
of organ dysfunction, hypoperfusion
and hypotension, including, but not limited,
to lactic acidosis, hypotension, oliguria or
acute deterioration of the mental status
Multiple organ
dysfunction
syndrome
Presence of altered organ function in
an acutely ill patient such that
homeostasis cannot be maintained
without intervention
Combined acute
respiratory and
renal failure
540
G. Berlot, M. Viviani, A. Tomasini
Do these definitions apply to different clinical settings?
The final goals of any classification are (l) to describe individuals or groups
characterized by different features; and, possibly, (2) to describe whether and
how these differences interact with other variables [i.e., the length of stay (LOS)
in the intensive care unit (ICU) or in the hospital, the final outcome, etc]. As far
as the ACCP-SCCM classification is concerned, several investigators were able
to demonstrate that subjects belonging to different diagnostic groups encountered different clinical courses. In a study involving 2,527 patients, RangelFrausto et al. [10] demonstrated several relevant findings. First, the mortality
rate was associated with the severity of the systemic disorders, ranging from 3%
in patients free from systemic inflammatory response syndrome (SIRS) to 46%
in those with septic shock; interestingly, the mortality of patients with SIRS
roughly paralleled the number of criteria recorded, being 7% in those with 2
and 10% and 17% in those with 3 or 4 signs, respectively. Second, there was a
progression of symptoms, as patients with 2 signs of SIRS developed a third criterion by day 7; furthermore, as many as 32%, 36%, and 45% of patients with 2,
3, or 4 criteria for SIRS developed sepsis within 14 days. The median interval
from sepsis to severe sepsis was remarkably shorter, being only 1 day, and that
from severe sepsis to septic shock was 28 days. Third, end-organ dysfunctions,
including acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and acute renal failure (ARF) were more frequent in
patients with severe sepsis and septic shock compared with patients with SIRS
and uncomplicated sepsis. Finally, blood cultures (BC) were positive only in
17% of patients with sepsis, 25% of patients with severe sepsis, and 69% of
patients with septic shock, further strengthening the concept that viable germs
in the bloodstream are not necessary to trigger the inflammatory reaction
eventually leading to the septic shock.
In another multicenter study that involved 1,100 patients, Salvo et al. [11]
observed that, on admission, 52% of patients could be diagnosed as SIRS,
whereas 4.5%, 2.1 %, and 3% belonged to the sepsis, severe sepsis, and septic
shock groups, respectively. The mortality rate of patients with septic shock was
substantially higher than in the study of Rangel-Frausto et al. [10], peaking at
82%. The causes of this difference are not clear. It is likely however that multiple factors, including a delay in the referral of the enrolled patients to the participating ICU s and an inappropriate choice of the antibiotic treatment, could
at least partially account for them. Similar to the previous study, the risk of progression towards septic shock was higher in patients with sepsis and severe sepsis than in patients with SIRS; moreover, patients diagnosed as having severe
sepsis or septic shock were sicker, as demonstrated by the higher severity
scores. The time-related progression of infection-related systemic disturbances
has been reported also by Berlot et al. [12] who observed that the rate of
SIRS, Sepsis, and MODS
541
patients dying with sepsis and severe sepsis increased with the LOS in the ICU,
whereas the incidence of septic shock remained fairly constant in patients
dying during the 2nd week in ICU or later.
Some conclusions can be drawn from these studies, thus answering the
question posed in the title of this section. First, the ACCM -SCCM definitions
describe fairly accurately patients with different clinical courses and risk of
death. Second, the progression from one condition to another is possible, and
the corresponding worsening of the clinical conditions is more likely in patients
who, at the time of admission, present with sepsis or severe sepsis; however, it
should be remembered that there is not a risk-free group. Third, it appears that
the longer the LOS in ICU, the higher the risk of developing sepsis and the related consequences, including ARDS, ARF, and DIC. Finally, in a relevant minority
of patients with severe sepsis and septic shock, BCs are negative, thus making
these diagnostic tools of limited usefulness in those patients who could take the
maximal advantage of early and precise antibiotic therapy.
Does these definitions reflect different physiopathological conditions?
Both non-infectious and infectious events can trigger an inflammatory reaction, ultimately leading to MODS. Several lines of evidence suggest that the
postinsult inflammatory response, as estimated from the concentration of some
mediators involved in the septic process, (1) is more marked in SIRS patients
shifting to sepsis than in those recovering from their condition, (2) is more pronounced in septic than in SIRS patients, and (3) in the majority of patients, its
persistence is associated with a poor prognosis. Several investigators demonstrated that, in septic patients, persistently elevated levels of inflammatory
mediators are associated with the development of MODS and a poor prognosis
[13-15]. Similar considerations also apply in circumstances apparently not
associated with infections. In a group of patients resuscitated from a cardiac
arrest, Geppert et al. [16] observed that (1) SIRS was frequent, being present in
66% of patients, and was unrelated to some variables related to the event,
including the duration of the cardiopulmonary resuscitation, the overall dose of
epinephrine, and the blood lactate levels, and (2) P-se1ectin levels were higher
in patients with SIRS and even more elevated in those who developed sepsis
later. In a group of abdominal postoperative patients, Haga et al. [17] observed
that both the number of diagnostic criteria of SIRS, its and duration, and the
peak values of the C-reactive protein (CRP) were correlated with some intraoperative variables, including blood loss and the duration of the intervention;
moreover, SIRS persisting beyond the 3rd postoperative day was associated
with the development of sepsis and MODS. However, since proinflammatory
542
G. Berlot, M. Viviani, A. Tomasini
mediators are produced along with substances aimed at blocking their actions,
including soluble receptors and cellular receptor blocking agents [18], the existence of a condition defined as a compensatory anti-inflammatory response
syndrome (CARS) has been hypothesized, in which blocking agents predominate due to the exhaustion of the inflammatory response [19]. Theoretically,
this condition could be at least as harmful as SIRS has been developed and
maintained throughout evolution to counteract the spreading of an initial
infection, and its blocking could favour an initially circumscribed septic focus.
Can the diagnostic tools available 10 years ago still be
considered valuable to differentiate between infectious
and non-infectious conditions?
With identical symptoms and biochemical markers, the presence of a suspected
or confirmed infection represents .the true border dividing SIRS from sepsis
and its more-severe consequences. However, the accuracy of the diagnosis cannot be considered, since a delayed or inappropriate antibiotic treatment, which
is not indicated in SIRS but absolutely mandatory in sepsis, has been associated
with a poor prognosis. While in many cases an infectious cause of a systemic
response can be reliably hypothesized even when a precise identification of the
responsible microorganisms is still pending (i.e., faecal peritonitis, urinary tract
infections, etc), in other cases the diagnosis is less straightforward. As an example, despite the elevated rate of ventilator-associated pneumonias among critically ill patients, the commonly adopted diagnostic criteria are not sensitive or
specific enough to allow a precise diagnosis in 100% of suspected cases [20].
Similar considerations apply to patients with severe sepsis and septic shock, in
whom cultures can remain negative in a significant number of cases [21].
Several factors can account for a failed growth of bacteria in the culture media,
including a low inoculum, the effect of antibiotics, wrong or untimely sampling,
and a poor processing of the sample itself; moreover, the host’s response can be
caused by the absorption of endotoxin and/or other bacterial byproducts from
the intestinal lumen, by the activation of the gut-associated immune cells [21]
or by its release following the administration of antibiotics [23].
Since the recent and impressive advances in genetic techniques make it possible to identify bacterial products in biological samples, it has been argued that
many cases of SIRS should be re-diagnosed as sepsis or sepsis-related complications and consequentially treated. Cursons et al. [24] used two different techniques of bacterial DNA amplification by means of the polymerase chain reaction (PCR) in 110 critically ill patients with suspected or documented infections, and were able to demonstrate that PCR was positive in 8 patients with
SIRS, Sepsis, and MODS
543
negative BC, whereas 7 patients had positive BC but negative PCRs; using a
more-refined technique of DNA amplification, in 29 patients with negative BC
the PCR was positive. In another study, Sleigh et al. [25] used the amplification
of the gene 16S rDNA, which is common to all bacteria, and demonstrated that
it was present in the bloodstream of 25 of 121 patients with negative BC. Other
false-positives resulted from non-pathogenic microorganisms or from coagulase-negative staphylococci recovered from samples drawn from the indwelling
vascular catheters. Other commonly used markers of sepsis and infections such
as white blood cell count and temperature, were similar in patients with positive BC and in those with negative BC but in whom the PCR was positive.
Despite these encouraging results, some points need to be clarified. First, as
stated by Sleigh et al. [25], as many as 40% of PCR-positive blood samples were
of doubtful clinical utility, due to different factors, including quality of the sample and the presence of DNA sequences derived from non-pathogenic or contaminant microorganism [26]. With these limitations in mind, the PCR could be
valuable especially in those patients in whom the signs of a systemic inflammatory reaction persist despite (1) the negativity of cultures and/or (2) the administration of an apparently appropriate antibiotic treatment, provided that the
presence of surgically amenable septic foci has been excluded.
The measurement of blood levels of some mediators involved in the septic
process, including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-1
receptor antagonists, soluble TNF-α receptors, elastase, has been advocated in
the monitoring of critically ill septic patients [8, 27]. However, this approach is
expensive, time and labour intensive, and in many cases the results are not
available rapidly. Moreover, blood levels reflect only part of the burden of
mediators, while most of their action is exerted at a tissue levels [28]. More
recently, the serial measurements of CRP [29-31] and of procalcitonin (PCT)
[32, 33] have been proposed both as a reliable marker of infection and as a
diagnostic tool to distinguish SIRS from sepsis. Several investigators demonstrated that although both substances are increased during sepsis, in septic
patients PCT levels are higher than CRP [34, 35], its variations are more rapid
and consistent with the clinical course, making this mediator a reliable marker
of the ongoing process and of the response to treatment. Moreover, CRP
increases in minor infections and in non-infectious conditions, including autoimmune and rheumatological disorders, acute coronary events, and malignancies [36-39]. Despite these shortcomings, the measurements of CRP are still
valuable, as they are far cheaper than those of PCT, do not require sophisticated laboratory facilities, and the results are rapidly available. Bearing in mind its
limitations, serial measurements of CRP have been advocated in the follow-up
of critically ill patients with sepsis to evaluate the effects of the treatment [40].
The advantages as well the limitations of the measurement of some septic
mediators are shown in Table 2.
544
G. Berlot, M. Viviani, A. Tomasini
Table 2. Advantages and disadvantages of the measurement of some inflammatory mediators in the diagnosis of SIRS and sepsis (PCT procalcitonin, CRP C-reactive protein)
Marker
Infectionspecific
Inflammation- Advantages
specific
Limitations
PCT
4+
1+
Rapid
appearance
T/2 24 h
Low specificity for focal
infections. High specificity
for severe sepsis and
septic shock
Relatively expensive
CRP
2+
2+
Not expensive
Widespread
availability
Low specificity
Slow appearance
No correlation with
the severity
Cytokines
1+
2+
High sensitivity
Expensive
Rapid appearance Time consuming
Labour intensive
In conclusion, the diagnostic tools available today allow (1) a good discrimination between SIRS and sepsis, and (2) monitoring of the clinical course
and the response to the treatments. In selected cases, one should take advantage
of DNA amplification technology to distinguish between the two conditions.
Are these criteria reliable?
The ultimate problem associated with the ACCM-SCCM diagnostic definitions
is their reliability to assist in the choice of treatment. Some investigations [6,
10, 11] suggest that the difference between SIRS and sepsis is rather narrow,
thus casting serious doubt on the possibility that some “false SIRS” could be
rather a “true sepsis”. This appears particularly relevant, since in critically ill
patients a delay in the appropriate therapy is unavoidably associated with a
higher rate of complications and a worse prognosis. From the above studies, it
appears that although the ACCP-SCCM definitions describe accurately most of
conditions presented by critically ill patients, a grey area persists in which both
the clinical signs and the commonly measured biological variables cannot discriminate between non-infectious and infectious source of disturbances [8].
SIRS, Sepsis, and MODS
545
Unfortunately, the threshold for either the administration of antibiotics or the
surgical drainage of a septic focus lies in this area. This “twilight zone” can be
reduced, but probably not totally eliminated, by the use of new diagnostic
tools, including the repeated measurement of selected mediators and the PCR
[26, 41, 42].
Conclusions
Despite their introduction into clinical practice nearly 10 years ago and the
criticisms raised, the ACCP-SCCM definitions are still widely used throughout
the world and seem to be robust, and should remain as described [9]. The main
criticism is based on their broadness and consequent lack of specificity, even
though signs and symptoms of sepsis [9] are, at the moment, more varied than
the initial criteria established in 1991 [2, 3]. It is likely that novel diagnostic
approaches based on PCR could enhance the diagnostic sensitivity, thus reducing the grey area between infections and non-infectious conditions. The serial
measurements of selected inflammatory mediators, including the CRP and
PCT, allow a fairly accurate discrimination between SIRS and sepsis and can
constitute a guide for treatment. The future may lie in developing a staging system that will characterize the progression of sepsis including predisposing factors, nature of infection, host response and extent of the resultant organ dysfunction.
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