SIRS, Sepsis, and MODS
G. B
ERLOT, A. T
OMASINI, M. V
IVIANIFor 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 sys- temic 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 respon- sible 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 sys- temic disturbances are related to the spillover of these substances from the ini- tial site of reaction [2].
In the late 1980s and in the early 1990s the interest of intensivists was cap- tured 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 pancre- atitis, 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 medi-
ators of this process became available. Preliminary experimental results in dif-
ferent models of sepsis, as well as in a small number of patients, were encour- aging, and large, internationals trials with different molecules were initiated.
Consequently, more-precise definitions of the degrees of severity of the infec- tion-related conditions were needed, in order to compare and to track the clin- ical 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 syn- drome (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 func- tion 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 condi- tions, 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 confer- ence including 29 participants. The published document reflected a process whereby a group of experts and opinion leaders revisited the 1992 sepsis guide- lines 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 defini- tions 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 rely-
ing upon the ACCP- SCCM definitions?
Table 1.ACCP/SCCM Consensus Conference definitions of sepsis, severe sepsis, and septic shock. Modified from reference [3]
Definitions Features Possible clinical settings
Systemic The systemic inflammatory response Acute pancreatitis inflammatory to a wide variety of severe clinical Status post repair of response syndrome insults, manifested by 2 or more of ruptured aortic
(SIRS) the following conditions: aneurysm
1. Temperature> 38°C or < 36°C Acute vasculitis 2. Heart rate> 90 bpm Postoperative status 3. Respiratory rate> 20 breaths/min Burns
or PaCO2< 32 mmHg Trauma
4. White blood cell count> l2,000/ml or < 4,000/ml or> 10% immature forms
Sepsis The systemic inflammatory response to Uncomplicated pneumonia a documented infection. The clinical Urinary infections manifestations should include 2 or more Uncomplicated of the following signs as a result of appendicitis 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
Severe sepsis SIRS or sepsis associated with signs of Complicated pneumonia organ dysfunction or hypoperfusion, or abdominal infection including, but not limited, to lactic
acidosis, hypotension, oliguria or acute deterioration of the mental status
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 Presence of altered organ function in Combined acute dysfunction an acutely ill patient such that respiratory and syndrome homeostasis cannot be maintained renal failure
without intervention
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 encoun- tered different clinical courses. In a study involving 2,527 patients, Rangel- Frausto 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 cri- terion 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 intravas- cular 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 multi-
ple factors, including a delay in the referral of the enrolled patients to the par-
ticipating 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 pro-
gression towards septic shock was higher in patients with sepsis and severe sep-
sis 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
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 relat- ed 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 physiopathologi- cal conditions?
Both non-infectious and infectious events can trigger an inflammatory reac- tion, 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 pro- nounced in septic than in SIRS patients, and (3) in the majority of patients, its persistence is associated with a poor prognosis. Several investigators de- monstrated 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 intraop- erative 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
mediators are produced along with substances aimed at blocking their actions, including soluble receptors and cellular receptor blocking agents [18], the exis- tence of a condition defined as a compensatory anti-inflammatory response syndrome (CARS) has been hypothesized, in which blocking agents predomi- nate 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 can- not 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 exam- ple, despite the elevated rate of ventilator-associated pneumonias among criti- cally 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 pos-
sible 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 compli-
cations and consequentially treated. Cursons et al. [24] used two different tech-
niques of bacterial DNA amplification by means of the polymerase chain reac-
tion (PCR) in 110 critically ill patients with suspected or documented infec-
tions, and were able to demonstrate that PCR was positive in 8 patients with
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 coagu- lase-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 posi- tive 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 sam- ple and the presence of DNA sequences derived from non-pathogenic or con- taminant microorganism [26]. With these limitations in mind, the PCR could be valuable especially in those patients in whom the signs of a systemic inflamma- tory reaction persist despite (1) the negativity of cultures and/or (2) the admin- istration 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 demon- strated 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 auto- immune and rheumatological disorders, acute coronary events, and malignan- cies [36-39]. Despite these shortcomings, the measurements of CRP are still valuable, as they are far cheaper than those of PCT, do not require sophisticat- ed 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.
In conclusion, the diagnostic tools available today allow (1) a good discri- mination 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 dis- criminate between non-infectious and infectious source of disturbances [8].
Table 2.Advantages and disadvantages of the measurement of some inflammatory media- tors in the diagnosis of SIRS and sepsis (PCT procalcitonin, CRP C-reactive protein)
Marker Infection- Inflammation- Advantages Limitations specific specific
PCT 4+ 1+ Rapid Low specificity for focal
appearance infections. High specificity T/2 24 h for severe sepsis and
septic shock Relatively expensive
CRP 2+ 2+ Not expensive Low specificity
Widespread Slow appearance availability No correlation with
the severity
Cytokines 1+ 2+ High sensitivity Expensive
Rapid appearance Time consuming Labour intensive
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 reduc- ing 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 sys- tem that will characterize the progression of sepsis including predisposing fac- tors, nature of infection, host response and extent of the resultant organ dys- function.
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