European Society of Anaesthesiologists UPDATE ON THE DIAGNOSIS OF SEPSIS

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1 European Society of Anaesthesiologists UPDATE ON THE DIAGNOSIS OF SEPSIS 12RC4 MICHAEL MEISNER, KONRAD REINHART Department of Anaesthesiology and Intensive Care TherapyMedicine, Friedrich Schiller University of Jena Jena, Germany Saturday June 5, :00-15:45 Room 3A During recent years, the efficacy of therapeutic regimens for sepsis have been re-evaluated. These include classical approaches as well as novel therapeutic strategies, for example early goal directed therapy or activated protein C. Using such strategies, improvement of the outcome from sepsis is possible. Prior to treatment, early and effective diagnosis of sepsis is necessary. Clinical parameters (e.g SIRS criteriae) are still the primary indicators of sepsis. However, these parameters are neither sensitive nor specific. To confirm the diagnosis of sepsis and to characterize the extent and severity of the systemic inflammatory response of the host, measurement of other parameters, with greater specificity is recommended. Such parameters, including procalcitonin and interleukin-6, are contained in the recently introduced PIRO concept. The currently identified parameters which are most useful for an early and accurate diagnosis of sepsis are outlined in this review. DIAGNOSIS OF SEPSIS Today, diagnosis of sepsis primarily is based on the criteria of the ACCP/SCCM concensus conference of 1992 [1]. Sepsis is defined as systemic inflammation, caused by infection, or occurring in the presence of clinical evidence of infection. Systemic inflammation ( SIRS or the systemic inflammatory response syndrome ) is defined by the presence of at least two of four parameters, which can be easily measured clinically, and which are sensitive parameters for the detection of systemic inflammation: changes in body temperature, leukocyte count, heart rate and respiration parameters (table 1). If these symptoms are complicated by organ dysfunction, the definition of severe sepsis is fulfilled. If persistent arterial hypotension is present, the term septic shock is applied. This definition may not be easy to apply in clinical practice. First, symptoms of SIRS are unspecific and a combination of symptoms does not greatly improve specificity for the diagnosis of sepsis. Second, the infectious focus may be obscure at least initially or positive microbiological results may be delayed for technical or biological reasons (e.g bacterial isolation and growth). Finally, diagnosis of severe sepsis by organ dysfunction is quite a loose definition of this multiple-featured and often rapidly progressive disease. Early therapeutic measures may thus be delayed when these criteriae alone are used. As a consequence, if sepsis is suspected (for example indicated by positive SIRS-criteria), more specific data should be sought. Having rapidly confirmed the diagnosis of systemic inflammation, a bacterial focus should be sought, and an assessment made of the type and severity of the systemic inflammation and estimation of the risk of developing organ dysfunction. These steps will guide treatment, (including antibiotics), elimination of the focus of infection and supportive therapy ( oxygen delivery and optimisation of hemodynamic status). Such strategies have significant impact on the outcome [2, 3] ( early goal directed therapy [4], activated protein C [5]). To better stratify the overall and individual risk of a patient with sepsis, the PIRO classification has been proposed by an international advisory board [6]. As yet, this classification is of limited practical use, since clinical evaluation and definition of the specific criteria and their stratification are pending. In the future, this concept may be used to better characterize the patient with sepsis and a systemic inflammatory response [7-10]. ADDITONAL PARAMETERS SUPPLEMENTING SIRS CRITERIA At present, procalcitonin (PCT) is one of the biomarkers of sepsis with greatest specificity and sensitivity. In numerous studies, PCT has been shown to be a useful indicator of a possible bacterial source of inflammation and a marker of the severity of inflammation, the course of the disease and to correlate with patient outcome. It is described in detail below. IL-6 is a cytokine which correlates with the severity of inflammation and outcome in patients with sepsis [11], (although it is not specific for infectious causes of inflammation). The acute phase protein, C-reactive protein (CRP) is increased in the presence of bacterial infection and may be more sensitive than PCT. However, it is of limited use in critically ill patients because it correlates poorly with the severity of inflammation and slowly induced and eliminated. In contrast, interleukin-6, is a very sensitive measure of systemic inflammation( as is PCT ) correlates well with the severity of inflammation, but is not preferentially 137

2 induced in patients with bacterial infection. Due to its widely varying plasma concentrations and its short halflife, the clinical use of IL-6 and of other cytokines is limited. The lipopolysaccharid binding protein (LBP) offers no advantage over PCT or over the other parameters. Currently, new parameters are being evaluated which may help to discriminate between circulatory failure due either to cardiac dysfunction or sepsis and to predict patient outcome: pro ANP (pro-atrial natriuretic peptide) and BNP (brain natriuretic peptide) are parameters which indicate cardiac dysfunction. However, major studies related to sepsis are not yet available TABLE 1 - DEFINITIONS OF SYSTEMIC INFLAMMATION AND SEPSIS according to the criteria of the Consensus Conference of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) (1992) [1]. Systemic inflammatory Response Syndrome SIRS : SIRS with non-infectious aetiology Sepsis : symptoms of SIRS and infectious aetiology: At least 2 of the following criteria must be satisfied:. Fever or hypothermia - Temperature in the core of the body > 38 C or < 36 C. Tachycardia - ventricular rate > 90 bpm. Tachypnoea or hyperventilation - > 20 breaths/min or PaCO2 < 4.3 kpa (< 32 mmhg). Leucocytosis or leucopoenia or left-shift in differential blood count - 12 G/l or < 4 G/l or immature/total neutrophil granulocyte count > 0.1 Severe sepsis : sepsis + organ dysfunction symptoms of sepsis and. Organ dysfunction and. Hypotension - arterial systolic blood pressure < 90 mmhg - fall in BP values of more than 40 mmhg - reversible after fluid resuscitation or. Hypoperfusion with systemic phenomena - lactate-acidosis - oliguria - CNS symptoms - Other organ manifestations Septic shock : sepsis/severe sepsis + hypotension sepsis or severe sepsis and. Hypotension - as in severe sepsis - despite fluid intake (need for catecholamines) and. Hypoperfusion - as in severe sepsis THE PIRO CLASSIFICATION The PIRO classification was proposed in 2001 and published in 2003 by an advisory board [12]. The classification is proposed to improve characterization and staging of patients with sepsis, severe sepsis or septic shock. Currently, SIRS criteria and ACCP/SCCM definitions of sepsis do not sufficiently characterize all dimensions of the disease. The PIRO system is intended to classify rather than to quantify. It incorporates recent developments insepsis diagnosis and allows a more individual stratification of patients with sepsis and their 138

3 individual response. The PIRO concept comprises the dimensions: predisposition, insult infection, response, organ dysfunction (table 2). Further evaluation and detailed characterization of the PRIO classification is pending. Thus, for clinical routine diagnosis the system is not yet established and further data will be required to evaluate this classification. TABLE 2: THE PIRO SYSTEM FOR STAGING SEPSIS [12] IL, interleukin; LPS, lipopolysaccharide; SIRS, systemic inflammatory response syndrome, PAF, platelet-activating factor; TLR, Toll-like receptor; TNF, tumor necrosis factor; CRP, C-reactive protein; PCT, procalcitonin; HLA-DR, human leukocyte antigen-dr; MODS, multiple organ dysfunction syndrome; SOFA, sepsis-related organ failure assessment; LODS, logistic organ dysfunction; PEMOD, pediatric multiple organ dysfunction; PELOD, pediatric logistic organ dysfunction; PROCALCITONIN Procalcitonin (PCT), a propeptide of the hormone calcitonin, is normally produced in the C-cells of the thyroid gland. In healthy individuals, procalcitonin levels are very low (<0.1 ng/ml). In patients with sepsis, however, procalcitonin levels increase dramatically, sometimes to more than several hundred nanograms per milliliter. In contrast to proinflammatory cytokines, PCT is stable in the drawn blood sample even at room temperature, and in-vivo has a half-life of approximately h. The induction period lasts 6-12 hours, which is more rapid than that for C-reactive protein (CRP), but slower than that of proinflammatory cytokines (Figure 1) [13-15]. PCT production has been described in the liver, and in various other cells of the human organism. Endotoxin is a potent stimulus for PCT production, but also other proinflammatory mediators and non-bacterial infectious conditions do induce PCT. The (patho)physiological role of PCT during sepsis is unclear, but positive effects of immunoneutralisation of PCT on the circulatory system and survival in experimental endotoxin shock models have been reported (for review see [16]). A number of studies support PCT as a marker of severe infections and of sepsis. In various studies different severities of sepsis as defined by the ACCP/SCCM consensus conference criteriae were accompanied by increasing plasma levels of PCT (table 3). PCT levels also correlated with score systems describing organ dysfunction (SOFA score, APACHE II score) [14]. Patients with PCT levels < 0.5 ng/ml are unlikely to have severe sepsis or septic shock. Increases in PCT levels may indicate the presence of infection. however, The PCT threshold for this association varies depending on the setting. In the intensive care unit setting for example,, only levels > 1.0 or 1.5 ng/ml tend to identify sepsis [17, 18]. A localized focus of bacterial infection, failing to induce systemic inflammation, is usually not accompanied by increased PCT concentrations. 139

4 PCT concentrations exceeding 10 ng/ml almost exclusively occur almost exclusively in patients with severe sepsis or septic shock. However, PCT levels may increase during noninfectious inflammation such as major trauma, major surgery, prolonged cardiogenic shock, birth stressparturition, or therapies with cytokines or antilymphocyte globulin (for review see [19]). In such situations, following the day-to-day changes in further this parameter is more informative than using a single value. Decreasing levels of PCT have been described 48 hours after relaparotomy in patients with peritonitis who survived, whereas it remained unchanged in non-survivors [20]. CRP and IL-6 were not able to differentiate responders from non-responders to this surgical interventions for source control [18]. In several studies investigating outcome prediction in critically ill patients, PCT proved to be superior to TNF-α, IL-6, and CRP (table 4) [14, 21]. Initially elevated PCT levels in multiple traumatised patients were indicative of greater risk of septic complications and multiple organ failure [22]. PTC may also be helpful in differentiating between bacterial and viral infections (table 4). Neonates and children with bacterial meningitis had significantly greater levels of PTC than those with viral meningitis [23, 24]. Likewise, in liver and heart-transplant patients, systemic fungal or bacterial infections may be differentiated from episodes of graft rejection. In conclusion, PCT can be helpful in differentiating infectious from non-infectious causes of organ dysfunction in critically ill patients. In this respect, it seems to be superior to other markers. PCT levels correlate closely with the severity of sepsis and the degree of organ dysfunction. It initially increases when an infection is no longer walled up but becomes generalised. In sepsis patients who are unresponsive to treatment PCT levels remain high or increase further during the course of the disease. This may explain why PCT differentiates relatively early between survivors and non-survivors. TABLE 3 Sensitivity and specificity for the diagnosis of sepsis and bacterial infection by various parameters of the inflammatory response and correlation of these parameters with patient outcome. AUC, area under the curve of receiver operating characteristic. PCT, procalcitonin; CRP, c-reactive protein ; IL, interleukin. 140

5 FIGURE 1 - TIME COURSE OF THE PLASMA LEVELS OF VARIOUS PARAMETERS OF THE SYSTEMIC INFLAMMATORY RESPONSE [15] C-REACTIVE PROTEIN (CRP) CRP is a clinical marker frequently used to assess the presence and severity of an inflammatory response. Some studies support CRP as a marker of infection or of sepsis [25]. CRP has been found to differentiate patients with pneumonia from those with endotracheal infections, to aid the diagnosis of appendicitis, to assess the severity of sepsis or to differentiate bacterial and from viral infections. Other studies, however, point to important properties of CRP that limit its usefulness as a marker of severe infection and sepsis. The dynamic concentration range of PCT is much wider (from < 0.5 to levels above 500 ng/ml) than that of CRP. In particular, during the more severe stages of infection, CRP fails to rise further, while PCT increases reflect the increasing severity of the systemic inflammatory response [14]. Plasma concentrations of CRP may increase during minor infections [26], but do not adequately reflect the severity of infection, nor differentiate between eventual survivors and non-survivors of sepsis (table 3 and table 4)[14, 26]. CRP is also elevated during inflammatory states of noninfectious etiology, e.g. autoimmune and rheumatic disorders, malignant tumors, postoperatively. In coronary artery disease, where it is an indicator of patients at risk of coronary occlusion. Furthermore, p,lasma levels of CRP increase up to 24 h later than those of other markers such as cytokines or PCT, and often remain elevated for several days (Figure 1) [14, 15]. Probably because of these limitations, the predictive value ofs CRP in various patient populations can beis poor for the diagnosis of sepsis and less soinadequate when assessing the severity of sepsis. INTERLEUKIN-6 Interleukin-6 (IL-6) is a proinflammatory cytokine, produced by various cell types, including monocytes, macrophages and endothelial cells. Numerous stimuli, among them pro-inflammatory mediators and endotoxin, induce IL-6 production. Various studies indicate the association between IL-6 and sepsis. Other studies have showed a correlation between increased IL-6 levels and survival. An IL-6 concentration >1000 pg/ml was highly predictive for increased risk of death due to sepsis [11]. Müller et al. described the close correlation of PCT and IL-6 to severity of sepsis according to ACCP/SCCM criteria [18]. However, PCT may be a more useful marker of sepsis and infectious disease than IL-6. Using logistic regression of ROC curves in septic patients, Oberhoffer et al. demonstrated that an AUC value of was predictive of outcome for IL-6, and an AUC of for PCT [21]. Harbarth et al. evaluated the combined diagnostic accuracy of IL-6 with PCT [27]. They demonstrated that the accuracy of IL-6 for diagnosis of sepsis is limited in critically ill patients by nonspecific elevation caused by the accompanying inflammation, (table 4). In conclusion, as with PCT, IL-6 is one of the best markers of disease severity in patients with systemic inflammation of any cause. However, IL-6 has a short half-life in-vitro and in-vivo, and is not preferentially induced by bacterial infections. 141

6 TABLE 4 Potential of procalcitonin (PCT), C-reactive protein (CRP) and other parameters of the inflammatory response to differentiate bacterial and non-bacterial causes of infection and minor from major infections. IL, interleukin. COAGULATION PARAMETERS Sepsis is the most common cause of disseminated intravascular coagulation (DIC). During sepsis, activation of the coagulation system occurs early and is closely linked to the development of MODS and a poor prognosis [28]. Levels of antithrombin III (AT III), activated Factor VII, prothrombin fragments 1, and 2, and D-dimers reflect the development of a hypercoagulable state before the onset of defined clinical parameters for severe sepsis or septic shock [29, 30]. The platelet count is decreased in the majority of patients with sepsis. In one study, thrombocytopenia below 100,000 was observed in 37 % of 54 patients. The mean platelet count decreased from L -1 i.e. to 63 % of the original level at the time of the clinical diagnosis [31]. Recently protein C has been described as diagnostic tool, related to the coagulation system. Protein C concentrations rapidly declined several hours before the development of the clinical signs for severe sepsis and septic shock [32]. Protein C acts in its activated form as an antithrombotic, profibrinolytic and anti-inflammatory and inactivates both factor VIIIa, and factor Va. It is activated by endothelial and platelet thrombinthrombomodulin complexes and requires protein S as cofactor for its anticoagulant functions. During sepsis and systemic inflammation, protein C levels usually are low. Hartman et al. demonstrated that more than 85% of patients with severe sepsis had acquired protein C deficiency [32]. Protein C levels also correlate with severity of sepsis and outcome in septic patients [29, 32-35]. In one study, protein C levels, measured 44 hours after the time of recruitment, correlated with 30-day mortality (p = 0.04)[34]. In a study conducted by Lorente et al., protein C levels were significantly different between between survivors and non-survivors. In non-survivors, protein C levels remained depressed throughout day 7 of observation but were greater from day 4 onward in survivors [33]. Fourrier et al. investigated 40 patients with septic shock and disseminated intravascular coagulation. In this study, all but two patients had low protein C levels; these levels were significantly lower in non-survivors. An initial protein C level <30% had a specificity of 0.86 and a sensitivity of 0.60 (chi-square, 9.26; p=0.005) as a prognostic marker for sepsis and death [29]. Further studies are necessary to evaluate the clinical usefulness of this parameter, especially its role in the follow up and monitoring of critically ill patients with sepsis. 142

7 BODY TEMPERATURE Fever is a common symptom of patients with infection. Changes in the core temperature react occur rapidly and are an easily measurable sign of inflammation and infection. In 399 out of 464 patients admitted to hospital with fever, infection was the cause [36]. Furthermore, an increase in body temperature is often the first sign of systemic inflammation and, coinicides with the liberation of microbiological products or live bacteria into the circulation [37]. During sepsis, hypothermia may also occur. However, in intensive care patients, changes of temperature are frequently seen and may stem frombe due to noninfectious causes. Since body temperature is an easilyy measurable parameter with a high level of sensitivity for infection, despite its low sensitivity for the diagnosis of sepsis and infections, monitoring this parameter is valuable, although it is not specific for the diagnosis of sepsis and infections. LEUKOCYTES Although elevation of the white blood cell count is commonly interpreted as evidence of infection, neutrophilia is neither a sensitive nor specific marker of infection. Similarly, the diagnostic value of a left shift, reflecting release of newly formed white cells from the bone marrow, is limited as a marker of systemic inflammation [38]. Since leukocyte count is a sensitive marker of inflammation, and is easily measured, leukocyte or differential blood count remain one of the cornerstones of infection monitoring. In some cases, differential leukocyte counts may provide further information, e.g. lymphocytosis during viral infection., however, dfunctional assays are presently beeing investigated, evaluating the reactiveness and immunologic response of leukocytes to various stimuli, e.g. phorbol myristat-acetate (PMA)-induced respiratory burst or endotoxin-stimulated cytokine production. Analysis of different immunologic markers of the cell surface have also been investigated. To date, non of these have been shown to be useful for routine clinical diagnosis. CONCLUSION Early therapeutic intervention, (whether support of organ dysfunction or treatment of an infectious focus) is an important aim in the management of septic patients. Patient history and physical examination, with or without routine laboratory parameters, may suffice to establish the diagnosis of sepsis. However, in some patients, diagnosis of sepsis, evaluation of the success of therapeutic measures, and the identification of a possible focus of infection, can be greatly supported by the measurment of novel laboratory parameters of the systemic inflammatory resonse and sepsis such as PCT, CRP and IL-6. PCT plasma concentrations correlate well with the severity of inflammation, and are especially induced in patients with sepsis and bacterial infection. Also Furthermore, PCT concentrations rapidly decline after successful elimination of the infectious focus and with the disappearance of the symptoms of the inflammatory response. Thus, PCT can also be used to assess the efficacy of therapeutic measures in controlling the source of sepsis. CRP may be a more sensitive parameter for the diagnosis of non-generalized infections, however, its limited range of concentrations during more severe stages of inflammation, and its slower kinetics limit its usefulness in critically ill patients. IL-6 concentrations correlate well with the severity of inflammation, but are not specifically induced during sepsis and infection. Although cytokines such as IL-6 and IL-8 correlate to some degree with the severity of sepsis and patient outcome, they are not used routinely for the diagnosis and for clinical decision-making at the bedside. Due to the many different characteristics of inflammation, only a combination of various indicators of infection and the inflammatory response provides the broad spectrum of information neccessary to rapidly diagnose infection and inflammation to monitor its course and severity or to guide further therapeutic and diagnostic steps. Among those parameters are clinical signs and conventional parameters such as core temperature, leukocytes and coagulation parameters as well as novel parameters of the inflammatory response, such as procalcitonin. 143

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