“The important thing is not to stop questioning.” Albert Einstein

SEPSIS C-Reactive Protein as a Prognosis Factor for Septic Patients Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com SEPSIS Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com

SEPSIS Sepsis is the body’s exacerbated response to infection that threatens patients of all ages. Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com

Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com

1 SEPSIS leading cause of death in noncoronary intensive care units Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com

SEPSIS It is defined as a complex syndrome characterized by simultaneous activation of inflammation and coagulation in response to infectious stimuli. Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com

body’s normal anti-inflammatory response SEPSIS inflammation body’s normal anti-inflammatory response systemic inflammatory response syndrome (SIRS) = sepsis severe sepsis septic shock Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com

SIRS manifests itself through the release of, among other molecular agents, proinflammatory cytokines CRP (C-Reactive Protein) – plasma protein released by the liver in response to proinflammatory cytokines: is an indicator of inflammation. Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com

CRP = Biomarker of sepsis Is CRP a good prognosis factor for septic patients? Prof. Doutor Armando Teixeira- Pinto Prof. Doutor Altamiro Costa-Pereira Introduction to Medicine 08/09 Class nr. 4 im4fmup@gmail.com

Problem / Research Question Is C-reactive protein a good prognosis factor for septic patients? - “Are the levels of this protein related to the degree of severity of sepsis?” - “How can these values influence a good prognosis?” - “Can it predict the mortality among patients?”

C-Reactive Protein: a Prognosis Factor for Septic Patients Systematic Review C-Reactive Protein: a Prognosis Factor for Septic Patients This is a pioneer study because, to the best of our knowledge, there are currently no published studies (systematic reviews or meta-analyses) that evaluate the quality of CRP as a prognosis factor for septic patients.

Key-Words C-reactive protein Sepsis Prognosis C-Reactive Protein: a Prognosis Factor for Septic Patients Key-Words C-reactive protein Sepsis Prognosis

Aims Analyze clinical data: C-Reactive Protein: a Prognosis Factor for Septic Patients Aims Verify if C-reactive protein is a good prognosis factor of septic patients; Analyze clinical data: Which are the values of C-reactive protein that can predict each degree of sepsis? What kind of therapeutic can be applied based on C-reactive protein’s values?

C-Reactive Protein: a Prognosis Factor for Septic Patients Methods

C-Reactive Protein: a Prognosis Factor for Septic Patients Query The search terms include the following, their synonymous and, when applicable, equivalent MeSH terms: "C-reactive protein” AND (“prognosis” OR “prognostic factor” OR “prognostic studies”) AND ("sepsis” OR “infection” OR “cross infection” OR “hospital acquired infection” OR “multiple organ dysfunction syndrome” OR “MODS” OR “septicemia” OR “septic shock” OR “systematic inflammatory response syndrome” OR “SIRS”) AND (“hospital” OR “critical care” OR “intensive care”)

Criteria C-Reactive Protein: a Prognosis Factor for Septic Patients Inclusion Criteria Exclusion Criteria - Articles written in Portuguese, Spanish or English; - Articles about studies realized among hospitalized patients in ICU (Intensive Care Unit) with a septic diagnosis; - Articles about studies that mention CRP as a prognosis factor of sepsis (alone or conjugated with other biomarkers); - Articles about studies that include consistent and organized data about CRP’s values in different samples of patients and references to outcomes in terms of morbidity and mortality. - Articles whose full-text can´t be achieved for free; - Articles about studies that not include samples of patients with a septic diagnosis; - Articles about studies that not mention CRP as a biomarker/prognosis factor of sepsis; - Articles about studies with insufficient or inconclusive data.

Pubmed (221 articles – until 13/03/2009) C-Reactive Protein: a Prognosis Factor for Septic Patients Research We’ve searched the following database using the query referred previously: Pubmed (221 articles – until 13/03/2009)

Quantitative Analysis C-Reactive Protein: a Prognosis Factor for Septic Patients Data Synthesis Quantitative Analysis Descriptive Analysis performing Meta-Analysis Variables Extracted organizing work in using Microsoft Visio SPSS 16.0 Microsoft Project

C-Reactive Protein: a Prognosis Factor for Septic Patients Selection of Studies The decision of inclusion or exclusion of each article was taken according to the inclusion or exclusion criteria determined.

Articles included were divided into 2 groups: C-Reactive Protein: a Prognosis Factor for Septic Patients Articles included were divided into 2 groups: Those with a positive association between prognostic value of CRP and sepsis (4 articles); Those with a negative association between prognostic value of CRP and sepsis (9 articles).

C-Reactive Protein: a Prognosis Factor for Septic Patients - We created two Databases in order to organize data and make articles’ analysis easier. - To do this we used SPSS 16.0 ®

Newcastle –Ottawa Scale (NOS) C-Reactive Protein: a Prognosis Factor for Septic Patients Quality Test Newcastle –Ottawa Scale (NOS) (“The Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses”; GA Wells, B Shea, D O’Connell, J Peterson, V Welch, M Losos, P Tugwell) Test’s scale goes from 0* (minimum) to 9* (maximum). Articles with negative association achieved a mean value of scores of 4,55* [(3-6); min. – max.] and the positive ones had a 4* mean score [(2-6); min. – max.].

Studies compare different cutoffs and groups: C-Reactive Protein: a Prognosis Factor for Septic Patients Studies compare different cutoffs and groups: survivors vs. non survivors; others consider groups according to the severity of sepsis (sepsis, severe sepsis, septic shock); The summary measures presented are means±SD, medians (IR) and medians (percentiles 5 – 95); Some studies present OR and RR values, ROC curves and diagrams.

C-Reactive Protein: a Prognosis Factor for Septic Patients - Articles presented a group of different variables, various measurement methods, different cutoff values of CRP and several ways of results’ presentation such as means associated with standard deviations, medians and interquartile range, ROC curves, odds ration and relative risks = Difficult to analyze the articles by quantitative means! - We opted to perform a systematic review and to classify the articles qualitatively through the NOS assessment method. Meta-Analysis Systematic Review

C-Reactive Protein: a Prognosis Factor for Septic Patients Discussion

C-Reactive Protein: a Prognosis Factor for Septic Patients All studies concerning CRP, sepsis, and prognosis are relatively recent; Studies that consider no association are, generally, older than those that state a positive association (except the study published by Silvestre J et al. in 2008); This can be explained by different parameters of evaluation of CRP levels and its relation with prognosis; different methods, cutoffs and scales used.

C-Reactive Protein: a Prognosis Factor for Septic Patients - CRP as a factor of prognosis of sepsis is not largely studied, and its prognostic power has to be proved consistently by further investigation in this area. - It seems to be an important single marker of inflammatory activation and one of the most suitable for use in clinical practice. However, its applicability in every day clinical practice as a prognosis factor is not yet established. - Many difficulty persists concerning the investigation’s methods and results’ interpretation regarding CRP. - Although promising, the clinical relevance of prognostic assessment based in CRP levels needs a deeper work in order to define the best cutoff, methodology and analysis procedures in each clinical setting and whether CRP is or isn’t a good factor of prognosis among septic patients.

C-Reactive Protein: a Prognosis Factor for Septic Patients - In summary, despite the large amount of evidence linking CRP with sepsis’ prognosis, current practice guidelines give no recommendations regarding when CRP should be measured and how to proceed with a patient with determined values of CRP. - We propose a standardization with additional studies, which need to be conducted in order to select the best methodology and to determined the appropriate measurements of CRP and how to valorize the result obtained.

Presenters: Margarita Yakubovich Sara Rodrigues Class 4 2008 / 2009