Pedro Póvoa

C-reactive protein: a valuable marker of sepsis.

The word sepsis originated from the old Greek word meaning “putrefaction”. Nowadays, this term is used to describe the host systemic response to infectious stimuli that is characterised by clinical, haemodynamic, biochemical and inflammatory responses [1]. Sepsis is still one of the leading causes of death in the critically ill [2]. Despite all the research performed over the last two decades, few specific treatments have been shown to improve outcome. In daily practice, clinicians are often faced with two dilemmas: whether a patient is infected or not, and whether the antibiotic therapy being given is effective. The distinction between infection and sepsis is frequently difficult to make. Infection without sepsis can occur if the process remains localised. A sepsis-like syndrome without infection is also a frequent finding in conditions such as trauma and pancreatitis [3]. The attention of the clinician must be directed towards the early diagnosis of infection [4]. However, bacteriological confirmation may be difficult to obtain and negative cultures do not exclude the presence of infection. In addition, manifestations of sepsis such as fever, leukocytosis and tachycardia are neither specific nor sensitive for infection, nor for monitoring the response to therapy [5]. Increasing understanding of the various inflammatory cascade mechanisms has given new insights and provided several markers that, in conjunction with other manifestations of sepsis, can be useful as indicators of infection. C-reactive protein (CRP) is one such marker.

C-reactive protein as an indicator of sepsis

Objective: To determine the use of plasma C-reactive protein (CRP) concentrations, body temperature (BT) and white blood cell count (WBC) in the detection of sepsis in critically ill patients. Design: All patients admitted for more than 24 h in the intensive care unit (ICU) were prospectively included. Patients were followed up to ICU discharge and each patient-day was classified in one of four categories according to the infectious status: 1) Negative, patient-day without systemic inflammatory response syndrome (SIRS); 2) Definite, patient-day with SIRS and a positive culture; 3) SIRS, patient-day with SIRS and negative or no cultures. The last group was subdivided according to the following criteria: a) new, or persistence of, pulmonary infiltrates, b) the presence of pus in a place known to be sterile. Patient-days without these criteria were classified as SIRS with improbable sepsis (Unlikely), and with one criteria or more as SIRS with probable sepsis (Probable). Setting: Medical/surgical intensive care unit. Patients: Twenty-three patients were followed. Measurements and results: A total of 306 patient-days were analysed: 20 Negative, 15 Definite, 63 Unlikely and 208 Probable. The median (range) CRP values for Negative, Unlikely, Probable and Definite groups were as follows: 24.5 (7–86), 34 (5–107), 143 (39–544), and 148 (52–320) mg/l. The plasma CRP levels were significantly related to the infectious status (Negative, Unlikely, Probable or Definite) of the patient-day classification (p < 0.05). Concentrations of CRP in the Negative and Unlikely groups were significantly lower than in the Probable and Definite ones (p < 0.05). A plasma CRP of 50 mg/l or more was highly suggestive of sepsis (sensitivity 98.5 %, specificity 75 %). Conclusions: Daily measurement of CRP is useful in the detection of sepsis and it is more sensitive than the currently used markers, such as BT and WBC.

Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams

IntroductionSeveral reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.MethodsWe performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded.ResultsA total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock.ConclusionsThe PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.

Early identification of intensive care unit-acquired infections with daily monitoring of C-reactive protein: a prospective observational study.

IntroductionManifestations of sepsis are sensitive but are poorly specific of infection. Our aim was to assess the value of daily measurements of C-reactive protein (CRP), temperature and white cell count (WCC) in the early identification of intensive care unit (ICU)-acquired infections.MethodsWe undertook a prospective observational cohort study (14 month). All patients admitted for ≥72 hours (n = 181) were divided into an infected (n = 35) and a noninfected group (n = 28). Infected patients had a documented ICU-acquired infection and were not receiving antibiotics for at least 5 days before diagnosis. Noninfected patients never received antibiotics and were discharged alive. The progression of CRP, temperature and WCC from day -5 to day 0 (day of infection diagnosis or of ICU discharge) was analyzed. Patients were divided into four patterns of CRP course according to a cutoff value for infection diagnosis of 8.7 mg/dl: pattern A, day 0 CRP >8.7 mg/dl and, in the previous days, at least once below the cutoff; pattern B, CRP always >8.7 mg/dl; pattern C, day 0 CRP ≤8.7 mg/dl and, in the previous days, at least once above the cutoff; and pattern D, CRP always ≤8.7 mg/dl.ResultsCRP and the temperature time-course showed a significant increase in infected patients, whereas in noninfected it remained almost unchanged (P < 0.001 and P < 0.001, respectively). The area under the curve for the maximum daily CRP variation in infection prediction was 0.86 (95% confidence interval: 0.752–0.933). A maximum daily CRP variation >4.1 mg/dl was a good marker of infection prediction (sensitivity 92.1%, specificity 71.4%), and in combination with a CRP concentration >8.7 mg/dl the discriminative power increased even further (sensitivity 92.1%, specificity 82.1%). Infection was diagnosed in 92% and 90% of patients with patterns A and B, respectively, and in only two patients with patterns C and D (P < 0.001).ConclusionDaily CRP monitoring and the recognition of the CRP pattern could be useful in the prediction of ICU-acquired infections. Patients presenting maximum daily CRP variation >4.1 mg/dl plus a CRP level >8.7 mg/dl had an 88% risk of infection.

The role of corticosteroids in severe community-acquired pneumonia: a systematic review

IntroductionThe purpose of this review was to evaluate the impact of corticosteroids on the outcomes of patients with severe community-acquired pneumonia (CAP).MethodsWe performed a systematic MEDLINE, Cochrane database, and CINAHL search (1966 to November 2007) to identify full-text publications that evaluated the use of corticosteroids in CAP.ResultsAn initial literature search yielded 109 articles, and 105 studies were excluded after the first analysis. We found four studies eligible for analysis. On the basis of their results, the use of corticosteroids as adjunctive therapy in severe CAP should be categorized as a weak recommendation (two studies) and a strong recommendation (two studies) with either low- or moderate-quality evidence. However, no evidence of adverse outcomes or harm is present in the evaluated studies.ConclusionAccording to the GRADE system, available studies do not support the recommendation of corticosteroids as a standard of care for patients with severe CAP. Further randomized controlled trials with this aim should enroll a larger number of severely ill patients. However, in patients needing corticosteroids, it may be reasonable to conclude that corticosteroid administration is safe in patients with severe infections receiving antimicrobial therapy.

Usefulness of C-reactive protein in monitoring the severe community-acquired pneumonia clinical course

BackgroundThe aim of the present study was to evaluate the C-reactive protein level, the body temperature and the white cell count in patients after prescription of antibiotics in order to describe the clinical resolution of severe community-acquired pneumonia.MethodsA cohort of 53 consecutive patients with severe community-acquired pneumonia was studied. The C-reactive protein levels, body temperature and white cell count were monitored daily.ResultsBy day 3 a C-reactive protein level 0.5 times the initial level was a marker of poor outcome (sensitivity, 0.91; specificity, 0.59). Patients were divided according to their C-reactive protein patterns of response to antibiotics, into fast response, slow response, nonresponse, and biphasic response. About 96% of patients with a C-reactive protein pattern of fast response and 74% of patients with a slow response pattern survived, whereas those patients with the patterns of nonresponse and of biphasic response had a mortality rate of 100% and 33%, respectively (P < 0.001). On day 3 of antibiotic therapy, a decrease in C-reactive protein levels by 0.31 or more from the previous days level was a marker of good prognosis (sensitivity, 0.75; specificity, 0.85).ConclusionDaily C-reactive protein measurement after antibiotic prescription is useful in identification, as early as day 3, of severe community-acquired pneumonia patients with poor outcome. The identification of the C-reactive protein pattern of response to antibiotic therapy was useful in the recognition of the individual clinical course, either improving or worsening, as well as the rate of improvement, in patients with severe community-acquired pneumonia.

Influence of vasopressor agent in septic shock mortality. Results from the Portuguese Community-Acquired Sepsis Study (SACiUCI study)

Objective:Guidelines for the adrenergic support of septic shock are controversial. In patients with community-acquired septic shock, we assessed the impact of the choice of vasopressor support on mortality. Design:Cohort, multiple center, observational study. Setting:Seventeen Portuguese intensive care units (ICUs). Patients:All adult patients admitted to a participating ICU between December 2004 and November 2005. Interventions:None. Measurements and Main Results:Patients were followed up during the first five ICU days, the day of discharge or death, and hospital outcome. Eight hundred ninety-seven consecutive patients with community-acquired sepsis (median age, 63 years; 577 men; and hospital mortality, 38%) were studied. Of the 458 patients with septic shock, 73% received norepinephrine and 50.5% dopamine. The norepinephrine group had a higher hospital mortality (52% vs. 38.5%, p = 0.002). A Kaplan–Meier survival curve showed diminished 28-day survival in the norepinephrine group (log-rank = 22.6, p < 0.001). A Cox proportional hazard analysis revealed that the administration of norepinephrine was associated with an increased risk of death (adjusted hazard ratio, 2.501; 95% confidence interval, 1.413–4.425; p = 0.002). In a multivariate analysis with ICU mortality as the dependent factor, Simplified Acute Physiology Score II and norepinephrine administration were independent risk factors for ICU mortality in patients with septic shock. Conclusions:In patients with community-acquired septic shock, our data suggest that norepinephrine administration could be associated with worse outcome.

C-reactive protein, an early marker of community-acquired sepsis resolution: a multi-center prospective observational study

IntroductionC-reactive protein (CRP) has been shown to be a valuable marker in the diagnosis of infection and in monitoring its response to antibiotics. Our objective was to evaluate serial CRP measurements after prescription of antibiotics to describe the clinical course of Community-Acquired Sepsis admitted to intensive care units (ICU).MethodsDuring a 12-month period a multi-center, prospective, observational study was conducted, segregating adults with Community-Acquired Sepsis. Patients were followed-up during the first five ICU days, day of ICU discharge or death and hospital outcome. CRP-ratio was calculated in relation to Day 1 CRP concentration. Patients were classified according to the pattern of CRP-ratio response to antibiotics: fast response if Day 5 CRP-ratio was < 0.4, slow response if Day 5 CRP-ratio was between 0.4 and 0.8, and no response if Day 5 CRP-ratio was > 0.8. Comparison between survivors and non-survivors was performed.ResultsA total of 891 patients (age 60 ± 17 yrs, hospital mortality 38%) were studied. There were no significant differences between the CRP of survivors and non-survivors until Day 2 of antibiotic therapy. On the following three days, CRP of survivors was significantly lower (P < 0.001). After adjusting for the Simplified Acute Physiology Score II and severity of sepsis, the CRP course was significantly associated with mortality (ORCRP-ratio = 1.03, confidence interval 95%= (1.02, 1.04), P < 0.001). The hospital mortality of patients with fast response, slow response and no response patterns was 23%, 30% and 41%, respectively (P = 0.001). No responders had a significant increase on the odds of death (OR = 2.5, CI95% = (1.6, 4.0), P < 0.001) when compared with fast responders.ConclusionsDaily CRP measurements after antibiotic prescription were useful as early as Day 3 in identification of Community-Acquired Sepsis patients with poor outcome. The rate of CRP decline during the first five ICU days was markedly associated with prognosis. The identification of the pattern of CRP-ratio response was useful in the recognition of the individual clinical course.

Incidence and prognosis of ventilator-associated tracheobronchitis (TAVeM): a multicentre, prospective, observational study

BACKGROUND Ventilator-associated tracheobronchitis has been suggested as an intermediate process between tracheobronchial colonisation and ventilator-associated pneumonia in patients receiving mechanical ventilation. We aimed to establish the incidence and effect of ventilator-associated tracheobronchitis in a large, international patient cohort. METHODS We did a multicentre, prospective, observational study in 114 intensive care units (ICU) in Spain, France, Portugal, Brazil, Argentina, Ecuador, Bolivia, and Colombia over a preplanned time of 10 months. All patients older than 18 years admitted to an ICU who received invasive mechanical ventilation for more than 48 h were eligible. We prospectively obtained data for incidence of ventilator-associated lower respiratory tract infections, defined as ventilator-associated tracheobronchitis or ventilator-associated pneumonia. We grouped patients according to the presence or absence of such infections, and obtained data for the effect of appropriate antibiotics on progression of tracheobronchitis to pneumonia. Patients were followed up until death or discharge from hospital. To account for centre effects with a binary outcome, we fitted a generalised estimating equation model with a logit link, exchangeable correlation structure, and non-robust standard errors. This trial is registered with ClinicalTrials.gov, number NCT01791530. FINDINGS Between Sept 1, 2013, and July 31, 2014, we obtained data for 2960 eligible patients, of whom 689 (23%) developed ventilator-associated lower respiratory tract infections. The incidence of ventilator-associated tracheobronchitis and that of ventilator-associated pneumonia at baseline were similar (320 [11%; 10·2 of 1000 mechanically ventilated days] vs 369 [12%; 8·8 of 1000 mechanically ventilated days], p=0·48). Of the 320 patients with tracheobronchitis, 250 received appropriate antibiotic treatment and 70 received inappropriate antibiotics. 39 patients with tracheobronchitis progressed to pneumonia; however, the use of appropriate antibiotic therapy for tracheobronchitis was associated with significantly lower progression to pneumonia than was inappropriate treatment (19 [8%] of 250 vs 20 [29%] of 70, p<0·0001; crude odds ratio 0·21 [95% CI 0·11-0·41]). Significantly more patients with ventilator-associated pneumonia died (146 [40%] of 369) than those with tracheobronchitis (93 [29%] of 320) or absence of ventilator-associated lower respiratory tract infections (673 [30%] of 2271, p<0·0001). Median time to discharge from the ICU for survivors was significantly longer in the tracheobronchitis (21 days [IQR 15-34]) and pneumonia (22 [13-36]) groups than in the group with no ventilator-associated lower respiratory tract infections (12 [8-20]; hazard ratio 1·65 [95% CI 1·38-1·97], p<0·0001). INTERPRETATION This large database study emphasises that ventilator-associated tracheobronchitis is a major health problem worldwide, associated with high resources consumption in all countries. Our findings also show improved outcomes with use of appropriate antibiotic treatment for both ventilator-associated tracheobronchitis and ventilator-associated pneumonia, underlining the importance of treating both infections, since inappropriate treatment of tracheobronchitis was associated with a higher risk of progression to pneumonia. FUNDING None.

Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review

Biomarkers of infection, namely C-reactive protein and procalcitonin (PCT), are potentially useful in the diagnosis of infection as well as in the assessment of its response to antibiotic therapy. C-reactive protein variations overtime appears to have a good performance for the diagnosis of infection. Procalcitonin shows a better correlation with clinical severity. In addition, to overcome the worldwide problem of antibiotic overuse as well as misuse, biomarker guidance of antibiotic stewardship represents a promising new approach. In several randomized, controlled trials, including adult critically ill patients, PCT guidance was repeatedly associated with a decrease in the duration of antibiotic therapy. However, these trials present several limitations, namely high rate of patients’ exclusion, high rate of algorithm overruling, long duration of antibiotic therapy in the control group, disregard the effect of renal failure on PCT level, and above all a possible higher mortality and higher late organ failure in the PCT arm. In addition, some infections (e.g., endocarditis) as well as frequent nosocomial bacteria (e.g., Pseudomonas aeruginosa) are not suitable to be assessed by PCT algorithms. Therefore, the true value of PCT-guided algorithm of antibiotic stewardship in assisting the clinical decision-making process at the bedside remains uncertain. Future studies should take into account the issues identified in the present review.