Iraklis Tsangaris

Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials.

Objective:There is increasing interest for strategies that could curtail antibiotic resistance in the critical care setting. We sought to determine the effectiveness and safety of procalcitonin-guided algorithms in the management of septic patients in the intensive care unit. Data Sources:MEDLINE, Scopus, Cochrane Central Register of Controlled Trials (through April 2010), reference lists of retrieved publications, and queries of corresponding authors. No language restrictions were applied. Study Selection:We included only randomized controlled studies reporting on antibiotic use and clinical outcomes of intensive care unit patients managed with a procalcitonin-guided algorithm or according to routine practice. Data Extraction:Data on study characteristics, interventions, and outcomes were retrieved by two independent reviewers. Pooled odds ratios, weighted mean differences, and 95% confidence intervals were calculated by implementing both the Mantel-Haenszel fixed effect model and the DerSimonian-Laird random effects model. Data Synthesis:Seven randomized controlled studies involving 1131 intensive care unit patients (adults = 1010; neonates = 121) were included. In comparison with routine practice, the implementation of procalcitonin-guided algorithms decreased the duration of antibiotic therapy for the first episode of infection by approximately 2 days (weighted mean difference = −2.36 days; 95% confidence interval, −3.11 to −1.61) and the total duration of antibiotic treatment by 4 days (fixed effect model: weighted mean difference: −4.19 days; 95% confidence interval, −4.98 to −3.39). The comparison between the procalcitonin and the routine practice group was not associated with any apparent adverse clinical outcome: 28-day mortality (fixed effect model: odds ratio = 0.93; 95% confidence interval, 0.69 to 1.26), intensive care unit length of stay (fixed effect model: pooled weighted mean difference = −0.49 days, 95% confidence interval, −1.55 to 0.57), and relapsed/persistent infection rate (fixed effect model: odds ratio = 0.97; 95% confidence interval, 0.56 to 1.69). Conclusions:The implementation of a procalcitonin-based algorithm may reduce antibiotic exposure in critically ill, septic patients without compromising clinical outcomes, but further research is necessary before the wide adoption of this strategy.

Impact of catheter-related bloodstream infections on the mortality of critically ill patients: a meta-analysis.

Objective: There is controversy on whether catheter-related bloodstream infections (CR-BSI) affect the mortality of critically ill patients. Design: Meta-analysis of comparative studies that reported on mortality of intensive care unit (ICU) adult patients with and without CR-BSI. Methods: PubMed, Current Contents, and reference lists of retrieved publications were searched with no language or time restrictions. Heterogeneity was assessed by means of I2-statistic and chi-square test. Publication bias was detected by the funnel plot method using Egger’s test. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated by implementing both the Mantel–Haenszel fixed effect and the DerSimonian–Laird random effects model. Results: Eight studies, involving 2,540 ICU patients, were included. Heterogeneity was detected (I2 = 0.67, 95% CI 0.32–0.85, p = 0.003). Publication bias was not found (Egger’s test, p = 0.28). All-cause in-hospital mortality was higher in ICU patients with CR-BSI than in those without CR-BSI (fixed effect model: OR = 1.81, 95% CI 1.44–2.28; random effects model: OR = 1.96, 95% CI 1.25–3.09). This was also the case for the subgroup analysis of the studies that were matched for severity of illness (fixed effect model: OR = 1.65, 95% CI 1.28–2.13; random effects model: OR = 1.70, 95% CI 1.00–2.90). Conclusion: Presence, as opposed to absence, of CR-BSI is associated with higher mortality in critically ill adult patients. This finding seems to justify and may enhance efforts to prevent CR-BSI in such patients.

Colistin Methanesulfonate and Colistin Pharmacokinetics in Critically Ill Patients Receiving Continuous Venovenous Hemodiafiltration

ABSTRACT This report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (Cmax) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/liter and CL/metabolized fraction (fm) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.

Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor.

IntroductionEarly risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed.MethodsA prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden.ResultsSerum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II ≥17 and suPAR ≥12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II <17 and suPAR <12 ng/ml with mortality 5.5%; ii) APACHE II < 17 and suPAR ≥12 ng/ml with mortality 17.4%; iii) APACHE II ≥ 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II ≥17 and suPAR ≥12 ng/ml with mortality 51.7%. This prediction rule was confirmed by the Swedish cohort.ConclusionsA novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR is proposed. Prognostication by this rule is confirmed by an independent cohort.

Prognostic importance of increased plasma amino-terminal pro-brain natriuretic peptide levels in a large noncardiac, general intensive care unit population.

The present study aimed to determine whether amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) predicts intensive care unit (ICU) mortality in a cohort of general, noncardiac, critically ill patients. To this end, a total of 233 consecutive mechanically ventilated patients (109 men) having a median age of 60 years and a wide range in admitting diagnoses, including medical (n = 118), surgical (n = 83), and multiple trauma (n = 32) cases were prospectively studied. Median Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores on ICU admission were 16 and 9, respectively. The study end point was ICU outcome. Blood samples were drawn on admission in the ICU and on postadmission days 1 and 2 to determine NT-pro-BNP levels. In a subgroup (n = 77), admission proinflammatory and anti-inflammatory cytokine levels, including TNF-&agr;, IL-6, and IL-10, were also measured. Nonsurvivors (n = 98) had significantly higher NT-pro-BNP levels than survivors (n = 135) on admission in the ICU (2,074 vs. 283 pg/mL; P < 0.001), on day 1 (2,197 vs. 221 pg/mL; P < 0.001), and on day 2 (2,726 vs. 139 pg/mL; P < 0.001). Median values for TNF-&agr;, IL-6, and IL-10 were 3.70, 131.57, and 111.88 pg/mL, respectively. Receiver operating characteristic analysis showed that the area under the receiver operating characteristic curve in predicting ICU mortality was 0.70 for APACHE II and 0.77 for admission NT-pro-BNP (P = 0.08). The cutoff in admission NT-pro-BNP that best predicted outcome was 941 pg/mL. Multiple logistic regression analysis revealed that APACHE II score (odds ratio, 1.06; P = 0.007) and the best cutoff point in admission NT-pro-BNP (odds ratio, 7.74; P < 0.001) independently predicted ICU mortality, even if cytokines were entered in the analysis. In conclusion, plasma NT-pro-BNP is frequently raised in noncardiac, mixed, critically ill patients, and nonsurvivors have consistently higher levels than survivors. Elevated admission NT-pro-BNP represents an independent predictor for poor ICU outcome in the presence of clinical severity scores.

Procalcitonin as an early indicator of outcome in sepsis: a prospective observational study

This study explores the role of procalcitonin (PCT) in predicting the outcome of sepsis. In a prospective multicentre observational investigation, blood was sampled within 24 h of onset of sepsis in 1156 hospitalised patients; 234 were in the intensive care unit (ICU) at the point of presentation of sepsis while 922 were not. PCT was estimated in serum by the ultrasensitive Kryptor assay in a double-blinded fashion. Among patients outside the ICU, mortality was 8% in those with PCT ≤0.12 ng/mL but 19.9% in those with PCT >0.12 ng/mL [P<0.0001, odds ratio (OR) for death: 2.606; 95% confidence interval (CI): 1.553-4.371]. Among patients whose sepsis presented in ICU, mortality was 25.6% in those with PCT ≤0.85 ng/mL but 45.3% in those with PCT >0.85 ng/mL (P=0.002; OR for death: 2.404; 95% CI: 1.385-4.171). It is concluded that PCT cut-off concentrations can contribute to predicting the outcome of sepsis and might be of particular value in identifying patients who would benefit from ICU admission.

Association of left ventricular diastolic dysfunction with elevated NT-pro-BNP in general intensive care unit patients with preserved ejection fraction: a complementary role of tissue Doppler imaging parameters and NT-pro-BNP levels for adverse outcome.

The mechanisms of the N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) release in intensive care unit (ICU) patients with preserved ejection fraction (EF) are unclear. We investigated whether left ventricular (LV) dysfunction, as assessed by tissue Doppler imaging (TDI), is related to NT-pro-BNP levels in ICU patients with preserved EF and has a complementary value to NT-pro-BNP in the determination of in-hospital mortality. We examined 58 mechanically ventilated patients with no history of heart failure (age, 60 ± 18 years; EF, 63% ± 7%). The systolic (S) and early diastolic (E&vprime;) velocity of the mitral annulus by TDI and the E/E&vprime; as well as NT-pro-BNP, troponin, lactate acid, blood oxygen (PO2/FiO2), sepsis, and ICU mortality were assessed. Systolic, E&vprime;, and E/E&vprime; correlated with age, PO2/FiO2, lactate acid, NT-pro-BNP, troponin, history of arterial hypertension, and diabetes (P < 0.05). By multivariate analysis, the determinants of NT-pro-BNP were S (P = 0.024), E/E&vprime; (P = 0.017), and sepsis (P = 0.015). An NT-pro-BNP greater than 941 pg/mL was a reliable predictor of LV diastolic dysfunction defined as a composite of E&vprime; less than or equal to 8 cm/s and/or mean E/E greater than or equal to 13 (area under the curve, 75%; P = 0.03). Patients with combined NT-pro-BNP greater than 941 pg/mL and abnormal TDI markers had increased creatinine levels and a lower MAP, PO2/FiO2, and survival rate than those with abnormal TDI or NT-pro-BNP alone or patients with normal TDI markers and NT-pro-BNP (25%, 60%, 70%, and 84%, respectively; P < 0.05). The addition of abnormal TDI in a model including NT-pro-BNP and sepsis increased the models value for in-hospital mortality (P for change = 0.01). In ICU patients with preserved EF, LV diastolic dysfunction and sepsis determine NT-pro-BNP levels. Tissue Doppler imaging markers and NT-pro-BNP have a complementary value for in-hospital mortality.

Diagnostic and prognostic value of procalcitonin among febrile critically ill patients with prolonged ICU stay

BackgroundProcalcitonin (PCT) has been proposed as a diagnostic and prognostic sepsis marker, but has never been validated in febrile patients with prolonged ICU stay.MethodsPatients were included in the study provided they were hospitalised in the ICU for > 10 days, were free of infection and presented a new episode of SIRS, with fever >38°C being obligatory. Fifty patients fulfilled the above criteria. PCT was measured daily during the ICU stay. The primary outcome was proven infection.ResultsTwenty-seven out of 50 patients were diagnosed with infection. Median PCT on the day of fever was 1.18 and 0.17 ng/ml for patients with and without proven infections (p < 0.001). The area under the curve for PCT was 0.85 (95% CI; 0.71-0.93), for CRP 0.65 (0.46-0.78) and for WBC 0.68 (0.49-0.81). A PCT level of 1 ng/mL yielded a negative predictive value of 72% for the presence of infection, while a PCT of 1.16 had a specificity of 100%. A two-fold increase of PCT between fever onset and the previous day was associated with proven infection (p 0.001) (OR = 8.55; 2.4-31.1), whereas a four-fold increase of PCT of any of the 6 preceding days was associated with a positive predictive value exceeding 69.65%. A PCT value less than 0.5 ng/ml on the third day after the advent of fever was associated with favorable survival (p 0.01).ConclusionThe reported data support that serial serum PCT may be a valuable diagnostic and prognostic marker in febrile chronic critically ill patients.

Validation of the new Sepsis-3 definitions: proposal for improvement in early risk identification

OBJECTIVES Sepsis-3 definitions generated controversies regarding their general applicability. The Sepsis-3 Task Force outlined the need for validation with emphasis on the quick Sequential Organ Failure Assessment (qSOFA) score. This was done in a prospective cohort from a different healthcare setting. METHODS Patients with infections and at least two signs of systemic inflammatory response syndrome (SIRS) were analysed. Sepsis was defined as total SOFA ≥2 outside the intensive care unit (ICU) or as an increase of ICU admission SOFA ≥2. The primary endpoints were the sensitivity of qSOFA outside the ICU and sepsis definition both outside and within the ICU to predict mortality. RESULTS In all, 3346 infections outside the ICU and 1058 infections in the ICU were analysed. Outside the ICU, respective mortality with ≥2 SIRS and qSOFA ≥2 was 25.3% and 41.2% (p <0.0001); the sensitivities of qSOFA and of sepsis definition to predict death were 60.8% and 87.2%, respectively. This was 95.9% for sepsis definition in the ICU. The sensitivity of qSOFA and of ≥3 SIRS criteria for organ dysfunction outside the ICU was 48.7% and 72.5%, respectively (p <0.0001). Misclassification outside the ICU with the 1991 and Sepsis-3 definitions into stages of lower severity was 21.4% and 3.7%, respectively (p <0.0001) and 14.9% and 3.7%, respectively, in the ICU (p <0.0001). Adding arterial pH ≤7.30 to qSOFA increased sensitivity for prediction of death to 67.5% (p 0.004). CONCLUSIONS Our analysis positively validated the use of SOFA score to predict unfavourable outcome and to limit misclassification into lower severity. However, qSOFA score had inadequate sensitivity for early risk assessment.