Ilias I. Siempos

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 the administration of probiotics on the incidence of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials

Background:Previous reviews showed no benefit for the administration of probiotics in critically ill patients, but they did not focus on ventilator-associated pneumonia. Design:Meta-analysis of randomized controlled trials comparing probiotics and control in patients undergoing mechanical ventilation and reporting on incidence of ventilator-associated pneumonia. Methods:PubMed, Scopus, Current Contents, Cochrane Central Register of Controlled Trials, and reference lists were searched. Weighted mean differences, pooled odds ratios, and 95% confidence intervals were calculated, implementing both the Mantel-Haenszel fixed effect and the DerSimonian-Laird random effects model. Results:Five randomized controlled trials were included. Administration of probiotics, compared with control, was beneficial in terms of incidence of ventilator-associated pneumonia (689 patients; fixed effect model: odds ratio, 0.61; 95% confidence interval, 0.41–0.91; random effects model: odds ratio, 0.55, 95% confidence interval, 0.31–0.98), length of intensive care unit stay (fixed effect model: weighted mean difference, –0.99 days; 95% confidence interval, –1.37–−0.61), and colonization of the respiratory tract with Pseudomonas aeruginosa (odds ratio, 0.35; 95% confidence interval, 0.13–0.93). However, no difference was revealed between comparators regarding intensive care unit mortality (odds ratio, 0.75; 95% confidence interval, 0.47–1.21), in-hospital mortality (odds ratio, 0.75; 95% confidence interval, 0.46–1.24), duration of mechanical ventilation (weighted mean difference, –0.01 days; 95% confidence interval, –0.31–−0.29), and diarrhea (odds ratio, 0.61; 95% confidence interval, 0.28–1.34). Conclusion:Administration of probiotics is associated with lower incidence of ventilator-associated pneumonia than control. Given the increasing antimicrobial resistance, this promising strategy deserves consideration in future studies, which should have active surveillance for probiotic-induced diseases.

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.

Impact of passive humidification on clinical outcomes of mechanically ventilated patients: A meta-analysis of randomized controlled trials*

Objective: Previous meta‐analyses reported advantages of passive (i.e., heat and moisture exchangers, or HMEs) compared with active (i.e., heated humidifiers, or HHs) humidifiers in reducing the incidence of ventilator‐associated pneumonia, but they did not examine the effect of these devices on mortality, length of intensive care unit stay, and duration of mechanical ventilation. In addition, relevant data were recently published. Design: Meta‐analysis of randomized controlled trials comparing HMEs with HHs for the management of mechanically ventilated patients to determine the impact of these devices on clinical outcomes of such patients. Methods: We searched PubMed and the Cochrane Central Register of Controlled Trials as well as reference lists from publications, with no language restrictions. We estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs), using a random effects model. Results: Thirteen randomized controlled trials, studying 2,580 patients, were included. There was no difference in incidence of ventilator‐associated pneumonia among patients managed with HMEs and HHs (OR 0.85, 95% CI 0.62–1.16). There was no difference between the compared groups regarding mortality (OR 0.98, 95% CI 0.80–1.20), length of intensive care unit stay (weighted mean differences, ‐0.68 days, 95% CI ‐3.65 to 2.30), duration of mechanical ventilation (weighted mean differences, 0.11 days, 95% CI ‐0.90 to 1.12), or episodes of airway occlusion (OR 2.26, 95% CI 0.55–9.28). HMEs were cheaper than HHs in each of the randomized controlled trials. Conclusion: The available evidence does not support the preferential performance of either passive or active humidifiers in mechanical ventilation patients in terms of ventilator‐associated pneumonia incidence, mortality, or morbidity.

Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials

Background: We investigated whether the use of respiratory fluoroquinolones was associated with better clinical outcomes compared with the use of macrolides and β- lactams among adults with pneumonia. Methods: We searched PubMed, Current Contents, Scopus, EMBASE, ClinicalTrials.gov and Cochrane with no language restrictions. Two reviewers independently extracted data from published trials that compared fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin) with macrolides or β-lactams or both. A meta-analysis was performed with the clinical outcomes of mortality, treatment success and adverse outcomes. Results: We included 23 trials in our meta-analysis. There was no difference in mortality among patients who received fluoroquinolones or the comparator antibiotics (OR 0.85, 95% CI 0.65–1.12). Pneumonia resolved in more patients who received fluoroquinolones compared with the comparator antibiotics for the included outcomes in the intention-to-treat population (OR 1.17, 95% CI 1.00–1.36), clinically evaluable population (OR 1.26, 95% CI 1.06–1.50) and the microbiologically assessed population (OR 1.67, 95% CI 1.28–2.20). Fluoroquinolones were more effective than a combination of β-lactam and macrolide (OR 1.39, 95% CI 1.02–1.90). They were also more effective for patients with severe pneumonia (OR 1.84, 95% CI 1.02–3.29), those who required admission to hospital (OR = 1.30, 95% CI 1.04–1.61) and those who required intravenous therapy (OR = 1.44, 15% CI 1.13–1.85). Fluoroquinolones were more effective than β-lactam and macrolide in open-label trials (OR = 1.35, 95% CI 1.08–1.69) but not in blinded randomized controlled trials (OR = 1.13, 95% CI 0.85–1.50). Interpretation: Fluoroquinolones were associated with higher success of treatment for severe forms of pneumonia; however, a benefit in mortality was not evident. A randomized controlled trial that includes patients with severe pneumonia with or without bacteremia is needed.

Prone positioning in hypoxemic respiratory failure: Meta-analysis of randomized controlled trials

PURPOSEnProne positioning is used to improve oxygenation in patients with hypoxemic respiratory failure (HRF). However, its role in clinical practice is not yet clearly defined. The aim of this meta-analysis was to assess the effect of prone positioning on relevant clinical outcomes, such as intensive care unit (ICU) and hospital mortality, days of mechanical ventilation, length of stay, incidence of ventilator-associated pneumonia (VAP) and pneumothorax, and associated complications.nnnMETHODSnWe used literature search of MEDLINE, Current Contents, and Cochrane Central Register of Controlled Trials. We focused only on randomized controlled trials reporting clinical outcomes in adult patients with HRF. Four trials met our inclusion criteria, including 662 patients randomized to prone ventilation and 609 patients to supine ventilation.nnnRESULTSnThe pooled odds ratio (OR) for the ICU mortality in the intention-to-treat analysis was 0.97 (95% confidence interval [CI], 0.77-1.22), for the comparison between prone and supine ventilated patients. Interestingly, the pooled OR for the ICU mortality in the selected group of the more severely ill patients favored prone positioning (OR, 0.34; 95% CI, 0.18-0.66). The duration of mechanical ventilation and the incidence of pneumothorax were not different between the 2 groups. The incidence of VAP was lower but not statistically significant in patients treated with prone positioning (OR, 0.81; 95% CI, 0.61-1.10). However, prone positioning was associated with a higher risk of pressure sores (OR, 1.49; 95% CI, 1.17-1.89) and a trend for more complications related to the endotracheal tube (OR, 1.30; 95% CI, 0.94-1.80).nnnCONCLUSIONSnDespite the inherent limitations of the meta-analytic approach, it seems that prone positioning has no discernible effect on mortality in patients with HRF. It may decrease the incidence of VAP at the expense of more pressure sores and complications related to the endotracheal tube. However, a subgroup of the most severely ill patients may benefit most from this intervention.

Vasopressin for cardiac arrest: Meta-analysis of randomized controlled trials☆

BACKGROUNDnPrior meta-analyses-reported results of randomised controlled trials (RCTs) published between 1997 and 2004 failed to show any vasopressin-related benefit in cardiac arrest. Based on new RCT-data and a hypothesis of a potentially increased vasoconstricting efficacy of vasopressin, we sought to determine whether the cumulative, current evidence supports or refutes an overall and/or selective benefit for vasopressin regarding sustained restoration of spontaneous circulation (ROSC), long-term survival, and neurological outcome.nnnMETHODSnTwo reviewers independently searched PubMed, EMBASE, and Cochrane Database for RCTs assigning adults with cardiac arrest to treatment with a vasopressin-containing regimen (vasopressin-group) vs adrenaline (epinephrine) alone (control-group) and reporting on long-term outcomes. Data from 4475 patients in 6 high-methodological quality RCTs were analyzed. Subgroup analyses were conducted according to initial cardiac rhythm and time from collapse to drug administration (T(DRUG))<20 min.nnnRESULTSnVasopressin vs. control did not improve overall rates of sustained ROSC, long-term survival, or favourable neurological outcome. However, in asystole, vasopressin vs. control was associated with higher long-term survival {odds ratio (OR)=1.80, 95% confidence interval (CI)=1.04-3.12, P=0.04}. In asystolic patients of RCTs with average T(DRUG)<20 min, vasopressin vs. control increased the rates of sustained ROSC (data available from 2 RCTs; OR=1.70, 95% CI=1.17-2.47, P=0.005) and long-term survival (data available from 3 RCTs; OR=2.84, 95% CI=1.19-6.79, P=0.02).nnnCONCLUSIONSnVasopressin use in the resuscitation of cardiac arrest patients is not associated with any overall benefit or harm. However, vasopressin may improve the long-term survival of asystolic patients, especially when average T(DRUG) is <20 min.

Pretreatment with atorvastatin attenuates lung injury caused by high-stretch mechanical ventilation in an isolated rabbit lung model.

Objective:We hypothesized that pretreatment with atorvastatin improves alveolar capillary permeability and hemodynamics and, thus, confers protection against lung injury caused by high-stretch mechanical ventilation. Methods:Twenty-four isolated sets of normal rabbit lungs were utilized. Treated animals received atorvastatin (20 mg/kg body weight/day by mouth) for 3 days before surgery. Lungs were perfused constantly (300 mL/min) and ventilated for 1 hr with pressure-control ventilation at either 23 (high pressure; resulting in tidal volume approximately 22 mL/kg) or 11 (low pressure; tidal volume approximately 10 mL/kg) cm H2O peak inspiratory pressure and positive end-expiratory pressure of 3 cm H2O. Four groups were examined: high pressure–no statin, high pressure–statin pretreatment, low pressure–no statin, and low pressure–statin pretreatment. Results:The high-pressure–no statin group sustained more damage than the low-pressure groups. In high-pressure groups, lungs of statin-pretreated vs. no statin-pretreated animals sustained a significantly lower increase in ultrafiltration coefficient (an accurate marker of alveolar capillary permeability; high-pressure–statin pretreatment vs. high-pressure–no statin, −0.013 ± 0.017 g/min/mm Hg/100g vs. 1.723 ± 0.495 g/min/mm Hg/100g; p < .001), lower weight gain (i.e., less edema formation; 4.62 ± 1.50 grams vs. 17.75 ± 4.71 grams; p = .005), improved hemodynamics (i.e., lower increase in mean pulmonary artery pressure; 0.56 ± 0.51 mm Hg vs. 5.62 ± 1.52 mm Hg; p = .04), lower protein concentration in bronchoalveolar lavage fluid (p < .001), and fewer histologic lesions (p = .013). Apoptosis of lung parenchyma cells was not different (p = .97). There was no difference between low-pressure–statin pretreatment and low-pressure–no statin groups regarding these outcomes. Conclusion:In this model, atorvastatin improves alveolar capillary permeability and hemodynamics and, thus, attenuates lung injury caused by high-stretch mechanical ventilation.

FREQUENCY AND PREDICTORS OF VENTILATOR-ASSOCIATED PNEUMONIA RECURRENCE: A META-ANALYSIS

Large clinical series focusing on the risk factors associated with recurrence after the onset of an initial episode of ventilator-associated pneumonia (VAP) produced inconsistent results. A meta-analysis would be helpful to shed light on the issue. Our objective was to estimate the frequency of VAP recurrence and to identify risk factors associated with it. PubMed, Scopus, Current Contents, and references of retrieved articles were searched without language restrictions. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using both the Mantel-Haenszel fixed-effect and the DerSimonian-Laird random effects models. The overall frequency of VAP recurrence in 969 patients of the seven eligible reports was 26.8%. Among the 20 evaluated risk factors, only acute lung injury/acute respiratory distress syndrome (OR, 1.76; 95% CI, 1.12-2.75) and shock (OR, 1.55; 95% CI, 1.01-2.41) at the day of diagnosis of the first VAP episode were found to be associated with VAP recurrence. There was also evidence, albeit inconsistent, that severity of illness at intensive care unit admission was associated with VAP recurrence. Recurrence involves almost one in four cases of VAP and is associated with acute lung injury/acute respiratory distress syndrome and shock, but not with first-episode causative pathogens. Recognition of these predictors may permit the timely implementation of measures to prevent recurrence of VAP.Abbreviations-VAP-ventilatorassociated pneumonia; OR-odds ratio; CI-confidence interval; MV-mechanical ventilation; ICU-intensive care unit

Metformin attenuates ventilator-induced lung injury

IntroductionDiabetic patients may develop acute lung injury less often than non-diabetics; a fact that could be partially ascribed to the usage of antidiabetic drugs, including metformin. Metformin exhibits pleiotropic properties which make it potentially beneficial against lung injury. We hypothesized that pretreatment with metformin preserves alveolar capillary permeability and, thus, prevents ventilator-induced lung injury.MethodsTwenty-four rabbits were randomly assigned to pretreatment with metformin (250 mg/Kg body weight/day per os) or no medication for two days. Explanted lungs were perfused at constant flow rate (300 mL/min) and ventilated with injurious (peak airway pressure 23 cmH2O, tidal volume ≈17 mL/Kg) or protective (peak airway pressure 11 cmH2O, tidal volume ≈7 mL/Kg) settings for 1 hour. Alveolar capillary permeability was assessed by ultrafiltration coefficient, total protein concentration in bronchoalveolar lavage fluid (BALF) and angiotensin-converting enzyme (ACE) activity in BALF.ResultsHigh-pressure ventilation of the ex-vivo lung preparation resulted in increased microvascular permeability, edema formation and microhemorrhage compared to protective ventilation. Compared to no medication, pretreatment with metformin was associated with a 2.9-fold reduction in ultrafiltration coefficient, a 2.5-fold reduction in pulmonary edema formation, lower protein concentration in BALF, lower ACE activity in BALF, and fewer histological lesions upon challenge of the lung preparation with injurious ventilation. In contrast, no differences regarding pulmonary artery pressure and BALF total cell number were noted. Administration of metformin did not impact on outcomes of lungs subjected to protective ventilation.ConclusionsPretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model.