José Artur Paiva

A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients.

RATIONALE The clinical relevance of Aspergillus-positive endotracheal aspirates in critically ill patients is difficult to assess. OBJECTIVES We externally validate a clinical algorithm to discriminate Aspergillus colonization from putative invasive pulmonary aspergillosis in this patient group. METHODS We performed a multicenter (n = 30) observational study including critically ill patients with one or more Aspergillus-positive endotracheal aspirate cultures (n = 524). The diagnostic accuracy of this algorithm was evaluated using 115 patients with histopathologic data, considered the gold standard. Subsequently, the diagnostic workout of the algorithm was compared on the total cohort (n = 524), with the categorization based on the diagnostic criteria of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group. MEASUREMENTS AND MAIN RESULTS Among 115 histopathology-controlled patients, 79 had proven aspergillosis. The algorithm judged 86 of 115 cases to have putative aspergillosis. This diagnosis was confirmed in 72 and rejected in 14 patients. The algorithm judged 29 patients to have Aspergillus colonization. This was confirmed in 22 and rejected in 7 patients. The algorithm had a specificity of 61% and a sensitivity of 92%. The positive and negative predictive values were 61 and 92%, respectively. In the total cohort (n = 524), 79 patients had proven invasive pulmonary aspergillosis (15.1%). According to the European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria, 32 patients had probable aspergillosis (6.1%) and 413 patients were not classifiable (78.8%). The algorithm judged 199 patients to have putative aspergillosis (38.0%) and 246 to have Aspergillus colonization (46.9%). CONCLUSIONS The algorithm demonstrated favorable operating characteristics to discriminate Aspergillus respiratory tract colonization from invasive pulmonary aspergillosis in critically ill patients.

Pharmacokinetics of Anidulafungin in Critically Ill Patients with Candidemia/Invasive Candidiasis

ABSTRACT The pharmacokinetics of intravenous anidulafungin in adult intensive care unit (ICU) patients were assessed in this study and compared with historical data from a general patient population and healthy subjects. Intensive plasma sampling was performed over a dosing interval at steady state from 21 ICU patients with candidemia/invasive candidiasis. All patients received the recommended dosing regimen (a 200-mg loading dose on day 1, followed by a daily 100-mg maintenance dose), except for a 54-year-old 240-kg female patient (who received a daily 150-mg maintenance dose instead). Plasma samples were assayed for anidulafungin using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters in ICU patients were calculated by a noncompartmental method. With the exclusion of the 240-kg patient, the median (minimum, maximum) age, weight, and body mass index (BMI) of 20 ICU patients were 57 (39, 78) years, 65 (48, 106) kg, and 23.3 (16.2, 33.8) kg/m2, respectively. The average anidulafungin area under the curve over the 24-hour dosing interval (AUC0-24), maximum concentration (Cmax), and clearance (CL) in 20 ICU patients were 92.7 mg · h/liter, 7.7 mg/liter, and 1.3 liters/h, respectively. The exposure in the 240-kg patient at a daily 150-mg dose was within the range observed in ICU patients overall. The average AUC0-24 and Cmax in the general patient population and healthy subjects were 110.3 and 105.9 mg · h/liter and 7.2 and 7.0 mg/liter, respectively. The pharmacokinetics of anidulafungin in ICU patients appeared to be comparable to those in the general patient population and healthy subjects at the same dosing regimen.

Effects of mechanical insufflation-exsufflation in preventing respiratory failure after extubation: a randomized controlled trial

IntroductionWeaning protocols that include noninvasive ventilation (NIV) decrease re-intubation rates and ICU length of stay. However, impaired airway clearance is associated with NIV failure. Mechanical insufflation-exsufflation (MI-E) has been proven to be very effective in patients receiving NIV. We aimed to assess the efficacy of MI-E as part of an extubation protocol.MethodPatients with mechanical ventilation (MV) for more than 48 hours with specific inclusion criteria, who successfully tolerated a spontaneous breathing trial (SBT), were randomly allocated before extubation, either for (A) a conventional extubation protocol (control group), or (B) the MI-E extubation protocol (study group). During the postextubation period (48 hours), group A patients received standard medical treatment (SMT), including NIV in case of specific indications, whereas group B received the same postextubation approach plus three daily sessions of mechanical in-exsufflation (MI-E). Reintubation rates, ICU length of stay, and NIV failure rates were analyzed.ResultsSeventy-five patients (26 women) with a mean age of 61.8 ± 17.3 years were randomized to a control group (n = 40; mean SAPS II, 47.8 ± 17.7) and to a study group (n = 35; mean SAPS II, 45.0 ± 15.0). MV time before enrollment was 9.4 ± 4.8 and 10.5 ± 4.1 days for the control and the study group, respectively. In the 48 hours after extubation, 20 control patients (50%) and 14 study patients (40%) used NIV. Study group patients had a significant lower reintubation rate than did controls; six patients (17%) versus 19 patients (48%), P < 0.05; respectively, and a significantly lower time under MV; 17.8 ± 6.4 versus 11.7 ± 3.5 days; P < 0.05; respectively. Considering only the subgroup of patients that used NIV, the reintubation rates related to NIV failure were significantly lower in the study group when compared with controls; two patients (6%) versus 13 (33%); P < 0.05, respectively. Mean ICU length of stay after extubation was significantly lower in the study group when compared with controls (3.1 ± 2.5 versus 9.8 ± 6.7 days; P < 0.05). No differences were found in the total ICU length of stay.ConclusionInclusion of MI-E may reduce reintubation rates with consequent reduction in postextubation ICU length of stay. This technique seems to be efficient in improving the efficacy of NIV in this patient population.

New antifungal antibiotics.

Purpose of review The incidence of both invasive fungal infections and respiratory mould infections is increasing and they cause significant costs, morbidity and mortality. Non-Aspergillus moulds are increasing as cause of lung infections in specific populations and new problems of susceptibility and resistance are appearing. Recent findings The antifungal armamentarium has markedly improved in the past 10 years and some new drugs are in the pipeline. The use of these new agents is one of the drivers of the changes in fungal epidemiology. These new antifungal drugs are discussed in this article. Summary A good selection of the antifungal, taking into consideration the pathogen, the host and the pharmacokinetic/pharmacodynamics of the drug, is paramount for clinical success.

Venovenous extracorporeal CO2 removal for early extubation in COPD exacerbations requiring invasive mechanical ventilation.

Dear Editor, Tracheal intubation and invasive mechanical ventilation (IMV) remain the standard treatment for severe hypercapnic respiratory failure in chronic obstructive pulmonary disease (COPD) exacerbations after non-invasive ventilation (NIV) failure [1]. Miniaturized systems have been developed allowing low-flow, singlesite venovenous extracorporeal CO2 removal (ECCO2R). In this feasibility study, we used ECCO2R in two patients with COPD exacerbations requiring IMV. The ethics committee of the Hospital S. João approved this study and written informed consent was obtained. Patient 1 A 78-year-old male exsmoker with a COPD exacerbation was admitted to our ICU under NIV. On day 1, tracheal intubation was performed owing to severe respiratory acidosis (pH 7.16; pCO2 103 mmHg). On day 2, weaning from IMV was not possible because of persistent respiratory acidosis and ECCO2R was initiated after bedside right internal jugular vein cannulation (19-Fr Avalon Elite ). The miniaturized ECCO2R circuit used was the PALP system (Maquet-CP-AG). Extubation was performed ca. 1 h after ECCO2R start. Active physical therapy and patient mobilization out of bed were possible from day 4. NIV discontinuation, ECCO2R stop, ICU discharge, and hospital discharge occurred on day 6, 7, 9, and 16, respectively. Patient 2 A 67-year-old heavy smoker male patient was admitted to our ICU with a COPD exacerbation. On day 1, tracheal intubation was performed and IMV initiated owing to persistent severe respiratory acidosis under NIV (pH 7.19; pCO2 110 mmHg). On day 2, deep sedation and neuromuscular blockade were still needed, precluding IMV weaning. ECCO2R was then initiated after bedside left internal jugular vein cannulation (19-Fr Avalon Elite ). The miniaturized ECCO2R circuit consisted in a standard pediatric ECMO system (Rotaflow and Quadrox-iD Pediatric; Maquet-CP-AG). Extubation was possible on day 3. Active physical therapy and patient mobilization out of bed were possible from day 4 and day 6, respectively. NIV discontinuation, ECCO2R stop,

Severe sepsis in community-acquired pneumonia — Early recognition and treatment

Despite remarkable advances in its management, community-acquired pneumonia (CAP) remains an important cause of morbidity and mortality leading to significant consumption of health, social and economic resources. The assessment of CAP severity is a cornerstone in its management, facilitating selection of the most appropriate site of care and empirical antibiotic therapy. Several clinical scoring systems based on 30-day mortality have been developed to identify those patients with the highest risk of death. Although well validated in appropriate patient groups, each system has its own limitations and each exhibits different sensitivity and specificity values. These problems have increased interest in the use of biomarkers to predict CAP severity. Although so far no ideal solution has been identified, recent advances in bacterial genomic load quantification have made this tool very attractive. Early antibiotic therapy is essential to the reduction of CAP mortality and the selection of antibiotic treatment according to clinical guidelines is also associated with an improved outcome. In addition, the addition of a macrolide to standard empirical therapy seems to improve outcome in severe CAP although the mechanism of this is unclear. Finally, the role of adjuvant therapy has not yet been satisfactorily established. In this review we will present our opinion on current best practice in the assessment of severity and treatment of severe CAP.

Assessing severity of patients with community-acquired pneumonia.

Despite all advances in its management, community-acquired pneumonia (CAP) is still an important cause of morbidity and mortality requiring a great consumption of health, social, and economic resources. An early and adequate severity assessment is of paramount importance to provide optimized care to these patients. In the last 2 decades, this issue has been the subject of extensive research. Based on 30 day mortality, several prediction rules have been proposed to aid clinicians in deciding on the appropriate site of care. In spite of being well validated, their sensitivity and specificity vary, which limits their widespread use. The utility of biomarkers to overcome this problem has been investigated. At this moment, their full clinical value remains undetermined, and no single biomarker is consistently ideal for assessing CAP severity. Biomarkers should be seen as a complement rather than superseding clinical judgment or validated clinical scores. The search for a gold standard is not over, and new tools, like bacterial DNA load, are in the pipeline. Until then, CAP severity assessment should be based in three key points: a pneumonia-specific score, biomarkers, and clinical judgment.

Antimicrobial drug interactions in the critically ill patients.

Critically ill patients are typically polymedicated and therefore at a high risk for potential drug interactions. Clinical consequences of drugs interactions vary in severity from mild to lethal events. Since infection is an important issue in the Intensive Care Unit (ICU), a significant number of patients will receive an antimicrobial at some stage during their ICU admission. Therefore an adequate knowledge about possible interactions between antimicrobials and other drugs is necessary, since it may not only impact on the effectiveness of the antimicrobial but also in the incidence of drug adverse events. This review describes important drug interactions involving antimicrobials in the critically ill patient.

The Use of Procalcitonin (PCT) for Diagnosis of Sepsis in Burn Patients: A Meta-Analysis.

The continuous development of resuscitation techniques and intensive care reduced the mortality rate induced by the initial shock in burn patients and, currently, infections (especially sepsis) are the main causes of mortality of these patients. The misuse of antimicrobial agents is strongly related to antimicrobial and adverse patient outcomes, development of microbial resistance and increased healthcare-related costs. To overcome these risks, antimicrobial stewardship is mandatory and biomarkers are useful to avoid unnecessary medical prescription, to monitor antimicrobial therapy and to support the decision of its stop. Among a large array of laboratory tests, procalcitonin (PCT) emerged as the leading biomarker to accurately and time-effectively indicate the presence of systemic infection. In the presence of systemic infection, PCT blood levels undergo a sudden and dramatic increase, following the course of the infection, and quickly subside after the control of the septic process. This work is a meta-analysis on PCT performance as a biomarker for sepsis. This meta–analysis showed that overall pooled area under the curve (AUC) is 0.83 (95% CI = 0.76 to 0.90); the estimated cut-off is 1.47 ng/mL. The overall sepsis effect in PCT levels is significant and strong (Cohens d is 2.1 and 95% CI = 1.1 to 3.2). This meta–analysis showed PCT may be considered as a biomarker with a strong diagnostic ability to discriminate between the septic from the non-septic burn patients. Thus, this work encourages the determination of PCT levels in clinical practice for the management of these patients, in order to timely identify the susceptibility to sepsis and to initiate the antimicrobial therapy, improving the patients’ outcomes.

Extracorporeal membrane oxygenation for refractory acute respiratory distress syndrome in severe malaria

BackgroundSevere malaria may be complicated by the acute respiratory distress syndrome (ARDS), which is associated with a high mortality. In the present report, a series of three cases of imported malaria complicated by refractory severe ARDS supported with extracorporeal membrane oxygenation (ECMO) is presented.MethodsOne female and two male adult patients (ages 39 to 53) were included. Two patients had Plasmodium falciparum infection and one patient had Plasmodium vivax and Plasmodium ovale co-infection. Anti-malarial therapy consisted in intravenous quinine (in two patients) and intravenous quinidine (in one patient), plus clindamycin or doxycycline.ResultsDespite lung protective ventilation, a conservative strategy of fluid management, corticosteroids (two patients), prone position (two patients) and inhaled nitric oxide (one patient), refractory severe ARDS supervened (PaO2 to FiO2 ratio 68) and venovenous ECMO was then initiated. In one patient, a bicaval dual-lumen cannula was inserted; in the two other patients, a two-site configuration was used. Two patients survived to hospital-discharge (duration of ECMO support: 8.5 days) and one patient died from nosocomial sepsis and multi-organ failure after 40 days of ECMO support.ConclusionsECMO support allowed adequate oxygenation and correction of hypercapnia under lung protective ventilation, therefore reducing ventilator-induced lung injury. ECMO referral should be considered early in malaria complicated by severe ARDS refractory to conventional treatment.