Emilio Maseda

Recalibration of the delirium prediction model for ICU patients (PRE-DELIRIC): a multinational observational study

PurposeRecalibration and determining discriminative power, internationally, of the existing delirium prediction model (PRE-DELIRIC) for intensive care patients.MethodsA prospective multicenter cohort study was performed in eight intensive care units (ICUs) in six countries. The ten predictors (age, APACHE-II, urgent and admission category, infection, coma, sedation, morphine use, urea level, metabolic acidosis) were collected within 24xa0h after ICU admission. The confusion assessment method for the intensive care unit (CAM-ICU) was used to identify ICU delirium. CAM-ICU screening compliance and inter-rater reliability measurements were used to secure the quality of the data.ResultsA total of 2,852 adult ICU patients were screened of which 1,824 (64xa0%) were eligible for the study. Main reasons for exclusion were length of stay <1xa0day (19.1xa0%) and sustained coma (4.1xa0%). CAM-ICU compliance was mean (SD) 82xa0±xa016xa0% and inter-rater reliability 0.87xa0±xa00.17. The median delirium incidence was 22.5xa0% (IQR 12.8–36.6xa0%). Although the incidence of all ten predictors differed significantly between centers, the area under the receiver operating characteristic (AUROC) curve of the eight participating centers remained good: 0.77 (95xa0% CI 0.74–0.79). The linear predictor and intercept of the prediction rule were adjusted and resulted in improved re-calibration of the PRE-DELIRIC model.ConclusionsIn this multinational study, we recalibrated the PRE-DELIRIC model. Despite differences in the incidence of predictors between the centers in the different countries, the performance of the PRE-DELIRIC-model remained good. Following validation of the PRE-DELIRIC model, it may facilitate implementation of strategies to prevent delirium and aid improvements in delirium management of ICU patients.

Multinational development and validation of an early prediction model for delirium in ICU patients

RationaleDelirium incidence in intensive care unit (ICU) patients is high and associated with poor outcome. Identification of high-risk patients may facilitate its prevention.PurposeTo develop and validate a model based on data available at ICU admission to predict delirium development during a patient’s complete ICU stay and to determine the predictive value of this model in relation to the time of delirium development.MethodsProspective cohort study in 13 ICUs from seven countries. Multiple logistic regression analysis was used to develop the early prediction (E-PRE-DELIRIC) model on data of the first two-thirds and validated on data of the last one-third of the patients from every participating ICU.ResultsIn total, 2914 patients were included. Delirium incidence was 23.6xa0%. The E-PRE-DELIRIC model consists of nine predictors assessed at ICU admission: age, history of cognitive impairment, history of alcohol abuse, blood urea nitrogen, admission category, urgent admission, mean arterial blood pressure, use of corticosteroids, and respiratory failure. The area under the receiver operating characteristic curve (AUROC) was 0.76 [95xa0% confidence interval (CI) 0.73–0.77] in the development dataset and 0.75 (95xa0% CI 0.71–0.79) in the validation dataset. The model was well calibrated. AUROC increased from 0.70 (95xa0% CI 0.67–0.74), for delirium that developed <2xa0days, to 0.81 (95xa0% CI 0.78–0.84), for delirium that developed >6xa0days.ConclusionPatients’ delirium risk for the complete ICU length of stay can be predicted at admission using the E-PRE-DELIRIC model, allowing early preventive interventions aimed to reduce incidence and severity of ICU delirium.

Micafungin pharmacokinetic/pharmacodynamic adequacy for the treatment of invasive candidiasis in critically ill patients on continuous venovenous haemofiltration

OBJECTIVESnTo explore the pharmacokinetics (PK) and pharmacodynamics (PD) of micafungin in patients undergoing continuous venovenous haemofiltration (CVVH).nnnPATIENTS AND METHODSnTen patients receiving CVVH treated with 100 mg/day micafungin were included (April-December 2012). CVVH was performed using polyethersulphone or polysulphone haemofilters. Dialysis membranes were not changed on sampling days. On Days 1 and 2, blood samples from arterial pre-filter and venous post-filter ports and ultrafiltrate samples were collected at the start and end of the infusion and at 3, 5, 8, 18 and 24 h. Concentrations were determined using HPLC. Values for the area under the concentration-time curve (AUC0-24) were calculated. Monte Carlo simulations were performed using pre-filter and post-filter AUC0-24/MIC ratios on Days 1 and 2. The probability of target attainment (PTA) was calculated using AUC0-24/MIC cut-offs: 285 (C. parapsilosis), 3000 (all Candida spp.) and 5000 (non-parapsilosis Candida spp.). Cumulative fraction responses (CFRs) were calculated using EUCAST MIC distributions.nnnRESULTSnMean post-filter AUC0-24 (mg·h/L) values were higher than pre-filter values on Day 1 (83.31u200a±u200a15.87 versus 71.31u200a±u200a14.24; Pu200a=u200a0.008) and Day 2 (119.01u200a±u200a27.20 versus 104.54u200a±u200a21.23; Pu200a=u200a0.005). PTAs were ≥90% for MICs of 0.125 mg/L (cut-offu200a=u200a285), 0.016 mg/L (cut-offu200a=u200a3000) and 0.008 mg/L (cut-offu200a=u200a5000) on Day 1, and for MICs of 0.25 mg/L (cut-offu200a=u200a285) and 0.016 mg/L (cut-offu200a=u200a3000 and 5000) on Day 2, without differences between pre- and post-filter values. On Day 2, CFRs >90% were obtained for C. albicans (cut-offu200a=u200a3000 and 5000) and C. glabrata (cut-offu200a=u200a3000), but not for C. parapsilosis.nnnCONCLUSIONSnThere was no removal of micafungin by CVVH or need for dose adjustment, and there was optimal PK/PD coverage for non-parapsilosis Candida and equivalence of pre- and post-filter PD.

Procalcitonin-guided therapy may reduce length of antibiotic treatment in intensive care unit patients with secondary peritonitis: A multicenter retrospective study

PURPOSEnBecause procalcitonin (PCT) might be surrogate for antimicrobial discontinuation in general intensive care units (ICUs), this study explored its use for secondary peritonitis in 4 surgical ICUs (SICUs).nnnMETHODSnA retrospective study including all consecutive patients with secondary peritonitis, controlled infection source, requiring surgery, and at least 48-hour SICU admission was performed (June 2012-June 2013). Patients were divided following notations in medical records into PCT-guided (notation of PCT-based antibiotic discontinuation) and non-PCT-guided (no notation) groups.nnnRESULTSnA total of 121 patients (52 PCT-guided, 69 non-PCT-guided) were included. No differences in clinical scores, biomarkers, or septic shock (30 [57.7%] PCT-guided vs 40 [58.0%] non-PCT-guided) were found. Length of intra-SICU (median, 5.0 days; both groups) or in-hospital (median, 20.0 vs 17.5 days) stay, and mortality intra-SICU (9.6% vs 13.0%), 28-day (15.4% vs 20.3%), or in-hospital (19.2% vs 29.0%) were not significantly different (PCT-guided vs non-PCT-guided). In septic shock patients, no mortality differences were found (PCT-guided vs non-PCT-guided): 16.7% vs 22.5% (intra-SICU), 26.7% vs 32.5% (28-day), and 33.3% vs 42.5% (in-hospital). Treatment was shorter in the PCT-guided group (5.1 ±2.1 vs 10.2 ± 3.7 days, P < .001), without differences between patients with and without septic shock.nnnCONCLUSIONnProcalcitonin guidance produced 50% reduction in antibiotic duration (P < .001, log-rank test).

Risk factors for colonization by carbapenemase-producing enterobacteria at admission to a Surgical ICU: A retrospective study

INTRODUCTIONnIn 2011, a hospital-wide outbreak of OXA-48 producing Klebsiella pneumoniae occurred in our hospital, an epidemiological setting of high ESBL-producing K. pneumoniae rates. This study identifies risk factors for colonization with carbapenemase-producing enterobacteria (CPE) at Surgical Intensive Care Unit (SICU) admission.nnnMETHODSnA 2-year retrospective study was performed in all patients admitted to the SICU that following routine had a rectal swab collected upon admission.nnnRESULTSnOf 254 patients admitted, 41 (16.1%) harbored CPE (five showing two carbapenemase-producing isolates). Most frequent carbapenemase-producing isolates and carbapenemases were K. pneumoniae (39/46, 84.8%) and OXA-48 (31/46; 76.1%), respectively. Carriers significantly had higher rates of chronic renal disease, previous digestive/biliary endoscopy, hospitalization, ICU/SICU admission, intraabdominal surgery, and antibiotic intake, as well as higher median values of clinical scores (SOFA, SAPS II and APACHE II). In the multivariate analysis (R2=0.309, p<0.001), CPE carriage was associated with prior administration of 3rd-4th generation cephalosporins (OR=27.96, 95%CI=6.88, 113.58, p<0.001), β-lactam/β-lactamase inhibitor (OR=11.71, 95%CI=4.51, 30.43, p<0.001), abdominal surgery (OR=6.33, 95%CI=2.12, 18.89, p=0.001), and prior digestive/biliary endoscopy (OR=3.88, 95%CI=1.56, 9.67, p=0.004).nnnCONCLUSIONSnA strong association between production of ESBLs and carriage of CPE (mainly OXA-48 producing K. pneumoniae) was found. According to the model, the co-selection of β-lactamases by previous exposure to broad-spectrum cephalosporins and β-lactam/β-lactamase inhibitors (with lower relative risk), abdominal surgery and prior digestive/biliary endoscopy were factors associated with CPE carriage.

Ceftolozane/tazobactam (CXA 201) for the treatment of intra-abdominal infections

During the mid-nineties, 95–97% of intra-abdominal infection (IAI)- associated microbes were susceptible to commonly used antibiotics. Nowadays, in Gram-negative bacilli, β-lactam resistance and the associated co-resistance to other antibiotics leading to multidrug resistance is reaching crisis proportions. This is a critical issue in the treatment of IAIs, especially for complicated IAIs and for those of nosocomial origin in severely ill patients. In this setting, this article reviews the place in the therapeutic armamentarium of ceftolozane/tazobactam, a new cephalosporin/β-lactamase inhibitor with good activity against extended spectrum β-lactamase producing Enterobacteriaceae, with stability to AmpC β-lactamases and good anti-pseudomonal activity being stable against the most common resistance mechanisms driven by mutation in Pseudomonas aeruginosa. A profound review of its in vitro activity, in vivo efficacy in animal models, pharmacodynamics, pharmacokinetics, clinical efficacy in clinical trials in complicated IAIs and safety data is performed.

Épico project. Development of educational recommendations using the DELPHI technique on invasive candidiasis in non-neutropenic critically ill adult patients

BACKGROUNDnAlthough there has been an improved management of invasive candidiasis in the last decade, controversial issues still remain, especially in the diagnostic and therapeutic approaches.nnnAIMSnWe sought to identify the core clinical knowledge and to achieve high level agreement recommendations required to care for critically ill adult patients with invasive candidiasis.nnnMETHODSnA prospective Spanish survey reaching consensus by the DELPHI technique was made. It was anonymously conducted by electronic mail in a first term to 25 national multidisciplinary experts in invasive fungal infections from five national scientific societies, including intensivists, anesthesiologists, microbiologists, pharmacologists and infectious diseases specialists, who answered to 47 questions prepared by a coordination group after a strict review of the literature in the last five years. The educational objectives spanned five categories, including epidemiology, diagnostic tools, prediction rules, and treatment and de-escalation approaches. The level of agreement achieved among the panel experts in each item should exceed 75% to be selected. In a second term, after extracting recommendations from the selected items, a face to face meeting was performed where more than 80 specialists in a second round were invited to validate the preselected recommendations.nnnRESULTSnIn the first term, 20 recommendations were preselected (Epidemiology 4, Scores 3, Diagnostic tools 4, Treatment 6 and De-escalation approaches 3). After the second round, the following 12 were validated: (1) Epidemiology (2 recommendations): think about candidiasis in your Intensive Care Unit (ICU) and do not forget that non-Candida albicans-Candida species also exist. (2) Diagnostic tools (4 recommendations): blood cultures should be performed under suspicion every 2-3 days and, if positive, every 3 days until obtaining the first negative result. Obtain sterile fluid and tissue, if possible (direct examination of the sample is important). Use non-culture based methods as microbiological tools, whenever possible. Determination of antifungal susceptibility is mandatory. (3) Scores (1 recommendation): as screening tool, use the Candida Score and determine multicolonization in high risk patients. (4) Treatment (4 recommendations): start early. Choose echinocandins. Withdraw any central venous catheter. Fundoscopy is needed. (5) De-escalation (1 recommendation): only applied when knowing susceptibility determinations and after 3 days of clinical stability. The higher rate of agreement was achieved in the optimization of microbiological tools and the withdrawal of the catheter, whereas the lower rate corresponded to de-escalation therapy and the use of scores.nnnCONCLUSIONSnThe management of invasive candidiasis in ICU patients requires the application of a broad range of knowledge and skills that we summarize in our recommendations. These recommendations may help to identify the potential patients, standardize their global management and improve their outcomes, based on the DELPHI methodology.

Prevalence of and Risk Factors for Biliary Carriage of Bacteria Showing Worrisome and Unexpected Resistance Traits

ABSTRACT Data on biliary carriage of bacteria and, specifically, of bacteria with worrisome and unexpected resistance traits (URB) are lacking. A prospective study (April 2010 to December 2011) was performed that included all patients admitted for <48 h for elective laparoscopic cholecystectomy in a Spanish hospital. Bile samples were cultured and epidemiological/clinical data recorded. Logistic regression models (stepwise) were performed using bactobilia or bactobilia by URB as dependent variables. Models (P < 0.001) showing the highest R 2 values were considered. A total of 198 patients (40.4% males; age, 55.3 ± 17.3 years) were included. Bactobilia was found in 44 of them (22.2%). The presence of bactobilia was associated (R 2 Cox, 0.30) with previous biliary endoscopic retrograde cholangiopancreatography (ERCP) (odds ratio [OR], 8.95; 95% confidence interval [CI], 2.96 to 27.06; P < 0.001), previous admission (OR, 2.82; 95% CI, 1.10 to 7.24; P = 0.031), and age (OR, 1.09 per year; 95% CI, 1.05 to 1.12; P < 0.001). Ten out of the 44 (22.7%) patients with bactobilia carried URB: 1 Escherichia coli isolate (CTX-M), 1 Klebsiella pneumoniae isolate (OXA-48), 3 high-level gentamicin-resistant enterococci, 1 vancomycin-resistant Enterococcus isolate, 3 Enterobacter cloacae strains, and 1 imipenem-resistant Pseudomonas aeruginosa strain. Bactobilia by URB (versus those by non-URB) was only associated (R 2 Cox, 0.19) with previous ERCP (OR, 11.11; 95% CI, 1.98 to 62.47; P = 0.006). For analyses of patients with bactobilia by URB versus the remaining patients, previous ERCP (OR, 35.284; 95% CI, 5.320 to 234.016; P < 0.001), previous intake of antibiotics (OR, 7.200; 95% CI, 0.962 to 53.906; P = 0.050), and age (OR, 1.113 per year of age; 95% CI, 1.028 to 1.206; P = 0.009) were associated with bactobilia by URB (R 2 Cox, 0.19; P < 0.001). Previous antibiotic exposure (in addition to age and previous ERCP) was a risk driver for bactobilia by URB. This may have implications in prophylactic/therapeutic measures.

EPICO 3.0. Recommendations on invasive candidiasis in patients with complicated intra-abdominal infection and surgical patients with ICU extended stay.

BACKGROUNDnAlthough in the last decade the management of invasive fungal infections has improved, a number of controversies persist regarding the management of complicated intra-abdominal infection and surgical extended length-of-stay (LOS) patients in intensive care unit (ICU).nnnAIMSnTo identify the essential clinical knowledge and elaborate a set of recommendations, with a high level of consensus, necessary for the management of postsurgical patients with complicated intra-abdominal infection and surgical patients with ICU extended stay.nnnMETHODSnA Spanish prospective questionnaire, which measures consensus through the Delphi technique, was anonymously answered and e-mailed by 30 multidisciplinary national experts, all of them specialists in fungal invasive infections from six scientific national societies; these experts were intensivists, anesthesiologists, microbiologists, pharmacologists and specialists in infectious diseases. They answered 11 questions drafted by the coordination group after conducting a thorough review of the literature published in the last few years. For a category to be selected, the level of agreement among the experts in each should be equal to or greater than 70%. In a second round, 73 specialists attended a face-to-face meeting which was held after extracting recommendations from the chosen topics and in which they validated the pre-selected recommendations and derived algorithm.nnnRESULTSnAfter the second Delphi round, the following 11 recommendations with high degree of consensus were validated. For surgical patients seven recommendations were validated: (1) risk factors for invasive candidiasis (IC), (2) usefulness of blood culture and direct examination of abdominal fluid to start empirical treatment; (3) PCR for treatment discontinuation; (4) start antifungal treatment in patients with anastomotic leaks; (5) usefulness of Candida score (CS) but not (6) the Dupont score for initiating antifungal therapy in the event of anastomotic leakage or tertiary peritonitis, and (7) the administration of echinocandins as first line treatment in this special population. For surgical ICU extended LOS patients four recommendations were validated: (1) risk factors for IC, (2) presence of multi-colonization by Candida as a required variable of the CS, (3) starting antifungal treatment with CS≥4, and (4) to perform non-culture-based microbiological techniques in stable septic patients without evident focus.nnnCONCLUSIONSnThe diagnosis and management of IC in ICU surgical patients requires the application of a broad range of knowledge and skills that we summarize in our recommendations. These recommendations, based on the DELPHI methodology, may help to identify potential patients, standardize their global management and improve their outcomes.

Duración del tratamiento antibiótico en la infección intraabdominal

The duration of antibiotic treatment in patients with an infectious process is based on empirical considerations and those with intraabdominal infections are no exception. Therefore, the recommended duration of antibiotic therapy in intraabdominal infection is controversial and no consensus has been reached due to the lack of controlled studies that would provide sufficient scientific evidence. Excessive duration of antibiotic therapy can increase the risk of developing bacterial resistance as well as treatment-associated costs. These considerations have led to the exploration of short-term treatment strategies, lasting 3-5 days, with encouraging results. However, the development of biomarkers such as procalcitonin opens the door to individualized treatment that might allow the duration of antibiotic treatment in intraabdominal and other infections to be individually tailed to patient response.Resumen La duracion del tratamiento antibiotico en los pacientes que presentan un proceso infeccioso se fundamenta en consideraciones empiricas. La infeccion intraabdominal no es ajena a este hecho. Por ello, la duracion aconsejable del tratamiento antibiotico de la infeccion intraabdominal es un tema controvertido y no hay consenso a este respecto debido a la ausencia de estudios controlados que aporten suficiente evidencia cientifica. Una duracion excesiva en el tratamiento antibiotico puede condicionar un mayor riesgo en el desarrollo de resistencias bacterianas y un aumento en los costes relacionados con el tratamiento. Estas consideraciones han tenido como consecuencia la exploracion de estrategias con “tratamientos cortos” de 3-5 dias con resultados alentadores. No obstante, el desarrollo de marcadores biologicos como la procalcitonina abre una puerta al tratamiento individualizado, de tal forma que la duracion del tratamiento antibiotico en la infeccion intraabdominal, asi como en otras infecciones, se ajuste a la respuesta individual de cada paciente.