Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI

BACKGROUND: Traumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy. METHODS: Plasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer's disease, with healthy controls. RESULTS: Plasma p-tau181 concentrations were significantly raised in patients with Alzheimer's disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates. CONCLUSIONS: Plasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration

Thoracic UltrasONOgraphy Reporting: The TUONO Study

Lung ultrasound (LUS) is a validated technique for the prompt diagnosis and bedside monitoring of critically ill patients due to its availability, safety profile, and cost-effectiveness. The aim of this work is to detect similarities and differences among LUS reports performed in ICUs and to provide a common ground for an integrated report form. We collected all LUS reports during an index week in 21 ICUs from the GiViTI network. First, we considered signs, chest areas, and terminology reported. Then, we compared different report structures and categorized them as structured reports (SRs), provided with a predefined model form, and free unstructured text reports (FTRs) that had no predetermined structure. We analyzed 171 reports from 21 ICUs, and 59 reports from 5 ICUs were structured. All the reports presented a qualitative description that mainly focused on the presence of B-lines, consolidations, and pleural effusion. Zones were defined in 66 reports (39%). In SRs, a complete examination of all the regions was more frequently achieved (96% vs. 74%), and a higher impact on therapeutic strategies was observed (17% vs. 6%). LUS reports vary significantly among different centers. Adopting an integrated SR seems to promote a systematic approach in scanning and reporting, with a potential impact on LUS clinical applications

Therapeutic monitoring of Piperacillin in ICU patients

Background Infections remain one of the major causes of morbidity and mortality in patients admitted to intensive care units (ICUs). The rate of nosocomial infections among patients admitted to ICUs is 5-10 times higher than other general medicine and surgery wards. The most common nosocomial infections are pulmonary, urinary and blood stream infections that are often caused by P. aeruginosa, S. aureus, K. pneumoniae, S. marcescens, P. mirabilis and C. albicans (Trubiano & Padiglione 2015). The infection determines a large number of victims each year. Indeed, it has been estimated that in Europe about 25,000 people annually risk death due to the infections by MDR organisms (Blair et al. 2014). Strong evidence in literature endorses the benefits of penicillin TDM and suggests the existence, in the population of critically ill patients, of a correlation between the exposure of the target to the drug and the outcomes (Blondiaux et al. 2010; Sime et al. 2012; Hayashi et al. 2013). Therefore, this study was aimed at developing and validating a simple HPLC method for monitoring plasma level of piperacillin in ICU patients. Methods The HPLC-UV method was developed for piperacillin quantitation, starting from 200 μl of plasma samples treated with 200 μl of ACN+H3PO4 conc. 5 % (v/v) for protein precipitation. In plasma samples, ticarcillin was added as internal standard (IS). The stationary phase was HAISIL HL C18 250 mm 4.6 mm 5 μm (Higgins Analytical Inc., USA). Mobile phase was composed by 20 mM phosphate buffer (pH 2.5)/acetonitrile (73.5/26.5, v/v). The mobile phase was pumped within the HPLC system at a flow of 1 ml/min, while 30 μl of each sample were injected within the system. Absorbance of piperacillin and IS was measured at a wavelength of 220 nm. The method was validated according to the EMA 2015 guidelines, then it was applied to measure drug concentrations in 248 plasma samples from ICU patients (AbioKin project, Mario Negri, Bergamo, Italy). Results The chromatographic run time was 20 minutes, with retention times of ticarcillin and piperacillin of 13.4 and 18.0 min, respectively. Results of validation were as follows: linearity range, from 10 up to 400 μg/ml (r2=0.9994), accuracy and precision (< 8%), reproducibility (< 9%), limit of detection (9.57 μg/ml) and limit of quantitation (3.15 μg/ml) and average recovery (>90%). The method was applied to 248 plasma samples, resulting in a mean±SD concentration of 86.88±79.40 μg/ml, with a median concentration of 65.10 μg/ml (MIN-MAX range, 0-399.56 μg/ml). Of note, no interfering peaks were detected within the chromatogram despite the number of co-administered drugs. The method allows the preparation and analysis of 3 samples/h, but the availability of chromatographic systems equipped with autoinjectors does extend the analyses overnight, thus increasing the output. Conclusions In conclusion, a new chromatographic method for selective quantitation of piperacillin was developed and validated in plasma samples, with optimal performance to be applied to drug monitoring for ICU patients. Indeed, the application of the present HPLC-UV method may result in a more appropriate prescription of piperacillin with a subsequent improvement in clinical outcomes while the risk for the selection of resistant clones will be reduced. Bibliography Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ V. 2014. Molecular mechanisms of antibiotic resistance. Nat Publ Gr. 13:42–51. Blondiaux N, Wallet F, Favory R, Onimus T, Nseir S, Courcol RJ, Durocher A, Roussel-Delvallez M. 2010. Daily serum piperacillin monitoring is advisable in critically ill patients. Int J Antimicrob Agents. 35:500–503. Hayashi Y, Lipman J, Udy AA, Ng M, McWhinney B, Ungerer J, Lust K, Roberts JA. 2013. β-Lactam therapeutic drug monitoring in the critically ill: Optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia. Int J Antimicrob Agents. 41:162–166. Sime FB, Roberts MS, Peake SL, Lipman J, Roberts JA. 2012. Does beta-lactam pharmacokinetic variability in critically III patients justify therapeutic drug monitoring? A systematic review. Ann Intensive Care. 2:1–11. Trubiano JA, Padiglione AA. 2015. Nosocomial infections in the intensive care unit. Anaesth Intensive Care Med [Internet]. 16:598–602. Available from: http://dx.doi.org/10.1016/j.mpaic.2015.09.01

Thoracic UltrasONOgraphy Reporting: The TUONO Consensus

The widespread use of the lung ultrasound (LUS) has not been followed by the development of a comprehensive standardized tool for its reporting in the intensive care unit (ICU) which could be useful to promote consistency and reproducibility during clinical examination. This work aims to define the essential features to be included in a standardized reporting tool and provides a structured model form to fully express the diagnostic potential of LUS and facilitate intensivists in the use of a LUS in everyday clinical ICU examination. We conducted a modified Delphi process to build consensus on the items to be integrated in a standardized report form and on its structure. A committee of 19 critical care physicians from 19 participating ICUs in Italy was formed, including intensivists experienced in ultrasound from both teaching hospitals and referral hospitals, and internationally renowned experts on the LUS. The consensus for 31 statements out of 33 was reached at the third Delphi round. A structured model form was developed based on the approved statements. The development of a standardized model as a backbone to report a LUS may facilitate the guidelines’ application in clinical practice and increase inter-operator agreement. Further studies are needed to evaluate the effects of standardized reports in critically ill patients

Benchmark of Intraoperative Activity in Cardiac Surgery: A Comparison between Pre- and Post-Operative Prognostic Models

Objectives: Despite its large diffusion and improvements in safety, the risks of complications after cardiac surgery remain high. Published predictive perioperative scores (EUROSCORE, STS, ACEF) assess risk on preoperative data only, not accounting for the intraopertive period. We propose a double-fold model, including data collected before surgery and data collected at the end of surgery, to evaluate patient risk evolution over time and assess the direct contribution of surgery. Methods: A total of 15,882 cardiac surgery patients from a Margherita-Prosafe cohort study were included in the analysis. Probability of death was estimated using two logistic regression models (preoperative data only vs. post-operative data, also including information at discharge from the operatory theatre), testing calibration and discrimination of each model. Results: Pre-operative and post-operative models were built and demonstrate good discrimination and calibration with AUC = 0.81 and 0.87, respectively. Relative difference in pre- and post-operative mortality in separate centers ranged from −0.36 (95% CI: −0.44–−0.28) to 0.58 (95% CI: 0.46–0.71). The usefulness of this two-fold preoperative model to benchmark medical care in single hospital is exemplified in four cases. Conclusions: Predicted post-operative mortality differs from predicted pre-operative mortality, and the distance between the two models represent the impact of surgery on patient outcomes. A double-fold model can assess the impact of the intra-operative team and the evolution of patient risk over time, and benchmark different hospitals on patients subgroups to promote an improvement in medical care in each center

Benchmark of Intraoperative Activity in Cardiac Surgery: A Comparison between Pre- and Post-Operative Prognostic Models

Objectives: Despite its large diffusion and improvements in safety, the risks of complications after cardiac surgery remain high. Published predictive perioperative scores (EUROSCORE, STS, ACEF) assess risk on preoperative data only, not accounting for the intraopertive period. We propose a double-fold model, including data collected before surgery and data collected at the end of surgery, to evaluate patient risk evolution over time and assess the direct contribution of surgery. Methods: A total of 15,882 cardiac surgery patients from a Margherita-Prosafe cohort study were included in the analysis. Probability of death was estimated using two logistic regression models (preoperative data only vs. post-operative data, also including information at discharge from the operatory theatre), testing calibration and discrimination of each model. Results: Pre-operative and post-operative models were built and demonstrate good discrimination and calibration with AUC = 0.81 and 0.87, respectively. Relative difference in pre- and post-operative mortality in separate centers ranged from −0.36 (95% CI: −0.44–−0.28) to 0.58 (95% CI: 0.46–0.71). The usefulness of this two-fold preoperative model to benchmark medical care in single hospital is exemplified in four cases. Conclusions: Predicted post-operative mortality differs from predicted pre-operative mortality, and the distance between the two models represent the impact of surgery on patient outcomes. A double-fold model can assess the impact of the intra-operative team and the evolution of patient risk over time, and benchmark different hospitals on patients subgroups to promote an improvement in medical care in each center

Effectiveness of a Multifaced Antibiotic Stewardship Program: A Pre-Post Study in Seven Italian ICUs

Multidrug resistance has become a serious threat for health, particularly in hospital-acquired infections. To improve patients’ safety and outcomes while maintaining the efficacy of antimicrobials, complex interventions are needed involving infection control and appropriate pharmacological treatments in antibiotic stewardship programs. We conducted a multicenter pre-post study to assess the impact of a stewardship program in seven Italian intensive care units (ICUs). Each ICU was visited by a multidisciplinary team involving clinicians, microbiologists, pharmacologists, infectious disease specialists, and data scientists. Interventions were targeted according to the characteristics of each unit. The effect of the program was measured with a panel of indicators computed with data from the MargheritaTre electronic health record. The median duration of empirical therapy decreased from 5.6 to 4.6 days and the use of quinolones dropped from 15.3% to 6%, both p < 0.001. The proportion of multi-drug-resistant bacteria (MDR) in ICU-acquired infections fell from 57.7% to 48.8%. ICU mortality and length of stay remained unchanged, indicating that reducing antibiotic administration did not harm patients’ safety. This study shows that our stewardship program successfully improved the management of infections. This suggests that policy makers should tackle multidrug resistance with a multidisciplinary approach based on continuous monitoring and personalised interventions

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.</p