Cardiac Adverse Events and Remdesivir in Hospitalized Patients With COVID-19: A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial.

BACKGROUND: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with coronavirus disease 2019 (COVID-19) who received remdesivir plus standard of care (SoC) compared with SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases. METHODS: This post hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19. Any first AE that occurred between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves, and Kaplan-Meier estimates were calculated for event rates. RESULTS: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (hazard ratio [HR], 1.0; 95% confidence interval [CI], .7-1.5; P = .98), even when serious and nonserious cardiac AEs were evaluated separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between the two groups in the occurrence of cardiac AE subclasses, including arrhythmic events (HR, 1.1; 95% CI, .7-1.7; P = .68). CONCLUSIONS: Remdesivir treatment was not associated with an increased risk of cardiac AEs compared with control in patients hospitalized with moderate or severe COVID-19. These results are consistent with other randomized, controlled trials and meta-analyses. Clinical Trials Registration. NCT04315948; EudraCT 2020-000936-23.

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients.

BACKGROUND: Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. METHODS: Blood and spot urine were collected in "severe" (n = 26), "critically ill" (n = 17) and "critically ill on VV-ECMO" (n = 17) patients with COVID-19 at days 1-2 (admission), 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. RESULTS: U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. CONCLUSIONS: U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

Treatment of invasive candidiasis in the era of Candida resistance.

PURPOSE OF REVIEW: The increasing incidence of drug-resistant Candida brings a new challenge to the treatment of invasive candidiasis. Although cross-resistance among azoles and echinocandins was generally uncommon, reports of multidrug-resistant (MDR) Candida markedly increased in the last decade. The purpose of this review is to understand mechanisms and risk factors for resistance and how to tackle antifungal resistance. RECENT FINDINGS: The paper describes the action of the three main classes of antifungals - azoles, echinocandins and polyenes - and Candida's mechanisms of resistance. The current evolution from cross-resistance to multiresistance among Candida explains the modern glossary - multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) - imported from bacteria. MDR Candida most commonly involves acquired resistance in species with intrinsic resistance, therefore it mostly involves C. glabrata, C. parapsilosis, C. krusei, C guilliermondii or C. auris , which is intrinsically multidrug resistant. Finally, strategies to tackle antifungal resistance became clearer, ideally implemented through antifungal stewardship. SUMMARY: Avoiding antifungal's overuse and selecting the best drug, dose and duration, when they are needed, is fundamental. Knowledge of risk factors for resistance, microbiological diagnosis to the species, use of susceptibility test supported by antifungal stewardship programs help attaining effective therapy and sustaining the effectiveness of the current antifungal armamentarium.

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. METHODS: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. RESULTS: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. CONCLUSION: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial.

BACKGROUND: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. OBJECTIVES: To estimate the effect of remdesivir in blocking viral replication. METHODS: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). RESULTS: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9-4.5 days). CONCLUSIONS: Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

Different epidemiology of bloodstream infections in COVID-19 compared to non-COVID-19 critically ill patients: a descriptive analysis of the Eurobact II study.

BACKGROUND: The study aimed to describe the epidemiology and outcomes of hospital-acquired bloodstream infections (HABSIs) between COVID-19 and non-COVID-19 critically ill patients. METHODS: We used data from the Eurobact II study, a prospective observational multicontinental cohort study on HABSI treated in ICU. For the current analysis, we selected centers that included both COVID-19 and non-COVID-19 critically ill patients. We performed descriptive statistics between COVID-19 and non-COVID-19 in terms of patients' characteristics, source of infection and microorganism distribution. We studied the association between COVID-19 status and mortality using multivariable fragility Cox models. RESULTS: A total of 53 centers from 19 countries over the 5 continents were eligible. Overall, 829 patients (median age 65 years [IQR 55; 74]; male, n = 538 [64.9%]) were treated for a HABSI. Included patients comprised 252 (30.4%) COVID-19 and 577 (69.6%) non-COVID-19 patients. The time interval between hospital admission and HABSI was similar between both groups. Respiratory sources (40.1 vs. 26.0%, p < 0.0001) and primary HABSI (25.4% vs. 17.2%, p = 0.006) were more frequent in COVID-19 patients. COVID-19 patients had more often enterococcal (20.5% vs. 9%) and Acinetobacter spp. (18.8% vs. 13.6%) HABSIs. Bacteremic COVID-19 patients had an increased mortality hazard ratio (HR) versus non-COVID-19 patients (HR 1.91, 95% CI 1.49-2.45). CONCLUSIONS: We showed that the epidemiology of HABSI differed between COVID-19 and non-COVID-19 patients. Enterococcal HABSI predominated in COVID-19 patients. COVID-19 patients with HABSI had elevated risk of mortality. Trial registration ClinicalTrials.org number NCT03937245 . Registered 3 May 2019.

High impact of COVID-19 in long-term care facilities, suggestion for monitoring in the EU/EEA, May 2020.

Residents in long-term care facilities (LTCF) are a vulnerable population group. Coronavirus disease (COVID-19)-related deaths in LTCF residents represent 30-60% of all COVID-19 deaths in many European countries. This situation demands that countries implement local and national testing, infection prevention and control, and monitoring programmes for COVID-19 in LTCF in order to identify clusters early, decrease the spread within and between facilities and reduce the size and severity of outbreaks.

Biomarkers of fungal lung infection.

PURPOSE OF REVIEW: The incidence of lung fungal infections, namely invasive pulmonary aspergillosis (IPA) and mucormycosis, is increasing in neutropenic and nonneutropenic patients. As they are a major cause of death, early diagnosis and antifungal therapy are crucial for outcome. The role of biomarkers in the management of this infections is the scope of this review. RECENT FINDINGS: Galactomannan in bronchoalveolar lavage shows the best discriminatory power for IPA diagnosis. At baseline, serum galactomannan may be useful to predict outcome and its kinetics may be informative to assess response to antifungal therapy. Recent standardization of PCR technology brought some improvements in IPA and mucormycosis diagnosis. Several new biomarkers are currently under investigation, but none showed a better performance than current available biomarkers. To improve diagnostic accuracy, a combination of biomarkers, including galactomannan, has been proposed. SUMMARY: Biomarkers may play an important role in the early diagnosis of fungal lung infections and in prognostic assessment and response monitoring, but more research is needed to determine the best strategy for their clinical use.

Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project.

BACKGROUND: The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. METHODS: A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). RESULTS: During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis. CONCLUSIONS: The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions.

Aspergillus and other respiratory fungal infections in the ICU: diagnosis and management.

PURPOSE OF REVIEW: Filamentous fungi respiratory infections, namely because of Aspergillus, Mucorales, Fusarium, or Scedosporium, show rising incidence and occur more in populations which are not classically immunosuppressed. This and their persistent dismal prognosis are the focus of this review. RECENT FINDINGS: Both an early diagnosis, rooted on a high level of suspicion and based on clinical picture, radiology, cultural microbiological exams, fungal biomarkers, PCR and biopsy, and an early therapy, including immunorecovery, whenever possible, good antifungal selection, and surgery for source control, are paramount to maximize the outcome in these diseases. An evolving antifungal armamentarium and a more Pharmacokinetics/Pharmacodynamics-based antifungal prescription may help to improve the prognosis. SUMMARY: Improved awareness of these infections may increase the level of suspicion, promoting early diagnosis and treatment, ideally supported with expert stewardship.

Pharmacokinetics-pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients.

Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients and beta-lactams are the most common antibiotic class used. Critically ill patient's pathophysiological factors lead to altered pharmacokinetics and pharmacodynamics of beta-lactams.A comprehensive bibliographic search in PubMed database of all English language articles published from January 2000 to December 2017 was performed, allowing the selection of articles addressing the pharmacokinetics or pharmacodynamics of beta-lactam antibiotics in critically ill patients.In critically ill patients, several factors may increase volume of distribution and enhance renal clearance, inducing high intra- and inter-patient variability in beta-lactam concentration and promoting the risk of antibiotic underdosing. The duration of infusion of beta-lactams has been shown to influence the fT > minimal inhibitory concentration and an improved beta-lactam pharmacodynamics profile may be obtained by longer exposure with more frequent dosing, extended infusions, or continuous infusions.The use of extracorporeal support techniques in the critically ill may further contribute to this problem and we recommend not reducing standard antibiotic dosage since no drug accumulation was found in the available literature and to maintain continuous or prolonged infusion, especially for the treatment of infections caused by multidrug-resistant bacteria.Prediction of outcome based on concentrations in plasma results in overestimation of antimicrobial activity at the site of infection, namely in cerebrospinal fluid and the lung. Therefore, although no studies have assessed clinical outcome, we recommend using higher than standard dosing, preferably with continuous or prolonged infusions, especially when treating less susceptible bacterial strains at these sites, as the pharmacodynamics profile may improve with no apparent increase in toxicity.A therapeutic drug monitoring-guided approach could be particularly useful in critically ill patients in whom achieving target concentrations is more difficult, such as obese patients, immunocompromised patients, those infected by highly resistant bacterial strains, patients with augmented renal clearance, and those undergoing extracorporeal support techniques.

Efficacy of anidulafungin in 539 patients with invasive candidiasis: a patient-level pooled analysis of six clinical trials.

Objectives: To evaluate the efficacy of anidulafungin for the treatment of candidaemia and invasive candidiasis in a large dataset, including patients with deep-seated tissue candidiasis, neutropenia and infection due to non- albicans Candida species. Methods: Data were pooled from six prospective, multicentre, multinational studies: four open-label, non-comparative studies of anidulafungin and two double-blind, double-dummy, randomized studies of anidulafungin versus caspofungin (clinical trial registrations: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351 and NCT00805740; ClinicalTrials.gov). In all studies, patients with culture-confirmed invasive candidiasis received a single intravenous (iv) loading dose of anidulafungin 200 mg on day 1, followed by 100 mg once-daily. Switch to oral fluconazole or voriconazole was permitted after 5-10 days of iv treatment in all studies except one. Antifungal treatment (iv plus oral therapy if applicable) was maintained for ≥14 days after the last positive Candida culture. The primary endpoint was successful global response at end of iv therapy (EOivT) in the modified ITT (mITT) population. Results: In total, 539 patients were included (mITT population). The most common baseline Candida species were Candida albicans (47.9%), Candida glabrata (21.0%), Candida tropicalis (13.7%), Candida parapsilosis (13.2%) and Candida krusei (3.5%). Median duration of anidulafungin iv treatment was 10.0 days. The global response success rate at EOivT was 76.4% (95% CI 72.9%-80.0%). All-cause mortality was 13.0% on day 14 and 19.1% on day 28. Adverse events (AEs) were consistent with the known AE profile for anidulafungin. Conclusions: These data demonstrate that anidulafungin is effective for treatment of candidaemia and invasive candidiasis in a broad patient population.

Characteristics and risk factors for 28-day mortality of hospital acquired fungemias in ICUs: data from the EUROBACT study.

BACKGROUND: To characterize and identify prognostic factors for 28-day mortality among patients with hospital-acquired fungemia (HAF) in the Intensive Care Unit (ICU). METHODS: A sub-analysis of a prospective, multicenter non-representative cohort study conducted in 162 ICUs in 24 countries. RESULTS: Of the 1156 patients with hospital-acquired bloodstream infections (HA-BSI) included in the EUROBACT study, 96 patients had a HAF. Median time to its diagnosis was 20 days (IQR 10.5-30.5) and 9 days (IQR 3-15.5) after hospital and ICU admission, respectively. Median time to positivity of blood culture was longer in fungemia than in bacteremia (48.7 h vs. 38.1 h; p = 0.0004). Candida albicans was the most frequent fungus isolated (57.1%), followed by Candida glabrata (15.3%) and Candida parapsilosis (10.2%). No clear source of HAF was detected in 33.3% of the episodes and it was catheter-related in 21.9% of them. Compared to patients with bacteremia, HAF patients had a higher rate of septic shock (39.6% vs. 21.6%; p = 0.0003) and renal dysfunction (25% vs. 12.4%; p = 0.0023) on admission and a higher rate of renal failure (26% vs. 16.2%; p = 0.0273) at diagnosis. Adequate treatment started within 24 h after blood culture collection was less frequent in HAF patients (22.9% vs. 55.3%; p < 0.001). The 28-day all cause fatality was 40.6%. According to multivariate analysis, only liver failure (OR 14.35; 95% CI 1.17-175.6; p = 0.037), need for mechanical ventilation (OR 8.86; 95% CI 1.2-65.24; p = 0.032) and ICU admission for medical reason (OR 3.87; 95% CI 1.25-11.99; p = 0.020) were independent predictors of 28-day mortality in HAF patients. CONCLUSIONS: Fungi are an important cause of hospital-acquired BSI in the ICU. Patients with HAF present more frequently with septic shock and renal dysfunction on ICU admission and have a higher rate of renal failure at diagnosis. HAF are associated with a significant 28-day mortality rate (40%), but delayed adequate antifungal therapy was not an independent risk factor for death. Liver failure, need for mechanical ventilation and ICU admission for medical reason were the only independent predictors of 28-day mortality.

Plateau Waves of Intracranial Pressure and Multimodal Brain Monitoring.

The aim of this study was to describe multimodal brain monitoring characteristics during plateau waves of intracranial pressure (ICP) in patients with head injury, using ICM+ software for continuous recording. Plateau waves consist of an abrupt elevation of ICP above 40 mmHg for 5-20 min. This is a prospective observational study of patients with head injury who were admitted to a neurocritical care unit and who developed plateau waves. We analyzed 59 plateau waves that occurred in 8 of 18 patients (44 %). At the top of plateau waves arterial blood pressure remained almost constant, but cerebral perfusion pressure, cerebral blood flow, brain tissue oxygenation, and cerebral oximetry decreased. After plateau waves, patients with a previously better autoregulation status developed hyperemia, demonstrated by an increase in cerebral blood flow and brain oxygenation. Pressure and oxygen cerebrovascular reactivity indexes (pressure reactivity index and ORxshort) increased significantly during the plateau wave as a sign of disruption of autoregulation. Bedside multimodal brain monitoring is important to characterize increases in ICP and give differential diagnoses of plateau waves, as management of this phenomenon differs from that of regular ICP.

Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes.

INTRODUCTION: Invasive aspergillosis (IA) is a fungal infection that particularly affects immunocompromised hosts. Recently, several studies have indicated a high incidence of IA in intensive care unit (ICU) patients. However, few data are available on the epidemiology and outcome of patients with IA in this setting. METHODS: An observational study including all patients with a positive Aspergillus culture during ICU stay was performed in 30 ICUs in 8 countries. Cases were classified as proven IA, putative IA or Aspergillus colonization according to recently validated criteria. Demographic, microbiologic and diagnostic data were collected. Outcome was recorded 12 weeks after Aspergillus isolation. RESULTS: A total of 563 patients were included, of whom 266 were colonized (47%), 203 had putative IA (36%) and 94 had proven IA (17%). The lung was the most frequent site of infection (94%), and Aspergillus fumigatus the most commonly isolated species (92%). Patients with IA had higher incidences of cancer and organ transplantation than those with colonization. Compared with other patients, they were more frequently diagnosed with sepsis on ICU admission and more frequently received vasopressors and renal replacement therapy (RRT) during the ICU stay. Mortality was 38% among colonized patients, 67% in those with putative IA and 79% in those with proven IA (P < 0.001). Independent risk factors for death among patients with IA included older age, history of bone marrow transplantation, and mechanical ventilation, RRT and higher Sequential Organ Failure Assessment score at diagnosis. CONCLUSIONS: IA among critically ill patients is associated with high mortality. Patients diagnosed with proven or putative IA had greater severity of illness and more frequently needed organ support than those with Aspergillus spp colonization.

Kidney-brain link in traumatic brain injury patients? A preliminary report.

BACKGROUND: Kidney hyperfiltration with augmented renal clearance is frequently observed in patients with traumatic brain injury. The aim of this study is to report preliminary findings about the relationship between brain autoregulation impairment, estimated kidney glomerular filtration rate and outcome in critically ill patients after severe traumatic brain injury. METHODS: Data collected from a cohort of 18 consecutive patients with severe traumatic brain injury managed with ICP monitoring in a Neurocritical Care Unit, were retrospectively analyzed. Early morning blood tests were performed for routine chemistry assessments and we analyzed creatinine and estimated creatinine clearance, osmolarity, and sodium. Daily norepinephrine dose, protein intake, and water balance were documented. Time average of brain monitoring data (intracranial pressure, cerebral perfusion pressure, and cerebrovascular reactivity pressure index--PRx) were calculated for 6 h before blood sample tests. Patient outcome was evaluated using Glasgow outcome scale at 6-month follow-up, considering nonfatal outcome if GOS ≥ 3 and fatal outcome if GOS < 3. Multiple linear regression models were used to study the crude and adjusted effects of the above variables on PRx throughout time. RESULTS: A total of 199 complete daily observations from 18 adult consecutive multiple trauma patients with severe traumatic brain injury were analyzed. At hospital admission, the median post-resuscitation Glasgow coma score was 6 (range 3-12), mean SAPSII score was 44.65 with predicted mortality of 36 %. Hospital mortality rate was 27 % and median GOS at 6 month after discharge was 3. Creatinine clearance (CrCl) was found to have a negative correlation with PRx (Pearson correlation--0.82), with statistically significant crude (p < 0.001) and adjusted (p = 0.001) effects. For each increase of 10 ml/min in CrCl (estimated either by the Cockcroft-Gault or by Modification of Diet in Renal Disease Study equations) a mean decrease in PRx of approximately 0.01 was expected. Amongst possible confounders only norepinephrine was shown to have a significant effect. Mean PRx value for outcome fatal status was greater than mean PRx for nonfatal status (p < 0.05), regardless of the model used for the CrCl estimation. CONCLUSIONS: Better cerebral autoregulation evaluated with cerebrovascular PRx is significantly correlated with augmented renal clearance in TBI patients and associates with better outcome.

Optimal Cerebral Perfusion Pressure Management at Bedside: A Single-Center Pilot Study.

BACKGROUND: Guidelines recommend cerebral perfusion pressure (CPP) values of 50-70 mmHg and intracranial pressure lower than 20 mmHg for the management of acute traumatic brain injury (TBI). However, adequate individual targets are still poorly addressed, since patients have different perfusion thresholds. Bedside assessment of cerebral autoregulation may help to optimize individual CPP-guided treatment. OBJECTIVE: To assess staff compliance and outcome impact of a new method of autoregulation-guided treatment (CPPopt) based on continuous evaluation of cerebrovascular reactivity (PRx). METHODS: Prospective pilot study of severe TBI adult patients managed with continuous multimodal brain monitoring in a single Neurocritical Care Unit (NCCU). Every minute CPPopt was automatically estimated, based on the previous 4-h window, as the CPP with the lowest PRx indicating the best cerebrovascular pressure reactivity. Patients were managed with CPPopt targets whenever possible and otherwise CPP was managed following general/international guidelines. In addition, other offline CPPopt estimates were calculated using cerebral oximetry (COx-CPPopt), brain tissue oxygenation (ORxs-CPPopt), and cerebral blood flow (CBFx-CPPopt). RESULTS: Eighteen patients with a total multimodal brain monitoring time of 5,520 h were enrolled. During the total monitoring period, 11 patients (61 %) had a CPPopt U-shaped curve, 5 patients (28 %) had either ascending or descending curves, and only 2 patients (11 %) had no fitted curve. Real CPP correlated significantly with calculated CPPopt (r = 0.83, p < 0.0001). Preserved autoregulation was associated with greater Glasgow coma score on admission (p = 0.01) and better outcome (p = 0.01). We demonstrated that patients with the larger discrepancy (>10 mm Hg) between real CPP and CPPopt more likely have had adverse outcome (p = 0.04). Comparison between CPPopt and the other estimates revealed similar limits of precision. The lowest bias (-0.1 mmHg) was obtained with COx-CPPopt (NIRS). CONCLUSION: Targeted individual CPP management at the bedside using cerebrovascular pressure reactivity seems feasible. Large deviation from CPPopt seems to be associated with adverse outcome. The COx-CPPopt methodology using non-invasive CO (NIRS) warrants further evaluation.

Pressures, flow, and brain oxygenation during plateau waves of intracranial pressure.

BACKGROUND: Plateau waves are common in traumatic brain injury. They constitute abrupt increases of intracranial pressure (ICP) above 40 mmHg associated with a decrease in cerebral perfusion pressure (CPP). The aim of this study was to describe plateau waves characteristics with multimodal brain monitoring in head injured patients admitted in neurocritical care. METHODS: Prospective observational study in 18 multiple trauma patients with head injury admitted to Neurocritical Care Unit of Hospital Sao Joao in Porto. Multimodal systemic and brain monitoring of primary variables [heart rate, arterial blood pressure, ICP, CPP, pulse amplitude, end tidal CO2, brain temperature, brain tissue oxygenation pressure, cerebral oximetry (CO) with transcutaneous near-infrared spectroscopy and cerebral blood flow (CBF)] and secondary variables related to cerebral compensatory reserve and cerebrovascular reactivity were supported by dedicated software ICM+ ( www.neurosurg.cam.ac.uk/icmplus) . The compiled data were analyzed in patients who developed plateau waves. RESULTS: In this study we identified 59 plateau waves that occurred in 44% of the patients (8/18). During plateau waves CBF, cerebrovascular resistance, CO, and brain tissue oxygenation decreased. The duration and magnitude of plateau waves were greater in patients with working cerebrovascular reactivity. After the end of plateau wave, a hyperemic response was recorded in 64% of cases with increase in CBF and brain oxygenation. The magnitude of hyperemia was associated with better autoregulation status and low oxygenation levels at baseline. CONCLUSIONS: Multimodal brain monitoring facilitates identification and understanding of intrinsic vascular brain phenomenon, such as plateau waves, and may help the adequate management of acute head injury at bed side.

Pneumococcal Septic Shock Syndrome: A Deadly Condition Despite Vaccination.

Invasive pneumococcal disease is a serious infection with an elevated case-fatality rate that can be even higher among patients with asplenia. Its impact has been blunted by the widespread use of vaccines; even recently, in 2021, two new pneumococcal conjugate vaccines emerged. The authors present a case of a 58-year-old male, splenectomised with the immunisation schedule complete, who died of invasive pneumococcal disease with a fulminant course. It is highlighted that fever in a patient with impaired splenic function is an emergency, and despite the success of immunisation in reducing pneumococcal carriage and invasive disease, serotypes continue to change. Also, the local epidemiology may help guide situations where the immunisation recommendations are dubious regarding the implementation of the new vaccines.