Abstract
Background
The combination lopinavir/ritonavir is recommended to treat HIV-infected patients at the dose regimen of 400/100 mg q12h, oral route. The usual lopinavir trough plasma ...concentrations are 3000–8000 ng/mL. A trend towards a 28 day mortality reduction was observed in COVID-19-infected patients treated with lopinavir/ritonavir.
Objectives
To assess the plasma concentrations of lopinavir and ritonavir in patients with severe COVID-19 infection and receiving lopinavir/ritonavir.
Patients and methods
Mechanically ventilated patients with COVID-19 infection included in the French COVID-19 cohort and treated with lopinavir/ritonavir were included. Lopinavir/ritonavir combination was administered using the usual adult HIV dose regimen (400/100 mg q12h, oral solution through a nasogastric tube). A half-dose reduction to 400/100 mg q24h was proposed if lopinavir Ctrough was >8000 ng/mL, the upper limit considered as toxic and reported in HIV-infected patients. Lopinavir and ritonavir pharmacokinetic parameters were determined after an intensive pharmacokinetic analysis. Biological markers of inflammation and liver/kidney function were monitored.
Results
Plasma concentrations of lopinavir and ritonavir were first assessed in eight patients treated with lopinavir/ritonavir. Median (IQR) lopinavir Ctrough reached 27 908 ng/mL (15 928–32 627). After the dose reduction to 400/100 mg q24h, lopinavir/ritonavir pharmacokinetic parameters were assessed in nine patients. Lopinavir Ctrough decreased to 22 974 ng/mL (21 394–32 735).
Conclusions
In mechanically ventilated patients with severe COVID-19 infections, the oral administration of lopinavir/ritonavir elicited plasma exposure of lopinavir more than 6-fold the upper usual expected range. However, it remains difficult to safely recommend its dose reduction without compromising the benefit of the antiviral strategy, and careful pharmacokinetic and toxicity monitoring are needed.
Background
The impact on infectious risk of ultrasound guidance at insertion remains controversial in short-term arterial catheters (ACs). The present study investigated the association between ...ultrasound guidance (US) during AC insertion and major catheter-related infections (MCRI), catheter-related bloodstream infections (CR-BSI) or colonization, using univariate and multivariate marginal Cox model for clustered data. The skin colonization at catheter removal was evaluated to explain our results.
Results
We used individual data from two multicenter randomized-controlled trials (RCTs) that included a total of 3029 patients, 10 ICUs and 3950 ACs. US guidance was used for 386 (9.8%) catheter placements. In the univariate Cox model analysis, AC insertion with US versus without US exhibited similar risks for MCRI (HR 0.86, CI 95% 0.27–2.72,
p
= 0.79), CR-BSI (HR 0.87, CI 95% 0.20–3.72,
p
= 0.85) and catheter colonization (HR 1.31, CI 95% 0.92–1.86,
p
= 0.13). After adjustment on confounders, risks associated with US guidance remained similar
versus
non-US for MCRI (HR 0.71, CI 95% 0.23–2.24,
p
= 0.56), CR-BSI (HR 0.71, CI 95% 0.17–3.00,
p
= 0.63) and catheter colonization (HR 0.92, CI 95% 0.63–1.34,
p
= 0.67). No differences between US and non-US for MCRI, CR-BSI and colonization were observed according to the insertion site, radial or femoral. At catheter removal, the skin colonization was similar between US and non-US groups (
p
= 0.69).
Conclusions
Using the largest dataset ever collected from large multi-centric RCTs conducted with relatively consistent insertion and maintenance catheter protocols, we showed that the risk of infectious complications for ACs inserted under US guidance is not superior compared to those inserted without US guidance.
Trial registration
These studies were registered within ClinicalTrials.gov (numbers NCT01629550 and NCT 01189682).
The optimal treatment for patients with severe coronavirus-19 disease (COVID-19) and hyper-inflammation remains debated.
A cohort study was designed to evaluate whether a therapeutic algorithm using ...steroids with or without interleukin-1 antagonist (anakinra) could prevent death/invasive ventilation. Patients with a ≥5-day evolution since symptoms onset, with hyper-inflammation (CRP≥50mg/L), requiring 3-5 L/min oxygen, received methylprednisolone alone. Patients needing ≥6 L/min received methylprednisolone + subcutaneous anakinra daily either frontline or in case clinical deterioration upon corticosteroids alone. Death rate and death or intensive care unit (ICU) invasive ventilation rate at Day 15, with Odds Ratio (OR) and 95% CIs, were determined according to logistic regression and propensity scores. A Bayesian analysis estimated the treatment effects.
Of 108 consecutive patients, 70 patients received glucocorticoids alone. The control group comprised 63 patients receiving standard of care. In the corticosteroid±stanakinra group (n = 108), death rate was 20.4%, versus 30.2% in the controls, indicating a 30% relative decrease in death risk and a number of 10 patients to treat to avoid a death (p = 0.15). Using propensity scores a per-protocol analysis showed an OR for COVID-19-related death of 0.9 (95%CI 0.80-1.01, p = 0.067). On Bayesian analysis, the posterior probability of any mortality benefit with corticosteroids+/-anakinra was 87.5%, with a 7.8% probability of treatment-related harm. Pre-existing diabetes exacerbation occurred in 29 of 108 patients (26.9%).
In COVID-19 non-ICU inpatients at the cytokine release phase, corticosteroids with or without anakinra were associated with a 30% decrease of death risk on Day 15.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
We previously showed that external cooling decreases day 14 mortality in febrile septic shock. Because cooling may participate in heart rate control, we studied the respective impact of heart ...rate and temperature lowering on mortality.
Methods
Post hoc analysis of the Sepsiscool randomized controlled trial database (NCT00527007). Cooling was applied to maintain normothermia (36.5–37 °C) during 48 h. We assessed the time spent below different thresholds of temperature and heart rate on day 14 mortality. The best threshold was selected by AUC-ROC and tested as a potential mediator of mortality reduction. Mediation analysis was adjusted for severity and treatments influencing temperature and heart rate evolution. Sensitivity analysis was done using only patients with appropriate antimicrobial therapy.
Results
A total of 197/200 patients with adequate heart rate and temperature monitoring were analyzed. The best threshold differentiating survivors and nonsurvivors was 38.4 °C for temperature and 95 b/min for heart rate. During the 48 h of intervention, cooling significantly increased the time spent with a temperature below 38.4 °C,
p
= 0.001, and with a heart rate below 95 b/min,
p
< 0.01. The longer was the time spent with a temperature below 38.4 °C, the lower was the mortality adjOR 0.17 (0.06–0.49),
p
= 0.001. The time spent with a heart rate below 95 b/min was similar in survivors and nonsurvivors adjOR 0.68 (0.27–1.72),
p
= 0.42. Mediation analysis showed that the time spent with a temperature below 38.4 °C was a significant mediator of mortality.
Conclusion
The time spent with a temperature below 38.4 °C was independently associated with patient’s outcome and explained 73 % of the effect of the randomization on the day 14 mortality. Heart rate lowering was not a mediator of mortality.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
As SARS-CoV-2 continues to spread, a thorough characterisation of healthcare needs and patient outcomes, and how they have changed over time, is essential to inform planning.
We developed a ...probabilistic framework to analyse detailed patient trajectories from 198,846 hospitalisations in France during the first nine months of the pandemic. Our model accounts for the varying age- and sex- distribution of patients, and explore changes in outcome probabilities as well as length of stay.
We found that there were marked changes in the age and sex of hospitalisations over the study period. In particular, the proportion of hospitalised individuals that were >80y varied between 27% and 48% over the course of the epidemic, and was lowest during the inter-peak period. The probability of hospitalised patients entering ICU dropped from 0·25 (0·24–0·26) to 0·13 (0·12–0·14) over the four first months as case numbers fell, before rising to 0·19 (0·19–0·20) during the second wave. The probability of death followed a similar trajectory, falling from 0·25 (0·24–0·26) to 0·10 (0·09–0·11) after the first wave before increasing again during the second wave to 0·19 (0·18–0·19). Overall, we find both the probability of death and the probability of entering ICU were significantly correlated with COVID-19 ICU occupancy.
There are large scale trends in patients outcomes by age, sex and over time. These need to be considered in ongoing healthcare planning efforts.
INCEPTION.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pneumonia is a dreaded complication of varicella-zoster virus (VZV) infection in adults; however, the data are limited. Our objective was to investigate the clinical features, management, and ...outcomes of critically ill patients with VZV-related community-acquired pneumonia (VZV-CAP).
This was an observational study of patients with VZV-CAP admitted to 29 intensive care units (ICUs) from January 1996 to January 2015.
One hundred and two patients with VZV-CAP were included. Patients were young (age 39 years (interquartile range 32-51)) and 53 (52%) were immunocompromised. Time since respiratory symptom onset was 2 (1-3) days. There was a seasonal distribution of the disease, with more cases during spring and winter time. All but four patients presented with typical skin rash on ICU admission. Half the patients received mechanical ventilation within 1 (1-2) day following ICU admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO
/FiO
) = 150 (80-284), 80% with acute respiratory distress syndrome (ARDS)). Sequential Organ Failure Assessment (SOFA) score on day 1 (odds ratio (OR) 1.90 (1.33-2.70); p < 0.001), oxygen flow at ICU admission (OR 1.25 (1.08-1.45); p = 0.004), and early bacterial co-infection (OR 14.94 (2.00-111.8); p = 0.009) were independently associated with the need for mechanical ventilation. Duration of mechanical ventilation was 14 (7-21) days. ICU and hospital mortality rates were 17% and 24%, respectively. All patients were treated with aciclovir and 10 received adjunctive therapy with steroids. Compared to 60 matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, ICU length of stay, and a similar hospital mortality, but experienced more ICU-acquired infections.
Severe VZV-CAP is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. Steroid therapy did not influence mortality, but increased the risk of superinfection.
We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin–producing Escherichia coli (STEC) in 96 adults enrolled in the cohort of the National Reference Center for ...Thrombotic Microangiopathies network in France during 2009–2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.
Full text
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
To describe the course of early organ dysfunction in a cohort of patients admitted in ICU suffering classic heatstroke.
Methods
Prospective observational single-centre cohort study with a ...1-year follow-up.
Interventions
None.
Measurements and main results
Clinical and biological data of 22 patients were analysed. Median body temperature on admission was 41.1°C. Respiratory, circulatory, haematological, hepatic and renal function all deteriorated within the first 24 h of admission. ICU-mortality was 63.6%. Cooling time, serum lactate, serum cardiac troponin I and creatinine were significantly higher in non-survivors. Early ICU-mortality (within 7 days of ICU stay) was due to multiple organ failure. Late ICU-mortality was due to neurological disability.
Conclusions
Classic heat stroke may demonstrate a rapidly worsening organ dysfunction course leading to death even though cooling procedures and intensive care management are promptly started.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Emerging resistance to antibiotics shows no signs of decline. At the same time, few new antibacterials are being discovered. There is a worldwide recognition regarding the danger of this situation. ...The urgency of the situation and the conviction that practices should change led the Société de Réanimation de Langue Française (SRLF) and the Société Française d’Anesthésie et de Réanimation (SFAR) to set up a panel of experts from various disciplines. These experts met for the first time at the end of 2012 and have since met regularly to issue the following 67 recommendations, according to the rigorous GRADE methodology. Five fields were explored: i) the link between the resistance of bacteria and the use of antibiotics in intensive care; ii) which microbiological data and how to use them to reduce antibiotic consumption; iii) how should antibiotic therapy be chosen to limit consumption of antibiotics; iv) how can antibiotic administration be optimized; v) review and duration of antibiotic treatments. In each institution, the appropriation of these recommendations should arouse multidisciplinary discussions resulting in better knowledge of local epidemiology, rate of antibiotic use, and finally protocols for improving the stewardship of antibiotics. These efforts should contribute to limit the emergence of resistant bacteria.
Full text
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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