Publications by authors named "Bruno Megarbane"

317 Publications

Relationship between acute kidney injury and mortality in poisoning - a systematic review and metanalysis.

Clin Toxicol (Phila) 2021 Jun 3:1-9. Epub 2021 Jun 3.

University of Paris, Inserm UMRS 1144, Paris, France.

Rationale: Three consensus classifications of acute kidney injury have been published. These are RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease published by the workgroup), AKIN (published by the ) and KDIGO (published by the workgroup). Acute kidney injury has been reported consistently as associated with worsened outcomes. However, toxicant-related acute kidney injury has been excluded from the studies used to validate the classifications of acute kidney injury.

Objective: To study whether poisoned patients who develop acute kidney injury, as defined by consensus definitions/classifications, have higher mortality compared to those who did not.

Methods: Databases were searched from 2004 to 2019 using the following keywords (KDIGO OR "Kidney Disease: Improving Global Outcomes" OR "Kidney Disease Improving Global Outcomes" OR AKIN OR "AKI network" OR "Acute kidney Injury Network" OR ADQI OR RIFLE OR "Acute dialysis quality initiative") AND (intoxication OR poisoning OR overdose OR ingestion) AND (AKI OR kidney OR renal OR ARF). If data were available, we used a random-effects meta-analysis model and Fisher's exact test to compare mortality in patients according to kidney function definitions (acute kidney injury not) and stages (stages no acute kidney injury), respectively. If data were available, we assessed the correlation between mortality and renal function (no acute kidney injury, risk/stage 1, injury/stage 2 and failure/stage 3) using the Spearman correlation. If available, we collected the results of statistical analyses in studies that have used acute kidney injury to predict mortality.

Results: Thirty-three relevant studies were found, 22/33 retrospective studies (67%) and 11/33 prospective studies (33%). Paraquat was the most frequent toxicant involved (13/33, 39%). We found a disparity between studies regarding the timeframe during which mortality was assessed, the temporality of the renal function considered to predict mortality (initial/worst) and the criteria used to define/grade acute kidney injury across studies. Consensus definitions/staging of acute kidney injury were associated with higher mortality, using univariate analyses, in twenty-eight (RIFLE = 7; AKIN = 12; KDIGO = 9) studies included but not in five (AKIN = 4, KDIGO = 1). When available data were pooled, RIFLE (5 studies), AKIN (16 studies) and KDIGO definitions (8 studies) of acute kidney injury were associated with a higher mortality (Log unadjusted Odds ratios [95%-confidence interval], 2.60 [2.23; 2.97], 2.02 [1.48; 2,52] and 3.22 [2,65; 3.78], respectively). However, we found high heterogeneity (I=54,7%) and publication bias among studies using AKIN. In ten studies with available data, the correlation between renal function (no acute kidney injury, risk/stage 1, injury/stage 2, failure/stage 3) and mortality was significant in 5 studies (RIFLE = 2; AKIN = 3), but not in five studies (RIFLE = 1; AKIN = 3; KDIGO = 1).. The definitions of acute kidney injury were associated with higher mortality in two studies (RIFLE = 2), but not in four studies (AKIN = 1 and KDIGO = 3. The stages of acute kidney injury (including one or more stages) were associated with higher mortality in four (RIFLE = 1, AKIN = 1 and KDIGO = 2).

Conclusions: All three consensus definitions/classifications were associated independently with increased mortality in poisoning but with disparity between studies reporting acute kidney injury.
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http://dx.doi.org/10.1080/15563650.2021.1928161DOI Listing
June 2021

The effects of naloxone, diazepam, and quercetin on seizure and sedation in acute on chronic tramadol administration: an experimental study.

Behav Brain Funct 2021 May 29;17(1). Epub 2021 May 29.

Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences (BUMS), Birjand, Iran.

Background: Tramadol is a widely used synthetic opioid. Substantial research has previously focused on the neurological effects of this drug, while the efficacy of various treatments to reduce the associated side effects has not been well studied. This study aimed to evaluate the protective effects of naloxone, diazepam, and quercetin on tramadol overdose-induced seizure and sedation level in male rats.

Methods: The project was performed with 72 male Wistar rats with an average weight of 200-250 g. The rats were randomly assigned to eight groups. Tramadol was administered intraperitoneally at an initial dose of 25 mg/kg/day. On the 14th day, tramadol was injected at 75 mg/kg, either alone or together with naloxone, diazepam, and quercetin (acute and chronic) individually or in combination. The rats were monitored for 6 h on the last day, and the number, the duration, and the severity of seizures (using the criteria of Racine) were measured over a 6-h observation period. The sedation level was also assessed based on a 4-point criterion, ranging from 0 to 3. Data were analyzed in SPSS software using Kruskal-Wallis, Chi-square, regression analysis, and generalized estimating equation (GEE) tests. The significance level was set at P < 0.05.

Results: The naloxone-diazepam combination reduced the number, severity, and cumulative duration of seizures compared to tramadol use alone and reduced the number of higher-intensity seizures (level 3, 4) to a greater extent than other treatments. Naloxone alone reduced the number and duration of seizures but increased the number of mild seizures (level 2). Diazepam decreased the severity and duration of seizures. However, it increased the number of mild seizures (level 2). In comparison with the tramadol alone group, the acute quercetin group exhibited higher numbers of mild (level 2) and moderate (level 3) seizures. Chronic quercetin administration significantly increased the number of mild seizures. In the GEE model, all groups had higher sedation levels than the saline only group (P < 0.001). None of the protocols had a significant effect on sedation levels compared to the tramadol group.

Conclusion: The combined administration of naloxone and diazepam in acute-on-chronic tramadol poisoning can effectively reduce most seizure variables compared to tramadol use alone. However, none of the treatments improved sedation levels.
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http://dx.doi.org/10.1186/s12993-021-00178-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164767PMC
May 2021

Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.

Intensive Care Med 2021 Jun 29;47(6):674-686. Epub 2021 May 29.

Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Purpose: Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA.

Methods: We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population).

Results: Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment.

Conclusion: The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.
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http://dx.doi.org/10.1007/s00134-021-06431-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164057PMC
June 2021

Early Bacterial Identification Among Intubated Patients with COVID-19 or Influenza Pneumonia: A European Multicenter Comparative Cohort Study.

Am J Respir Crit Care Med 2021 May 26. Epub 2021 May 26.

Hôpital Pellegrin-Tripode , Service de Reanimation , Bordeaux, France.

Rationale: Early empirical antimicrobial treatment is frequently prescribed to critically ill patients with COVID-19, based on Surviving Sepsis Campaign guidelines.

Objective: We aimed to determine the prevalence of early bacterial identification in intubated patients with SARS-CoV-2 pneumonia, as compared to influenza pneumonia, and to characterize its microbiology and impact on outcomes.

Methods: Multicenter retrospective European cohort performed in 36 ICUs. All adult patients receiving invasive mechanical ventilation >48h were eligible if they had SARS-CoV-2 or influenza pneumonia at ICU admission. Bacterial identification was defined by a positive bacterial culture, within 48h after intubation, in endotracheal aspirates, bronchoalveolar lavage, blood cultures, or a positive pneumococcal or legionella urinary antigen test.

Measurements And Main Results: 1,050 patients were included (568 in SARS-CoV-2 and 482 in influenza groups). The prevalence of bacterial identification was significantly lower in patients with SARS-CoV-2 pneumonia as compared to patients with influenza pneumonia (9.7 vs 33.6%, unadjusted odds ratio (OR) 0.21 (95% confidence interval (CI) 0.15 to 0.30), adjusted OR 0.23 (95% CI 0.16 to 0.33), p<0.0001). Gram-positive cocci were responsible for 58% and 72% of co-infection in patients with SARS-CoV-2 and influenza pneumonia, respectively. Bacterial identification was associated with increased adjusted hazard ratio for 28-day mortality in patients with SARS-CoV-2 pneumonia (1.57 (95% CI 1.01 to 2.44), p=0.043). However, no significant difference was found in heterogeneity of outcomes related to bacterial identification between the two study groups, suggesting that the impact of co-infection on mortality was not different between SARS-CoV-2 and influenza patients.

Conclusions: Bacterial identification within 48h after intubation is significantly less frequent in patients with SARS-CoV-2 pneumonia as compared to patients with influenza pneumonia. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1164/rccm.202101-0030OCDOI Listing
May 2021

Relationship between ventilator-associated pneumonia and mortality in COVID-19 patients: a planned ancillary analysis of the coVAPid cohort.

Crit Care 2021 05 25;25(1):177. Epub 2021 May 25.

Département de Médecine Intensive-Réanimation, CHU D'Angers, Université D'Angers, 4 rue Larrey, 49933, Angers Cedex 9, France.

Background: Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients.

Methods: Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox's regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event.

Findings: Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 (adjusted HR 1.70 (95% CI 1.16-2.47), p = 0.006), and influenza groups (1.75 (1.03-3.02), p = 0.045), but not in the no viral infection group (1.07 (0.64-1.78), p = 0.79). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups.

Interpretation: VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality.

Clinical Trial Registration: The study was registered at ClinicalTrials.gov, number NCT04359693.
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http://dx.doi.org/10.1186/s13054-021-03588-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146175PMC
May 2021

Does MARS™ beneficially affect hemodynamics in refractory vasoplegic shock due to calcium-channel blocker poisoning? Evidence is missing.

Int J Artif Organs 2021 May 25:3913988211019757. Epub 2021 May 25.

Université de Paris, Paris, France.

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http://dx.doi.org/10.1177/03913988211019757DOI Listing
May 2021

Comparison of Circulating Immune Cells Profiles and Kinetics Between Coronavirus Disease 2019 and Bacterial Sepsis.

Crit Care Med 2021 May 18. Epub 2021 May 18.

APHP, Hôpital Lariboisière, Department of Anesthesiology and Critical Care, FHU PROMICE, DMU Parabol, Paris, France. Université de Paris, Inserm U942 MASCOT, Paris, France. Service d'Hématologie Biologique, Pôle B2P, Hôpital Lariboisière, APHP, Paris, France. Department of Medical and Toxicological Critical Care, Lariboisière Hospital, Paris University, Paris, France; INSERM UMRS 1144, Paris, France. Service de Medecine Intensive et Réanimation, Groupe Hospitalier Paris Saint Joseph, APHP, Paris, France.

Objectives: Although clinical presentation of coronavirus disease 2019 has been extensively described, immune response to severe acute respiratory syndrome coronavirus 2 remains yet not fully understood. Similarities with bacterial sepsis were observed; however, few studies specifically addressed differences of immune response between both conditions. Here, we report a longitudinal analysis of the immune response in coronavirus disease 2019 patients, its correlation with outcome, and comparison between severe coronavirus disease 2019 patients and septic patients.

Design: Longitudinal, retrospective observational study.

Setting: Tertiary-care hospital during the first 2020 coronavirus disease 2019 outbreak in France.

Patients: All successive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection admitted to the emergency department, medical ward, and ICU with at least one available immunophenotyping performed during hospital stay.

Measurements And Main Results: Between March and April 2020, 247 patients with coronavirus disease 2019 were included and compared with a historical cohort of 108 severe septic patients. Nonsevere coronavirus disease 2019 patients (n = 153) presented normal or slightly altered immune profiles. Severe coronavirus disease 2019 (n = 94) immune profile differed from sepsis. Coronavirus disease 2019 exhibited profound and prolonged lymphopenia (mostly on CD3, CD4, CD8, and NK cells), neutrophilia, and human leukocyte antigen D receptor expression on CD14+ monocytes down-regulation. Surprisingly, coronavirus disease 2019 patients presented a unique profile of B cells expansion, basophilia, and eosinophilia. Lymphopenia, human leukocyte antigen D receptor expression on CD14+ monocytes down-regulation, and neutrophilia were associated with a worsened outcome, whereas basophilia and eosinophilia were associated with survival. Circulating immune cell kinetics differed between severe coronavirus disease 2019 and sepsis, lack of correction of immune alterations in coronavirus disease 2019 patients during the first 2 weeks of ICU admission was associated with death and nosocomial infections.

Conclusions: Circulating immune cells profile differs between mild and severe coronavirus disease 2019 patients. Severe coronavirus disease 2019 is associated with a unique immune profile as compared with sepsis. Several immune features are associated with outcome. Thus, immune monitoring of coronavirus disease 2019 might be of help for patient management.
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http://dx.doi.org/10.1097/CCM.0000000000005088DOI Listing
May 2021

Covid-19 in the Caribbean: lessons learned from the ongoing international medical and scientific cooperation.

Global Health 2021 05 10;17(1):55. Epub 2021 May 10.

Intensive Care Unit, Cayenne General Hospital, Av des Flamboyants, 97306, Cayenne, French Guiana.

The coronavirus disease (Covid-19) crisis presents as human, social and economic challenges. The advent of Covid-19, unfortunate as it is, has highlighted the need for close medical cooperation between states. Medical cooperation is the key counter to fight against the Covid-19 pandemic.
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http://dx.doi.org/10.1186/s12992-021-00706-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107407PMC
May 2021

Persistent brainwave disruption and cognitive impairment induced by acute sarin surrogate sub-lethal dose exposure.

Toxicology 2021 May 19;456:152787. Epub 2021 Apr 19.

Departement of Toxicology and Chemical Risks, French Armed Forces Biomedical Research Institute, Bretigny sur Orge, France. Electronic address:

Warfare neurotoxicants such as sarin, soman or VX, are organophosphorus compounds which irreversibly inhibit cholinesterase. High-dose exposure with nerve agents (NA) is known to produce seizure activity and related brain damage, while less is known about the effects of acute sub-lethal dose exposure. The aim of this study was to characterize behavioral, brain activity and neuroinflammatory modifications at different time points after exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. In order to decipher the impacts of sub-lethal exposure, we chose 4 different doses of NIMP each corresponding to a fraction of the median lethal dose (LD). First, we conducted a behavioral analysis of symptoms during the first hour following NIMP challenge and established a specific scoring scale for the intoxication severity. The intensity of intoxication signs was dose-dependent and proportional to the cholinesterase activity inhibition evaluated in mice brain. The lowest dose (0.3 LD) did not induce significant behavioral, electrocorticographic (ECoG) nor cholinesterase activity changes. Animals exposed to one of the other doses (0.5, 0.7 and 0.9 LD) exhibited substantial changes in behavior, significant cholinesterase activity inhibition, and a disruption of brainwave distribution that persisted in a dose-dependent manner. To evaluate long lasting changes, we conducted ECoG recording for 30 days on mice exposed to 0.5 or 0.9 LD of NIMP. Mice in both groups showed long-lasting impairment of theta rhythms, and a lack of restoration in hippocampal ChE activity after 1-month post-exposure. In addition, an increase in neuroinflammatory markers (IBA-1, TNF-α, NF-κB) and edema were transiently observed in mice hippocampus. Furthermore, a novel object recognition test showed an alteration of short-term memory in both groups, 1-month post-NIMP intoxication. Our findings identified both transient and long-term ECoG alterations and some long term cognitive impairments following exposure to sub-lethal doses of NIMP. These may further impact morphopathological alterations in the brain.
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http://dx.doi.org/10.1016/j.tox.2021.152787DOI Listing
May 2021

Extracorporeal membrane oxygenation network organisation and clinical outcomes during the COVID-19 pandemic in Greater Paris, France: a multicentre cohort study.

Lancet Respir Med 2021 Apr 19. Epub 2021 Apr 19.

Department of Cardiovascular and Thoracic Surgery, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France; Sorbonne University, INSERM UMRS_1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.

Background: In the Île-de-France region (henceforth termed Greater Paris), extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS) was considered early in the COVID-19 pandemic. We report ECMO network organisation and outcomes during the first wave of the pandemic.

Methods: In this multicentre cohort study, we present an analysis of all adult patients with laboratory-confirmed SARS-CoV-2 infection and severe ARDS requiring ECMO who were admitted to 17 Greater Paris intensive care units between March 8 and June 3, 2020. Central regulation for ECMO indications and pooling of resources were organised for the Greater Paris intensive care units, with six mobile ECMO teams available for the region. Details of complications (including ECMO-related complications, renal replacement therapy, and pulmonary embolism), clinical outcomes, survival status at 90 days after ECMO initiation, and causes of death are reported. Multivariable analysis was used to identify pre-ECMO variables independently associated with 90-day survival after ECMO.

Findings: The 302 patients included who underwent ECMO had a median age of 52 years (IQR 45-58) and Simplified Acute Physiology Score-II of 40 (31-56), and 235 (78%) of whom were men. 165 (55%) were transferred after cannulation by a mobile ECMO team. Before ECMO, 285 (94%) patients were prone positioned, median driving pressure was 18 cm HO (14-21), and median ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen was 61 mm Hg (IQR 54-70). During ECMO, 115 (43%) of 270 patients had a major bleeding event, 27 of whom had intracranial haemorrhage; 130 (43%) of 301 patients received renal replacement therapy; and 53 (18%) of 294 had a pulmonary embolism. 138 (46%) patients were alive 90 days after ECMO. The most common causes of death were multiorgan failure (53 [18%] patients) and septic shock (47 [16%] patients). Shorter time between intubation and ECMO (odds ratio 0·91 [95% CI 0·84-0·99] per day decrease), younger age (2·89 [1·41-5·93] for ≤48 years and 2·01 [1·01-3·99] for 49-56 years vs ≥57 years), higher pre-ECMO renal component of the Sequential Organ Failure Assessment score (0·67, 0·55-0·83 per point increase), and treatment in centres managing at least 30 venovenous ECMO cases annually (2·98 [1·46-6·04]) were independently associated with improved 90-day survival. There was no significant difference in survival between patients who had mobile and on-site ECMO initiation.

Interpretation: Beyond associations with similar factors to those reported on ECMO for non-COVID-19 ARDS, 90-day survival among ECMO-assisted patients with COVID-19 was strongly associated with a centre's experience in venovenous ECMO during the previous year. Early ECMO management in centres with a high venovenous ECMO case volume should be advocated, by applying centralisation and regulation of ECMO indications, which should also help to prevent a shortage of resources.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(21)00096-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055207PMC
April 2021

Pediatric Acute Alcohol Intoxication Admitted to the ICU: A Review of 102 Cases in France.

Crit Care Med 2021 Apr 19. Epub 2021 Apr 19.

Paediatric Intensive Care Unit, Kremlin Bicêtre University Hospital, AP-HP, Paris, France. Intensive Care Department, Grand Hôpital de l'Est Francilien, Jossigny Hospital, Marne la Vallée, France. Pediatric Intensive Care Department, Lyon University Hospital, Lyon, France. Intensive Care Department, Lariboisière University Hospital, AP-HP, Paris, France. Intensive Care Department, Lariboisière University Hospital, APHP, Paris, France. Pediatric Intensive Care Unit, Robert Debré University Hospital, AP-HP, Paris, France. Pediatric Intensive Care Unit, University Hospital, Lille, France. Pediatric Intensive Care Department, Hôpital Jeanne de Flandre, University Hospital, Lille, France. Intensive Care Department, Cochin University Hospital, AP-HP, Paris, France. Intensive Care Department, Cochin University Hospital, APHP, Paris, France. Pediatric Intensive Care Unit, Raymond Poincaré University Hospital, AP-HP, Garches, France.

Objectives: To describe the profile and clinical outcomes of children (<18 yr) admitted to intensive care for acute alcohol intoxication, with special attention to complications and to the subgroup that required intubation.

Design: Retrospective observational study.

Setting: Seven pediatric and three adult ICUs in France.

Patients: Children 1-17 yr admitted to intensive care for acute alcohol intoxication between January 1, 2010, and December 30, 2017.

Interventions: The study was observational and patients received standard care.

Measurements And Main Results: We included 102 patients, with 71 males (69.6%) and 31 females (30.4%). Mean age was not different between males and females (14.0 ± 3.0 yr [range, 2-17 yr] and 14.2 ± 1.3 yr [range, 11-17 yr]; p = 0.67); six children were younger than 10 years. Mean blood alcohol concentration was not significantly different in males and females (2.42 ± 0.86 and 2.20 ± 0.54 g/L, respectively; p = 0.51). Of the 102 patients, 58 (57%) required intubation. Factors significantly associated with requiring intubation were lower Glasgow Coma Scale score (p = 0.002), lower body temperature (p = 0.045), and higher blood alcohol concentration (p = 0.012); vascular filling, and electrolyte disturbances were not associated with needing intubation. Mean intubation time was 9.7 ± 5.2 hours. Among the 59 patients with Glasgow Coma Scale score less than 8, 12 did not require intubation. The most common metabolic disturbance was a high lactate level (48%), followed by hypokalemia (27.4%); 59 (58.2%) patients had hyperglycemia and three had hypoglycemia.

Conclusions: Male adolescents make up the majority of pediatric patients admitted to intensive care for acute alcohol intoxication. A need for intubation was associated with a worse Glasgow Coma Scale, lower body temperature, and higher blood alcohol concentration. Intubation was usually required for less than 12 hours. Other acute medical complications reported in adults with acute alcohol intoxication, such as electrolyte disturbances and aspiration pneumonia, were rare in our pediatric patients.
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http://dx.doi.org/10.1097/CCM.0000000000005032DOI Listing
April 2021

Management of Chloroquine and Hydroxychloroquine Poisoning: Do Not Miss the Time of Tracheal Intubation and Mechanical Ventilation.

West J Emerg Med 2021 Jan 11;22(2):454-455. Epub 2021 Jan 11.

IRCCS Maugeri Hospital and University of Pavia, Department of Toxicology, Pavia, Italy.

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http://dx.doi.org/10.5811/westjem.2020.10.49826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972374PMC
January 2021

Vascular access for renal replacement therapy among 459 critically ill patients: a pragmatic analysis of the randomized AKIKI trial.

Ann Intensive Care 2021 Apr 8;11(1):56. Epub 2021 Apr 8.

French National Institute of Health and Medical Research (INSERM), UMR_S1155, Remodeling and Repair of Renal Tissue, Hôpital Tenon, Sorbonne Université, 75020, Paris, France.

Background: Vascular access for renal replacement therapy (RRT) is routine question in the intensive care unit. Randomized trials comparing jugular and femoral sites have shown similar rate of nosocomial events and catheter dysfunction. However, recent prospective observational data on RRT catheters use are scarce. We aimed to assess the site of RRT catheter, the reasons for catheter replacement, and the complications according to site in a large population of critically ill patients with acute kidney injury.

Patients And Methods: We performed an ancillary study of the AKIKI study, a pragmatic randomized controlled trial, in which patients with severe acute kidney injury (KDIGO 3 classification) with invasive mechanical ventilation, catecholamine infusion or both were randomly assigned to either an early or a delayed RRT initiation strategy. The present study involved all patients who underwent at least one RRT session. Number of RRT catheters, insertion sites, factors potentially associated with the choice of insertion site, duration of catheter use, reason for catheter replacement, and complications were prospectively collected.

Results: Among the 619 patients included in AKIKI, 462 received RRT and 459 were finally included, with 598 RRT catheters. Femoral site was chosen preferentially (n = 319, 53%), followed by jugular (n = 256, 43%) and subclavian (n = 23, 4%). In multivariate analysis, continuous RRT modality was significantly associated with femoral site (OR = 2.33 (95% CI (1.34-4.07), p = 0.003) and higher weight with jugular site [88.9 vs 83.2 kg, OR = 0.99 (95% CI 0.98-1.00), p = 0.03]. Investigator site was also significantly associated with the choice of insertion site (p = 0.03). Cumulative incidence of catheter replacement did not differ between jugular and femoral site [sHR 0.90 (95% CI 0.64-1.25), p = 0.67]. Catheter dysfunction was the main reason for replacement (n = 47), followed by suspected infection (n = 29) which was actually seldom proven (n = 4). No mechanical complication (pneumothorax or hemothorax) occurred.

Conclusion: Femoral site was preferentially used in this prospective study of RRT catheters in 31 French intensive care units. The choice of insertion site depended on investigating center habits, weight, RRT modality. A high incidence of catheter infection suspicion led to undue replacement.
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http://dx.doi.org/10.1186/s13613-021-00843-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032839PMC
April 2021

Toxicity resulting from colchicine used to treat COVID-19 patients: a new challenge for clinical toxicologists.

Clin Toxicol (Phila) 2021 Mar 26:1-2. Epub 2021 Mar 26.

Department of Medical and Toxicological Critical Care, Federation of Toxicology APHP, Lariboisière Hospital, INSERM UMR-S1144, University of Paris, Paris, France.

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http://dx.doi.org/10.1080/15563650.2021.1904141DOI Listing
March 2021

A comprehensive insight into the role of zinc deficiency in the renin-angiotensin and kinin-kallikrein system dysfunctions in COVID-19 patients.

Saudi J Biol Sci 2021 Jun 16;28(6):3540-3547. Epub 2021 Mar 16.

Department of Medical and Toxicological Critical Care, Lariboisière Hospital, University of Paris, INSERM UMRS-1144, Paris, France.

Hypozincemia is prevalent in severe acute respiratory syndrome coronavirus-2 (SARS-COV-2)-infected patients and has been considered as a risk factor in severe coronavirus disease-2019 (COVID-19). Whereas zinc might affect SARS-COV-2 replication and cell entry, the link between zinc deficiency and COVID-19 severity could also be attributed to the effects of COVID-19 on the body metabolism and immune response. Zinc deficiency is more prevalent in the elderly and patients with underlying chronic diseases, with established deleterious consequences such as the increased risk of respiratory infection. We reviewed the expected effects of zinc deficiency on COVID-19-related pathophysiological mechanisms focusing on both the renin-angiotensin and kinin-kallikrein systems. Mechanisms and effects were extrapolated from the available scientific literature. Zinc deficiency alters angiotensin-converting enzyme-2 (ACE2) function, leading to the accumulation of angiotensin II, des-Arg9-bradykinin and Lys-des-Arg9-bradykinin, which results in an exaggerated pro-inflammatory response, vasoconstriction and pro-thrombotic effects. Additionally, zinc deficiency blocks the activation of the plasma contact system, a protease cascade initiated by factor VII activation. Suggested mechanisms include the inhibition of Factor XII activation and limitation of high-molecular-weight kininogen, prekallikrein and Factor XII to bind to endothelial cells. The subsequent accumulation of Factor XII and deficiency in bradykinin are responsible for increased production of inflammatory mediators and marked hypercoagulability, as typically observed in COVID-19 patients. To conclude, zinc deficiency may affect both the renin-angiotensin and kinin-kallikrein systems, leading to the exaggerated inflammatory manifestations characteristic of severe COVID-19.
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http://dx.doi.org/10.1016/j.sjbs.2021.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962980PMC
June 2021

Variation of drugs involved in acute drug toxicity presentations based on age and sex: an epidemiological approach based on European emergency departments.

Clin Toxicol (Phila) 2021 Mar 16:1-13. Epub 2021 Mar 16.

Emergency Department, Hospital Clínic, IDIBAPS, Barcelona, Spain.

Objective: To analyse the relative percentage of acute recreational drug toxicity emergency department (ED) presentations involving the main drug groups according to age and sex and investigate different patterns based on sex and age strata.

Methods: We analysed all patients with acute recreational drug toxicity included by the Euro-DEN Plus dataset (22 EDs in 14 European countries) between October 2013 and December 2016 (39 months). Drugs were grouped as: opioids, cocaine, cannabis, amphetamines, gamma-hydroxybutyrate (GHB), hallucinogens, new psychoactive substances (NPS), benzodiazepines and ketamine. Descriptive data by age and sex are presented and compared among age/sex categories and among drug families.

Results: Of 17,371 patients were included during the 39-month period, 17,198 (99.0%) had taken at least one of the investigated drugs (median age: 31 years; 23.9% female; ethanol co-ingestion recorded in 41.5%, unknown in 31.2%; multiple drug use in 37.9%). Opioids (in 31.4% of patients) and amphetamines (23.3%) were the most frequently involved and hallucinogens (1.9%) and ketamine (1.7%) the least. Overall, female patients were younger than males, both in the whole cohort (median age 29 vs. 32 years;  < 0.001) and in all drug groups except benzodiazepines (median age 36 vs. 36 years;  = 0.83). The relative proportion of each drug group was different at every age strata and some patterns could be clearly described: cannabis, NPS and hallucinogens were the most common in patients <20 years; amphetamines, ketamine and cocaine in the 20- to 39-year group; GHB/GBL in the 30- to 39-year group; and opioids and benzodiazepines in patients ≥40 years. Ethanol and other drug co-ingestion was more frequent at middle-ages, and multidrug co-ingestion was more common in females than males.

Conclusion: Differences in the drugs involved in acute drug toxicity presentations according to age and sex may be relevant for developing drug-prevention and education programs for some particular subgroups of the population based on the increased risk of adverse events in specific sex and/or age strata.
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http://dx.doi.org/10.1080/15563650.2021.1884693DOI Listing
March 2021

Temporal Trends of Out-of-Hospital Cardiac Arrests Without Resuscitation Attempt by Emergency Medical Services.

Circ Cardiovasc Qual Outcomes 2021 Mar 12;14(3):e006626. Epub 2021 Mar 12.

European Georges Pompidou Hospital, Cardiology Department, Paris, France (V.W., N.K., A.S., E.M., X.J.).

Background: Significant improvements in survival from out-of-hospital cardiac arrest (OHCA) have been reported; however, these are based only on data from OHCA in whom resuscitation is initiated by emergency medical services (EMS). We aimed to assess the characteristics and temporal trends of OHCA without resuscitation attempt by EMS.

Methods: Prospective population-based study between 2011 and 2016 in the Greater Paris area (6.7 million inhabitants). All cases of OHCA were included in collaboration with EMS units, 48 different hospitals, and forensic units.

Results: Among 15 207 OHCA (mean age 70.7±16.9 years, 61.6% male), 5486 (36.1%) had no resuscitation attempt by EMS. Factors that were independently associated with increase in likelihood of no resuscitation attempt included: age of patients (odds ratio, 1.06 per year [95% CI, 1.05-1.06], <0.001), female sex (odds ratio, 1.21 [95% CI, 1.10-1.32], =0.002), OHCA at home location (odds ratio, 3.38 [95%CI, 2.86-4.01], <0.001), and absence of bystander (odds ratio, 1.94 [95% CI, 1.74-2.16], <0.001). Overall, the annual number of OHCA increased by 9.1% (from 2923 to 3189, =0.028). This increase was related to an increase of the annual number of OHCA without resuscitation attempt by EMS by 26.3% (from 993 to 1253, =0.012), while the annual number of OHCA with resuscitation attempt by EMS did not significantly change (from 1930 to 1936, =0.416). Considering only cases with resuscitation attempt, survival rate at hospital discharge increased (from 7.3% to 9.5%, =0.02). However, when considering all OHCA, survival improvement did not reach statistical significance (from 4.8% to 5.7%, =0.17).

Conclusions: We demonstrated an increase of the total number of OHCA related to an increase of the number of OHCA without resuscitation attempt by EMS. This increasing proportion of OHCA without resuscitation attempt attenuates improvement in survival rates achieved in EMS-treated patients.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.006626DOI Listing
March 2021

Temporal Trends of Out-of-Hospital Cardiac Arrests Without Resuscitation Attempt by Emergency Medical Services.

Circ Cardiovasc Qual Outcomes 2021 Mar 12;14(3):e006626. Epub 2021 Mar 12.

European Georges Pompidou Hospital, Cardiology Department, Paris, France (V.W., N.K., A.S., E.M., X.J.).

Background: Significant improvements in survival from out-of-hospital cardiac arrest (OHCA) have been reported; however, these are based only on data from OHCA in whom resuscitation is initiated by emergency medical services (EMS). We aimed to assess the characteristics and temporal trends of OHCA without resuscitation attempt by EMS.

Methods: Prospective population-based study between 2011 and 2016 in the Greater Paris area (6.7 million inhabitants). All cases of OHCA were included in collaboration with EMS units, 48 different hospitals, and forensic units.

Results: Among 15 207 OHCA (mean age 70.7±16.9 years, 61.6% male), 5486 (36.1%) had no resuscitation attempt by EMS. Factors that were independently associated with increase in likelihood of no resuscitation attempt included: age of patients (odds ratio, 1.06 per year [95% CI, 1.05-1.06], <0.001), female sex (odds ratio, 1.21 [95% CI, 1.10-1.32], =0.002), OHCA at home location (odds ratio, 3.38 [95%CI, 2.86-4.01], <0.001), and absence of bystander (odds ratio, 1.94 [95% CI, 1.74-2.16], <0.001). Overall, the annual number of OHCA increased by 9.1% (from 2923 to 3189, =0.028). This increase was related to an increase of the annual number of OHCA without resuscitation attempt by EMS by 26.3% (from 993 to 1253, =0.012), while the annual number of OHCA with resuscitation attempt by EMS did not significantly change (from 1930 to 1936, =0.416). Considering only cases with resuscitation attempt, survival rate at hospital discharge increased (from 7.3% to 9.5%, =0.02). However, when considering all OHCA, survival improvement did not reach statistical significance (from 4.8% to 5.7%, =0.17).

Conclusions: We demonstrated an increase of the total number of OHCA related to an increase of the number of OHCA without resuscitation attempt by EMS. This increasing proportion of OHCA without resuscitation attempt attenuates improvement in survival rates achieved in EMS-treated patients.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.006626DOI Listing
March 2021

Prior Exposure to Angiotensin II Receptor Blockers in Patients With Septic Shock to Individualize Mean Arterial Pressure Target? A Post Hoc Analysis of the Sepsis and Mean Arterial Pressure (SEPSISPAM) Trial.

Crit Care Med 2021 04;49(4):e412-e422

Department of Medical Intensive Care, Bicêtre University Hospital, AP-HP, Paris-Saclay University, Le Kremlin Bicêtre, France.

Objectives: Individualizing a target mean arterial pressure is challenging during the initial resuscitation of patients with septic shock. The Sepsis and Mean Arterial Pressure (SEPSISPAM) trial suggested that targeting high mean arterial pressure might reduce the occurrence of acute kidney injury among those included patients with a past history of chronic hypertension. We investigated whether the class of antihypertensive medications used before the ICU stay in chronic hypertensive patients was associated with the severity of acute kidney injury occurring after inclusion, according to mean arterial pressure target.

Design: Post hoc analysis of the SEPSISPAM trial.

Setting: The primary outcome was the occurrence of severe acute kidney injury during the ICU stay defined as kidney disease improving global outcome stage 2 or higher. Secondary outcomes were mortality at day 28 and mortality at day 90.

Patients: All patients with chronic hypertension included in SEPSISPAM with available antihypertensive medications data in the hospitalization report were included.

Measurements And Main Results: We analyzed 297 patients. Severe acute kidney injury occurred in 184 patients, without difference according to pre-ICU exposure to antihypertensive medications. Patients with pre-ICU exposure to angiotensin II receptor blockers had significantly less severe acute kidney injury in the high mean arterial pressure target group (adjusted odd ratio 0.24 with 95% CI [0.09-0.66]; p = 0.006). No statistically significant association was found after adjustment for pre-ICU exposure to antihypertensive medications and survival.

Conclusions: Our results suggest that patients with septic shock and chronic hypertension treated with angiotensin II receptor blocker may benefit from a high mean arterial pressure target to reduce the risk of acute kidney injury occurrence.
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http://dx.doi.org/10.1097/CCM.0000000000004872DOI Listing
April 2021

Oral corticoid, aspirin, anticoagulant, colchicine, and furosemide to improve the outcome of hospitalized COVID-19 patients - the COCAA-COLA cohort study.

J Infect 2021 06 9;82(6):276-316. Epub 2021 Feb 9.

Department of Medical and Toxicological Critical Care, Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, INSERM UMRS-1144, 75010, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2021.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871882PMC
June 2021

Extracorporeal treatment for calcium channel blocker poisoning: systematic review and recommendations from the EXTRIP workgroup.

Clin Toxicol (Phila) 2021 May 8;59(5):361-375. Epub 2021 Feb 8.

Research Center, CIUSSS du Nord-de-l'île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, QC, Canada.

Background: Calcium channel blockers (CCBs) are commonly used to treat conditions such as arterial hypertension and supraventricular dysrhythmias. Poisoning from these drugs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in the management of CCB poisoning.

Methods: We conducted systematic reviews of the literature, screened studies, extracted data, summarized findings, and formulated recommendations following published EXTRIP methods.

Results: A total of 83 publications (6 and 1 animal experiments, 55 case reports or case series, 19 pharmacokinetic studies, 1 cohort study and 1 systematic review) met inclusion criteria regarding the effect of ECTR. Toxicokinetic or pharmacokinetic data were available on 210 patients (including 32 for amlodipine, 20 for diltiazem, and 52 for verapamil). Regardless of the ECTR used, amlodipine, bepridil, diltiazem, felodipine, isradipine, mibefradil, nifedipine, nisoldipine, and verapamil were considered not dialyzable, with variable levels of evidence, while no dialyzability grading was possible for nicardipine and nitrendipine. Data were available for clinical analysis on 78 CCB poisoned patients (including 32 patients for amlodipine, 16 for diltiazem, and 23 for verapamil). Standard care (including high dose insulin euglycemic therapy) was not systematically administered. Clinical data did not suggest an improvement in outcomes with ECTR. Consequently, the EXTRIP workgroup recommends against using ECTR in addition to standard care for patients severely poisoned with either amlodipine, diltiazem or verapamil (strong recommendations, very low quality of the evidence (1D)). There were insufficient clinical data to draft recommendation for other CCBs, although the workgroup acknowledged the low dialyzability from, and lack of biological plausibility for, ECTR.

Conclusions: Both dialyzability and clinical data do not support a clinical benefit from ECTRs for CCB poisoning. The EXTRIP workgroup recommends against using extracorporeal methods to enhance the elimination of amlodipine, diltiazem, and verapamil in patients with severe poisoning.
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http://dx.doi.org/10.1080/15563650.2020.1870123DOI Listing
May 2021

The role of brain barriers in the neurokinetics and pharmacodynamics of lithium.

Pharmacol Res 2021 Apr 4;166:105480. Epub 2021 Feb 4.

Université de Paris, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France; Biologie du Médicament, AP-HP, Hôpital Cochin, 27 rue du Faubourg, St. Jacques, 75679 Paris Cedex 14, France. Electronic address:

Lithium (Li) is the most widely used mood stabilizer in treating patients with bipolar disorder. However, more than half of the patients do not or partially respond to Li therapy, despite serum Li concentrations in the serum therapeutic range. The exact mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) relationships of lithium are still poorly understood and alteration in the brain pharmacokinetics of lithium may be one of the mechanisms explaining the variability in the clinical response to Li. Brain barriers such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a crucial role in controlling blood-to-brain and brain-to-blood exchanges of various molecules including central nervous system (CNS) drugs. Recent in vivo studies by nuclear resonance spectroscopy revealed heterogenous brain distribution of Li in human that were not always correlated with serum concentrations, suggesting regional and variable transport mechanisms of Li through the brain barriers. Moreover, alteration in the functionality and integrity of brain barriers is reported in various CNS diseases, as a cause or a consequence and in this regard, Li by itself is known to modulate BBB properties such as the expression and activity of various transporters, metabolizing enzymes, and the specialized tight junction proteins on BBB. In this review, we will focus on recent knowledge into the role of the brain barriers as key-element in the Li neuropharmacokinetics which might improve the understanding of PK-PD of Li and its interindividual variability in drug response.
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http://dx.doi.org/10.1016/j.phrs.2021.105480DOI Listing
April 2021

Pathophysiological Processes Underlying the High Prevalence of Deep Vein Thrombosis in Critically Ill COVID-19 Patients.

Front Physiol 2020 8;11:608788. Epub 2021 Jan 8.

Department of Clinical Physiology, Hôpital Lariboisière, APHP, Faculté de Santé, Université de Paris, Paris, France.

Coronavirus disease 2019 (COVID-19) predisposes to deep vein thrombosis (DVT) and pulmonary embolism (PE) particularly in mechanically ventilated adults with severe pneumonia. The extremely high prevalence of DVT in the COVID-19 patients hospitalized in the intensive care unit (ICU) has been established between 25 and 84% based on studies including systematic duplex ultrasound of the lower limbs when prophylactic anticoagulation was systematically administrated. DVT prevalence has been shown to be markedly higher than in mechanically ventilated influenza patients (6-8%). Unusually high inflammatory and prothrombotic phenotype represents a striking feature of COVID-19 patients, as reflected by markedly elevated reactive protein C, fibrinogen, interleukin 6, von Willebrand factor, and factor VIII. Moreover, in critically ill patients, venous stasis has been associated with the prothrombotic phenotype attributed to COVID-19, which increases the risk of thrombosis. Venous stasis results among others from immobilization under muscular paralysis, mechanical ventilation with high positive end-expiratory pressure, and pulmonary microvascular network injuries or occlusions. Venous return to the heart is subsequently decreased with increase in central and peripheral venous pressures, marked proximal and distal veins dilation, and drops in venous blood flow velocities, leading to a spontaneous contrast "sludge pattern" in veins considered as prothrombotic. Together with endothelial lesions and hypercoagulability status, venous stasis completes the Virchow triad and considerably increases the prevalence of DVT and PE in critically ill COVID-19 patients, therefore raising questions regarding the optimal doses for thromboprophylaxis during ICU stay.
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http://dx.doi.org/10.3389/fphys.2020.608788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820906PMC
January 2021

Is Lockdown Effective in Limiting SARS-CoV-2 Epidemic Progression?-a Cross-Country Comparative Evaluation Using Epidemiokinetic Tools.

J Gen Intern Med 2021 03 13;36(3):746-752. Epub 2021 Jan 13.

University of Paris, INSERM UMRS-1144, , Paris, France.

Background: To date, the risk/benefit balance of lockdown in controlling severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemic is controversial.

Objective: We aimed to investigate the effectiveness of lockdown on SARS-CoV-2 epidemic progression in nine different countries (New Zealand, France, Spain, Germany, the Netherlands, Italy, the UK, Sweden, and the USA).

Design: We conducted a cross-country comparative evaluation using a susceptible-infected-recovered (SIR)-based model completed with pharmacokinetic approaches.

Main Measures: The rate of new daily SARS-CoV-2 cases in the nine countries was calculated from the World Health Organization's published data. Using a SIR-based model, we determined the infection (β) and recovery (γ) rate constants; their corresponding half-lives (t and t); the basic reproduction numbers (R as β/γ); the rates of susceptible S(t), infected I(t), and recovered R(t) compartments; and the effectiveness of lockdown. Since this approach requires the epidemic termination to build the (I) compartment, we determined S(t) at an early epidemic stage using simple linear regressions.

Key Results: In New Zealand, France, Spain, Germany, the Netherlands, Italy, and the UK, early-onset stay-at-home orders and restrictions followed by gradual deconfinement allowed rapid reduction in SARS-CoV-2-infected individuals (t ≤ 14 days) with R ≤ 1.5 and rapid recovery (t ≤ 18 days). By contrast, in Sweden (no lockdown) and the USA (heterogeneous state-dependent lockdown followed by abrupt deconfinement scenarios), a prolonged plateau of SARS-CoV-2-infected individuals (terminal t of 23 and 40 days, respectively) with elevated R (4.9 and 4.4, respectively) and non-ending recovery (terminal t of 112 and 179 days, respectively) was observed.

Conclusions: Early-onset lockdown with gradual deconfinement allowed shortening the SARS-CoV-2 epidemic and reducing contaminations. Lockdown should be considered as an effective public health intervention to halt epidemic progression.
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http://dx.doi.org/10.1007/s11606-020-06345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806254PMC
March 2021

Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: a European multicenter cohort study.

Intensive Care Med 2021 02 3;47(2):188-198. Epub 2021 Jan 3.

Assistance Publique-Hôpitaux de Paris, CHU Henri Mondor, Service de réanimation médicale, Créteil, France.

Purpose: Although patients with SARS-CoV-2 infection have several risk factors for ventilator-associated lower respiratory tract infections (VA-LRTI), the reported incidence of hospital-acquired infections is low. We aimed to determine the relationship between SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, and the incidence of VA-LRTI.

Methods: Multicenter retrospective European cohort performed in 36 ICUs. All adult patients receiving invasive mechanical ventilation > 48 h were eligible if they had: SARS-CoV-2 pneumonia, influenza pneumonia, or no viral infection at ICU admission. VA-LRTI, including ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP), were diagnosed using clinical, radiological and quantitative microbiological criteria. All VA-LRTI were prospectively identified, and chest-X rays were analyzed by at least two physicians. Cumulative incidence of first episodes of VA-LRTI was estimated using the Kalbfleisch and Prentice method, and compared using Fine-and Gray models.

Results: 1576 patients were included (568 in SARS-CoV-2, 482 in influenza, and 526 in no viral infection groups). VA-LRTI incidence was significantly higher in SARS-CoV-2 patients (287, 50.5%), as compared to influenza patients (146, 30.3%, adjusted sub hazard ratio (sHR) 1.60 (95% confidence interval (CI) 1.26 to 2.04)) or patients with no viral infection (133, 25.3%, adjusted sHR 1.7 (95% CI 1.2 to 2.39)). Gram-negative bacilli were responsible for a large proportion (82% to 89.7%) of VA-LRTI, mainly Pseudomonas aeruginosa, Enterobacter spp., and Klebsiella spp.

Conclusions: The incidence of VA-LRTI is significantly higher in patients with SARS-CoV-2 infection, as compared to patients with influenza pneumonia, or no viral infection after statistical adjustment, but residual confounding may still play a role in the effect estimates.
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http://dx.doi.org/10.1007/s00134-020-06323-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778569PMC
February 2021

Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort.

Clin Microbiol Infect 2020 Dec 13. Epub 2020 Dec 13.

Université de Paris, Laboratoire de Parasitologie-Mycologie, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Molecular Mycology Unit, CNRS UMR2000, National Reference Centre for Invasive Mycoses and Antifungals (NRCMA), Institut Pasteur, Paris, France. Electronic address:

Objectives: The main objective of this study was to determine the incidence of invasive pulmonary aspergillosis (IPA) in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU), and to describe the patient characteristics associated with IPA occurrence and to evaluate its impact on prognosis.

Methods: We conducted a retrospective cohort study including all successive COVID-19 patients, hospitalized in four ICUs, with secondary deterioration and one or more respiratory samples sent to the mycology department. We used a strengthened IPA testing strategy including seven mycological criteria. Patients were classified as probable IPA according to the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group Education and Research Consortium (MSGERC) classification if immunocompromised, and according to the recent COVID-19-associated IPA classification otherwise.

Results: Probable IPA was diagnosed in 21 out of the 366 COVID-19 patients (5.7%) admitted to the ICU and in the 108 patients (19.4%) who underwent respiratory sampling for deterioration. No significant differences were observed between patients with and without IPA regarding age, gender, medical history and severity on admission and during hospitalization. Treatment with azithromycin for ≥3 days was associated with the diagnosis of probable IPA (odds ratio 3.1, 95% confidence interval 1.1-8.5, p = 0.02). A trend was observed with high-dose dexamethasone and the occurrence of IPA. Overall mortality was higher in the IPA patients (15/21, 71.4% versus 32/87, 36.8%, p < 0.01).

Conclusion: IPA is a relatively frequent complication in severe COVID-19 patients and is responsible for increased mortality. Azithromycin, known to have immunomodulatory properties, may contribute to increase COVID-19 patient's susceptibility to IPA.
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http://dx.doi.org/10.1016/j.cmi.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733556PMC
December 2020

Ultrasound guidance and risk for central venous catheter-related infections in the ICU. A post hoc analysis of individual data of three multi-centric randomized trials.

Clin Infect Dis 2020 Dec 5. Epub 2020 Dec 5.

University of Paris, INSERM IAME, U1137, Team DesCID, Paris, France.

Background: Ultrasound (US) guidance is frequently used in critically ill patients for central venous catheter (CVC) insertion. The effect of US on infectious risk remains controversial and randomized-controlled trials (RCTs) assessed mainly non-infectious complications. This study assessed infectious risk associated with catheters inserted with US guidance versus use of anatomical 'landmarks' (AL).

Methods: We used individual data from three large RCTs for which a prospective, high-quality data collection was performed. Adult patients were recruited in various intensive care units (ICU) in France as soon as they required short-term CVC insertion. We applied marginal Cox models with inverse probability weighting to estimate the effect of US-guided insertion on catheter-related bloodstream infections (CRBSI, primary outcome) and major catheter-related infections (MCRI, secondary outcome).We also evaluated insertion site colonization at catheter removal.

Results: Our post hoc analysis included 4636 patients and 5502 catheters inserted in 2088 jugular, 1733 femoral and 1681 subclavian veins, respectively, in 19 ICUs. US was used for 2147 catheter insertions. Among jugular and femoral CVCs and after weighting, we found an association between US and CRBSI (HR 2.21, 95% CI 1.17-4.16, p=0.014) and between US and MCRI (HR 1.55, 95% CI 1.01-2.38, p=0.045). Catheter insertion site colonization at removal was more common in the US-guided group (p=0.0045) among jugular and femoral CVCs in situ for ≤7 days (n=606).

Conclusions: In prospectively collected data in which catheters were not randomized to insertion by US or AL, US guidance was associated with increased risk of infection.
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http://dx.doi.org/10.1093/cid/ciaa1817DOI Listing
December 2020