Cerebral microbleeds in the poisoned patient: An observational magnetic resonance imaging study.

Critical illness-associated cerebral microbleeds of poorly understood pathophysiology have been observed on magnetic resonance imaging (MRI) in severely hypoxaemic patients similarly to high-altitude cerebral oedema patients. The prevalence and circumstances of occurrence of such cerebral microbleeds in the severely poisoned patients are unknown. We retrospectively reviewed all cerebral MRIs performed in the poisoned patients with atypical neurological presentation or outcome admitted to our intensive care unit in 2014-2021. Three out of 64 patients (4.7%) investigated with cerebral MRI among the 2986 severely poisoned patients presented cerebral microbleeds. Microbleeds were localized in the white cerebral matter mainly in the corpus callosum. Ingested toxicants included dichlorvos, methadone and tramadol. Patients were found comatose with possibly prolonged severe hypoxaemia requiring prompt tracheal intubation and mechanical ventilation. They presented delayed arousal and dysexecutive syndrome leading to sequelae. Microbleeds on MRI can occur in the critically ill poisoned patients and seems to be a multifactorial phenomenon. A direct relationship with the toxicant seems improbable. Physicians should be aware of such a non-specific complication accounting for sequelae.

Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?

In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells in vitro and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy.

Life-Threatening Cardiogenic Shock Related to Venlafaxine Poisoning-A Case Report with Metabolomic Approach.

Metabolomics in clinical toxicology aim at reliably identifying and semi-quantifying a broad array of endogenous and exogenous metabolites using dedicated analytical methods. Here, we developed a three-step-based workflow to investigate the metabolic impact of the antidepressant drug venlafaxine in a poisoned patient who developed life-threatening cardiac failure managed with extracorporeal membrane oxygenation. Both targeted quantitative and untargeted semi-quantitative metabolomic analyses using liquid chromatography hyphenated to high-resolution tandem mass spectrometry were performed to determine the plasma kinetics of venlafaxine, O-desmethyl-venlafaxine, and N-desmethyl-venlafaxine and to identify sixteen different venlafaxine-derived metabolites including one unknown (i.e., venlafaxine conjugated to a hexosyl-radical), respectively. Correlations between the quantitative metabolomic data and annotated endogenous metabolites suggested impaired amino acid and lipid metabolism, Krebs cycle, and kynurenine pathway. This preliminary study represents a first step towards a more extensive application of toxicometabolomics in clinical toxicology and a useful workflow to identify the biomarkers of toxicity.

Extracorporeal life support in cardiotoxicant poisoning-A narrative review.

Extracorporeal life support (ECLS) improves circulation in life-threatening cardiac dysfunction or arrest patients. Its benefits in drug-induced cardiovascular complications are debated. Indications and outcomes are poorly established. We performed a narrative review discussing ECLS indications, timing and results in cardiotoxicant-poisoned patients. The review was focused on antiarrhythmic drugs and aluminium phosphide. Literature analysis was limited to the past 30 years in adults. Most reports were single cases and retrospective except one prospective case series of limited size, two of them controlled. ECLS indications and timing were at the discretion of physicians in charge but mostly included persistent cardiovascular failure despite elevated doses of inotropic/vasopressor support associated with elevated blood lactate concentrations (usually, >5 mmol/L) and collapsed left ventricular ejection fraction (LVEF; usually, ≤40%). Survival improved using ECLS versus standard care in one study. Survival was ~80% if ECLS was implemented in refractory cardiovascular failure and 25%-66% if implemented in cardiac arrest. In two controlled studies, survival of ECLS-treated aluminium phosphide-poisoned patients was improved versus standard care, if implemented in the presence of systolic blood pressure ≤80 mmHg despite inotropic/vasopressor treatment, arterial pH ≤ 7.0 and LVEF ≤ 40%. Despite low-to-moderate level of evidence, ECLS seems effective to improve survival in selected cardiotoxicant-poisoned patients. Selection criteria need clarification.

[Substitution treatments for opiate-dependent users. An experience of the Integrated Addiction Treatment Center in Dakar]. / Traitement de substitution des usagers dépendants des opiacés - L'expérience du Centre de prise en charge intégré des addictions de Dakar.

Methadone and buprenorphine are the two maintenance treatments in opiate addicts authorised in France since the end of the 1990's. More recently, some African countries such as Senegal have implemented a new health policy focused on reducing the risks by encouraging the use of methadone as maintenance treatment. The objectives of maintenance therapy are to reduce morbidity and mortality related to the consumption of heroin and other street opioids, to promote the integration of drug users into the healthcare system, and more generally, to improve their social integration. However, this strategy might have limitations in practice. Here, we report the experience of the Integrated Addiction Treatment Center in Dakar, Senegal, and discuss ethical considerations at both the individual and collective levels, which may improve care of opiate-dependent users in practice, especially in Africa.

Title: Traitement de substitution des usagers dépendants des opiacés - L'expérience du Centre de prise en charge intégré des addictions de Dakar. Abstract: La méthadone et la buprénorphine sont les deux traitements de substitution des opiacés autorisés en France depuis la fin des années 1990. Plus récemment, certains pays africains, comme le Sénégal, ont mis en place une nouvelle politique de santé axée sur la réduction des risques, en encourageant le recours aux traitements de substitution des opiacés. Les objectifs de la substitution sont de réduire la morbi-mortalité liée à la consommation d'héroïne ou d'autres opioïdes de rue, de favoriser l'insertion des usagers de drogue dans le système de soins, et, plus généralement, de faciliter leur insertion sociale. Cette nouvelle stratégie trouve néanmoins des limites dans la pratique. Nous rapportons dans cette revue l'expérience du Centre de prise en charge intégré des addictions de Dakar, au Sénégal, et proposons une réflexion éthique, tant individuelle que collective, afin d'améliorer le traitement de substitution des opiacés, notamment en Afrique.

Impact of Early Limitation of Therapeutic Effort in Elderly COVID-19 Patients Admitted to the Intensive Care Unit-A Cohort Study.

(1) Background: Admission to the ICU and intensity of care provided to elderly COVID-19 patients are difficult choices guided by the expected patient-centered benefits. However, the impact of an early discussion of limitation of therapeutic effort (LTE) has been poorly investigated. (2) Methods: We performed a single-center retrospective cohort study including all ≥70-year-old COVID-19 patients admitted to the ICU. Factors associated with early LTE discussion (defined as before or up to 2 days post-ICU admission) and in-hospital mortality were evaluated. (3) Results: Eighty-two patients (59 M/23 F; 78 years (74−82) [median (interquartile range)]; 43/82 with LTE) were included. The in-hospital mortality rate was 55%. Early LTE was decided upon for 22/82 patients (27%), more frequently in older (p < 0.001) and frailer patients (p = 0.004). Using a multivariable logistic regression model including clinical frailty scale grade ≥4, hospital acquisition of COVID-19, ventilation support modality and SOFA score on admission, early LTE was not associated with mortality (adjusted odds ratio = 0.57 (0.15−2.00), p = 0.39). LTE resulted in less frequent invasive mechanical ventilation (23% versus 65%, p = 0.001), renal replacement therapy (5% versus 27%, p = 0.03) and norepinephrine infusion (23% versus 60%, p = 0.005), and shorter ICU stay (6 days (2−12) versus 14 days (7−24), p = 0.001). (4) Conclusions: In this small sample exploratory study, we were unable to demonstrate any increase in in-hospital mortality associated with early LTE discussion in elderly COVID-19 patients while reducing the use of organ support techniques. These findings require confirmation in larger studies.

Massive tramadol ingestion resulting in fatal brain injury - a pharmacokinetic study with discussion on the involved mechanisms of toxicity.

BACKGROUND: Tramadol-attributed toxicity may involve opioid-like, serotoninergic, and noradrenergic mechanisms. We investigated the mechanisms of toxicity in a massive tramadol ingestion case by examining serial clinical, imaging, electroencephalography, pharmacokinetics, and genotyping data. CASE REPORT: A 32-year-old female who presumably ingested 9000 mg sustained-release tramadol was found comatose without hypoglycemia, bradypnea, hypotension, marked hypoxemia or seizures. She developed eyelid myoclonus and non-reactive mydriasis. Electroencephalogram showed non-reactive encephalopathy. MRI showed extensive brain injury. Despite supportive care and ventricular derivation, brain death occurred on day 12. METHODS: Plasma concentrations of tramadol and metabolites were measured using a liquid chromatography-tandem mass spectrometry assay. Genotyping for the presence of metabolizing cytochrome P450 (CYP) gene polymorphisms was performed. RESULTS: Plasma concentrations of tramadol and metabolites were extremely high (∼70-fold the therapeutic concentrations) and slowly decreased during the first ∼146 h post-admission, possibly due to prolonged gastrointestinal absorption. Elimination half-lives were 2-3-fold longer than usual values. The patient was an intermediate CYP2D6 metabolizer with decreased CYP3A4 and CYP2B6 activities. Clinical and electroencephalographic data did not support the hypotheses of opioid or serotoninergic toxicity nor prolonged/repeated seizures. Based on serial imaging showing progressive extension of ischemic edema in the context of prolonged high plasma concentrations, we hypothesized a cerebral vasospasm as mechanism of injury. CONCLUSION: Massive tramadol ingestion with prolonged high plasma concentrations can result in severe brain injury, possibly involving vasospasm.

Factors associated with prolonged intensive care stay among self-poisoned patients.

CONTEXT: Since recovery or death is generally observed within a few days after intensive care unit (ICU) admission of self-poisoned patients in the developed countries, reasons for the prolonged ICU stay are of interest as they have been poorly investigated. We aimed to identify the characteristics, risk factors, outcome, and predictors of death in self-poisoned patients requiring prolonged ICU management. METHODS: We conducted an eight-year single-center cohort study including all self-poisoned patients who stayed at least seven days in the ICU. Patients admitted with drug adverse events and chronic overdoses were excluded. Using multivariate analyses, we investigated risk factors for prolonged ICU stay in comparison with a group of similar size of self-poisoned patients with <7day-ICU stay and studied risk factors for death. RESULTS: Among 2,963 poisoned patients admitted in the ICU during the study period, the number who stayed beyond seven days was small (398/2,963, 13.1%), including 239 self-poisoned patients (125 F/114M; age, 51 years [38-65] (median [25th-75th percentiles]); SAPSII, 56 [43-69]). Involved toxicants included psychotropic drugs (59%), cardiotoxicants (31%), opioids (15%) and street drugs (13%). When compared with patients who stayed <7days in the ICU, acute kidney injury (odds ratio (OR), 3.15; 95% confidence interval (1.36-7.39); p = .008), multiorgan failure (OR, 8.06 (3.43-19.9); p < .001), aspiration pneumonia (OR, 8.48 (4.28-17.3); p < .001), and delayed awakening related to the persistent toxicant effects, hypoxic encephalopathy and/or oversedation (OR, 8.64 (2.58-40.7); p = .002) were independently associated with prolonged ICU stay. In-hospital mortality rate was 9%. Cardiac arrest occurring in the prehospital setting and during the first hours of ICU management (OR, 27.31 (8.99-158.76); p < .001) and delayed awakening (OR, 14.94 (6.27-117.44); p < .001) were independently associated with increased risk of death, whereas exposure to psychotropic drugs (OR, 0.08 (0.02-0.36); p = .002) was independently associated with reduced risk of death. CONCLUSION: Self-poisoned patients with prolonged ICU stay of ≥7days are characterized by concerning high rates of morbidities and poisoning-attributed complications. Acute kidney injury, multiorgan failure, aspiration pneumonia, and delayed awakening are associated with ICU stay prolongation. Cardiac arrest occurrence and delayed awakening are predictive of death. Further studies should focus on the role of early goal-directed therapy and patient-targeted sedation in reducing ICU length of stay among self-poisoned patients.

Cytological patterns of bronchoalveolar lavage fluid in mechanically ventilated COVID-19 patients on extracorporeal membrane oxygenation.

INTRODUCTION: Coronavirus disease-2019 (COVID-19) may lead to acute respiratory distress syndrome requiring extracorporeal membrane oxygenation (ECMO). Patterns of inflammatory bronchoalveolar cells in COVID-19 patients treated with ECMO are not well described. OBJECTIVE: We aimed to describe inflammatory cell subpopulations in blood and bronchoalveolar lavages (BALs) obtained in critically ill COVID-19 patients shortly after ECMO implementation. METHODS: BAL was performed in the middle lobe in 12 consecutive ECMO-treated COVID-19 patients. Trained cytologists analyzed peripheral blood and BAL cells using flow cytometry and routine staining, respectively. Data were interpreted in relation to dexamethasone administration and weaning from ECMO and ventilator. RESULTS: High neutrophil proportions (66% to 88% of total cells) were observed in the absence of bacterial superinfection and more frequently in dexamethasone-free patients (83% [82-85] vs. 29% [8-68], P = 0.006), suggesting that viral infection could be responsible of predominantly neutrophilic lung inflammation. Successful weaning from ECMO/ventilator could not be predicted by the peripheral white blood and BAL cell pattern. CONCLUSION: High neutrophil proportions can be observed in critically ill COVID-19 patients despite the lack of microbiological evidence on BAL of bacterial superinfection. Dexamethasone was associated with lower neutrophil proportions in BAL. Our study was probably underpowered to provide BAL cell pattern helpful to predict weaning from ECMO/ventilator.

Cumulative Radiation Exposure in Covid-19 Patients Admitted to the Intensive Care Unit.

Medical imaging plays a major role in coronavirus disease-2019 (COVID-19) patient diagnosis and management. However, the radiation dose received from medical procedures by these patients has been poorly investigated. We aimed to estimate the cumulative effective dose (CED) related to medical exposure in COVID-19 patients admitted to the intensive care unit (ICU) in comparison to the usual critically ill patients. We designed a descriptive cohort study including 90 successive ICU COVID-19 patients admitted between March and May 2020 and 90 successive non-COVID-19 patients admitted between March and May 2019. In this study, the CED resulting from all radiological examinations was calculated and clinical characteristics predictive of higher exposure risk identified. The number of radiological examinations was 12.0 (5.0-26.0) [median (interquartile range) in COVID-19 vs. 4.0 (2.0-8.0) in non-COVID-19 patient (P < 0.001)]. The CED during a four-month period was 4.2 mSv (1.9-11.2) in the COVID-19 vs. 1.2 mSv (0.13-6.19) in the non-COVID-19 patients (P < 0.001). In the survivors, the CED in COVID-19 vs. non-COVID-19 patients was ≥100 mSv in 3% vs. 0%, 10-100 mSv in 23% vs. 15%, 1-10 mSv in 56% vs. 30% and <1 mSv in 18% vs. 55%. The CED (P < 0.001) and CED per ICU hospitalization day (P = 0.004) were significantly higher in COVID-19 than non-COVID-19 patients. The CED correlated significantly with the hospitalization duration (r = 0.45, P < 0.001) and the number of conventional radiological examinations (r = 0.8, P < 0.001). To conclude, more radiological examinations were performed in critically ill COVID-19 patients than non-COVID-19 patients resulting in higher CED. In COVID-19 patients, contribution of strategies to limit CED should be investigated in the future.

L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships.

BACKGROUND: Valproic acid (VPA) poisoning is responsible for life-threatening neurological and metabolic impairments. Despite only low-level evidence of effectiveness, L-carnitine has been used for years to prevent or reverse VPA-related toxicity. We aimed to evaluate the effects of L-carnitine used to treat acute VPA poisoning on the time-course of plasma VPA concentrations and VPA-related toxicity. We designed a single-center cohort study including all VPA-poisoned patients admitted to the intensive care unit. We studied VPA toxicokinetics using a nonlinear mixed-effects model-based population approach and modeled individual plasma VPA/blood lactate concentration relationships. Then, we evaluated L-carnitine-attributed effects by comparing VPA elimination half-lives and time-courses of blood lactate levels and organ dysfunction [assessed by the Sequential Organ Failure Assessment (SOFA) score] between matched L-carnitine-treated and non-treated patients using a multivariate analysis including a propensity score. RESULTS: Sixty-nine VPA-poisoned patients (40F/29 M; age, 41 years [32-47]) (median [25th-75th percentiles]; SOFA score, 4 [1-6]) were included. The presumed VPA ingested dose was 15 g [10-32]. Plasma VPA concentration on admission was 231 mg/L [147-415]. The most common manifestations were coma (70%), hyperlactatemia (3.9 mmol/L [2.7-4.9]) and hyperammonemia (127 mmol/L [92-159]). VPA toxicokinetics well fitted a one-compartment linear model with a mean elimination half-life of 22.9 h (coefficient of variation, 28.1%). Plasma VPA (C)/blood lactate concentration (E) relationships were well described by an exponential growth equation [[Formula: see text]; with baseline E0 = 1.3 mmol/L (43.9%) and rate constant of the effect, k = 0.003 L/mg (59.5%)]. Based on a multivariate analysis, peak blood lactate concentration was the only factor independently associated with L-carnitine administration (odds ratio, 1.9, 95% confidence interval, 1.2-2.8; P = 0.004). We found no significant contribution of L-carnitine to enhancing VPA elimination, accelerating blood lactate level normalization and/or preventing organ dysfunction. CONCLUSIONS: VPA poisoning results in severe toxicity. While L-carnitine does not contribute to enhancing VPA clearance, its impact on accelerating blood lactate level normalization and/or preventing organ dysfunction remains uncertain. Investigating VPA toxicokinetics and concentration/effect relationships may help understanding how to improve VPA-poisoned patient management.

Case series of massive direct oral anticoagulant ingestion-Treatment and pharmacokinetics data.

BACKGROUND: Direct oral anticoagulants (DOAC) are widely used due to favourable benefit/risk ratio. However, consequences of massive ingestion have been poorly investigated. OBJECTIVES: We aimed to report outcome and pharmacokinetic parameters in patients who massively ingested DOACs. METHODS: We conducted a 5-year cohort study including consecutive massive DOAC ingestion patients admitted to two critical care departments. Patients were managed in accordance with standards of care. We collected the main history, clinical, laboratory, management and outcome data. The time-course of plasma DOAC concentrations measured using specific assays was modelled. RESULTS: Twelve patients (3F/9M; age, 55 years [41-63], median [25th-75th percentiles]) were included. Ingestions involved rivaroxaban (n = 7), apixaban (n = 3) and dabigatran (n = 2), with presumed doses of 9.4-fold [5.0-22.0] the full daily dose. Six patients received activated charcoal but no antidote nor blood-derived product. No bleeding was observed. One patient died due to refractory cardiogenic shock related to bisoprolol co-intoxication. Highest observed peak plasma concentrations were 1720 ng/ml (rivaroxaban), 750 ng/ml (apixaban) and 644 ng/ml (dabigatran). Times to reach DOAC concentration below 50 ng/ml were ~20-45 h (rivaroxaban), ~125 h (apixaban) and ~30-50 h (dabigatran). Elimination half-lives were 2.5-25.5 h (rivaroxaban), 22.0 and 36.5 h (apixaban), and 5.8 and 15.5 h (dabigatran), with substantial interindividual variability and prolongation in case of cardiovascular failure related to co-intoxicants. Charcoal administration, even if delayed, may have contributed to limit toxicity, possibly by reducing absorption and/or enteroenteric recycling. CONCLUSION: No bleeding was observed in this series of massive DOAC ingestions despite elevated plasma concentrations. No patient required specific haemostatic agents. Charcoal administration should be considered to limit toxicity.

Marked and prolonged serotonin toxicity in a tramadol-poisoned patient with a pharmacokinetic study.

BACKGROUND: Tramadol poisoning rarely causes serotonin toxicity, which mechanisms remain poorly understood. We investigated alterations in tramadol pharmacokinetics in a tramadol-poisoned patient who presented with marked and prolonged serotonin toxicity. CASE REPORT: A 21-year-old male self-ingested 750 mg-tramadol, 200 mg-sotalol, 400 mg-propranolol and 6 mg-lorazepam. He was a kidney transplant patient treated with mycophenolate, tacrolimus, prednisone, and paroxetine. He developed transitory cardiovascular failure and prolonged serotonin toxicity requiring sedation, muscle paralysis, and cyproheptadine, with a favorable outcome. METHODS: We measured plasma concentrations of tramadol, M1, M2, and M5 using liquid-chromatography-tandem mass spectrometry, calculated elimination half-lives and metabolic ratios of the compounds, and genotyped cytochromes involved in tramadol metabolism. RESULTS: Elimination half-lives of tramadol (6.1 h) and M1 (7.1 h) were normal while those of M2 (26.5 h) and M5 (16.7 h) prolonged. M1 metabolic ratio (0.12) was 2-fold reduced, M2 metabolic ratio (197) 1000-fold increased and M5 metabolic ratio (0.12) normal. This metabolic profile in a patient with normal CYP2D6-metabolizer status based on genotyping supports CYP2D6 inhibition by paroxetine and propranolol, two strong mechanism-based inhibitors. Only M2 present in sufficient concentrations up to 48 h could explain the prolonged serotonin toxicity. CONCLUSION: Marked and prolonged serotonin toxicity was attributed to increased M2 production due to paroxetine- and propranolol-related CYP2D6 inhibition of tramadol metabolism.

Does the ICU Requirement Score allow the poisoned patient to be safely managed without admission to the intensive care unit? - a validation cohort study.

BACKGROUND: The Intensive care unit (ICU) Requirement Score (IRS) has been defined as identifying poisoned patients on hospital admission who do not require ICU referral, in an effort to reduce health expenses. However, this score has been poorly validated. We aimed to evaluate the IRS in a large cohort of poisoned patients. METHODS: We performed a single-center retrospective cohort study. IRS was calculated using clinical parameters obtained on admission including age, systolic blood pressure, heart rate, Glasgow coma score, intoxication type, co-morbidities (i.e., arrhythmia, cirrhosis, and respiratory insufficiency), and the combination of the intoxication with another reason for ICU admission. We evaluated the ability of IRS < 6 determined on admission to predict the lack of need for ICU treatment, defined as the need for mechanical ventilation, vasopressors, and/or renal replacement therapy in the first 24 h post-admission and/or death during the hospital stay. This score was compared to the usual prognostic scores, i.e., SAPS II and III, SOFA score, and PSS. RESULTS: During the 10-year study period, 2,514 poisoned patients were admitted, 1,011 excluded as requiring ICU treatment on admission, and 1,503 included. Among these patients, 232 met the endpoint whereas only 23/510 patients with IRS < 6 (4.5%) presented the endpoint and one patient died. The area under the curve of the IRS ROC curve was 0.736 (95% confidence interval (CI), 0.702-0.770). The negative predictive value of IRS < 6 was 95% (95% CI, 93-97), sensitivity 89% (95% CI, 85-93), specificity 38% (95% CI, 36-41), and positive predictive value 21% (95% CI, 18-24). IRS performance was similar to those of the other tested scores, which are however not readily available on admission. CONCLUSION: Our data demonstrate the excellent negative predictive value of the IRS, allowing the exclusion of ICU requirements for poisoned patients with IRS < 6. IRS usefulness should be confirmed based on a prospective multicenter cohort study before extensive routine use.

Reversibility of total airway closure and alveolar consolidation in a COVID-19 patient: A case study.

Coronavirus disease 2019 (COVID-19) may be complicated by life-threatening pneumonia requiring tracheal intubation, mechanical ventilation and veno-venous extracorporeal membrane oxygenation (vvECMO). It is not yet clear to what extent and after which delay the most severe cases of COVID-19 pneumonia are reversible. Here, we present a 39-year-old patient who developed a severe COVID-19-attributed acute respiratory distress syndrome (ARDS) resulting in complete alveolar consolidation and airway closure for several weeks. His remarkable ventilatory pattern was established using ventilator airway pressure curve analysis and computed tomography imaging. The patient was managed with supportive care, mechanical ventilation and vvECMO. He received dexamethasone and tocilizumab as immunomodulatory drugs. Despite multiple complications, he recovered and was weaned from vvECMO, ventilator and oxygen on days 75, 95 and 99 post-intubation, respectively. He was discharged from hospital on day 113. This case study strongly supports the remarkable potential for reversibility of ARDS in COVID-19 patients and discusses the implications for critical care nursing regarding mechanical ventilation and ECMO device management in patients who may become entirely dependent on vvECMO for oxygenation and carbon dioxide elimination.

Outcome of Critically Ill COVID-19 Patients According to the Setting of Corticosteroid Initiation-A Retrospective Observational Cohort Study.

(1) Background: Corticosteroids lower 28-day all-cause mortality in critically ill COVID-19 patients. However, the outcome of COVID-19 patients referred to the intensive care unit (ICU) for respiratory deterioration despite corticosteroids initiated during hospitalization before ICU admission has been poorly investigated. Our objective was to determine survival according to corticosteroid initiation setting. (2) Methods: We conducted a cohort study including all successive critically ill COVID-19 patients treated with corticosteroids and managed in our ICU. We compared survival, whether corticosteroids were initiated before (Cb-group) or after ICU admission (Ca-group), using a propensity score matching. (3) Results: Overall, 228 patients (67 years (56-74); 168M/60F; invasive mechanical ventilation on admission, 17%) were included with 63 patients in the Cb-group and 165 patients in the Ca-group. Survival to hospital discharge was 43% versus 69%, respectively (p = 0.001). In a multivariable analysis, factors associated with death were age (odds ratio, 1.07; 95%-confidence interval, (1.04-1.11); p < 0.0001), the sequential organ failure assessment (SOFA) score on ICU admission (1.30 (1.14-1.50); p = 0.0001) and corticosteroid initiation before ICU admission (2.64 (1.30-5.43); p = 0.007). No significant differences in outcome related to corticosteroid regimen were found. (4) Conclusions: Critically ill COVID-19 patients transferred to the ICU with deterioration despite corticosteroids initiated before admission have a less favorable outcome than patients receiving corticosteroids initiated after ICU admission.

Dismal Survival in COVID-19 Patients Requiring ECMO as Rescue Therapy after Corticosteroid Failure.

(1) Background: COVID-19 may lead to refractory hypoxemia requiring venovenous extracorporeal membrane oxygenation (ECMO). Survival rate if ECMO is implemented as rescue therapy after corticosteroid failure is unknown. We aimed to investigate if ECMO implemented after failure of the full-recommended 10-day corticosteroid course can improve outcome. (2) Methods: We conducted a three-center cohort study including consecutive dexamethasone-treated COVID-19 patients requiring ECMO between 03/2020 and 05/2021. We compared survival at hospital discharge between patients implemented after (ECMO-after group) and before the end of the 10-day dexamethasone course (ECMO-before group). (3) Results: Forty patients (28M/12F; age, 57 years (51-62) (median (25th-75th percentiles)) were included, 28 (70%) in the ECMO-before and 12 (30%) in the ECMO-after group. In the ECMO-before group, 9/28 patients (32%) received the 6 mg/day dexamethasone regimen versus 12/12 (100%) in the ECMO-after group (p < 0.0001). The rest of the patients received an alternative dexamethasone regimen consisting of 20 mg/day during 5 days followed by 10 mg/day during 5 days. Patients in the ECMO-before group tended to be younger (57 years (51-59) versus 62 years (57-67), p = 0.053). In the ECMO-after group, no patient (0%) survived while 12 patients (43%) survived in the ECMO-before group (p = 0.007). (4) Conclusions: Survival is poor in COVID-19 patients requiring ECMO implemented after the full-recommended 10-day dexamethasone course. Since these patients may have developed a particularly severe presentation, new therapeutic strategies are urgently required.

Plasma procalcitonin may be an early predictor of liver injury in acetaminophen poisoning: A prospective cohort study.

BACKGROUND AND AIMS: Acetaminophen is a common cause of poisoning and liver injury worldwide; however, patient stratification is suboptimal. We aimed to assess the contribution of admission plasma procalcitonin concentration (PCT) to better identify acetaminophen-poisoned patients likely to develop liver injury. METHODS: We conducted a prospective observational cohort study including all acetaminophen-poisoned patients requiring N-acetylcysteine admitted in a toxicological intensive care unit between 2012 and 2017. Multivariate analysis was performed using a Cox regression model to investigate factors associated with liver injury, defined as an increase in alanine aminotransferase (ALT) >100 IU/L. RESULTS: One hundred seventeen patients (age, 32 years (21-53), median [25th-75th percentiles]) were included after self-ingesting 16 g (9-30) acetaminophen and received N-acetylcysteine infusion administered within a median 6 h-delay (4-12) from exposure. Co-ingestions were reported in 77% of patients. Rumack-Matthew nomogram was non-interpretable in 47% cases. Liver injury occurred in 38 patients (32%) with a median peak ALT of 2020 IU/L (577-4248). In liver injury patients, admission PCT was significantly increased in comparison to patients without liver injury (21.5 ng/ml (3.2-44.9) versus 0.1 ng/ml (0-0.4), respectively, p < 0.01). The increase in PCT preceded the increase in ALT by 33 h (10-74). In a multivariate analysis, PCT > 1 ng/ml was significantly associated with liver injury (hazard ratio, 7.2 [95% confidence interval, 2.3-22.6; p < 0.001]). PCT (area under the receiver-operating characteristics curve, 0.91 [95%CI: 0.84-0.97]) predicted liver injury with sensitivity, specificity, negative, and positive predictive values of 0.92, 0.84, 0.96, and 0.73, respectively. CONCLUSION: PCT on admission is associated with liver injury in acetaminophen poisoning. PCT might be used as a predictive tool of liver injury to improve clinical decision-making.

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

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 (LD50). 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 LD50) 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 LD50) 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 LD50 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.