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.

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.

Hypothermia for Neuroprotection in Convulsive Status Epilepticus.

BACKGROUND: Convulsive status epilepticus often results in permanent neurologic impairment. We evaluated the effect of induced hypothermia on neurologic outcomes in patients with convulsive status epilepticus. METHODS: In a multicenter trial, we randomly assigned 270 critically ill patients with convulsive status epilepticus who were receiving mechanical ventilation to hypothermia (32 to 34°C for 24 hours) in addition to standard care or to standard care alone; 268 patients were included in the analysis. The primary outcome was a good functional outcome at 90 days, defined as a Glasgow Outcome Scale (GOS) score of 5 (range, 1 to 5, with 1 representing death and 5 representing no or minimal neurologic deficit). The main secondary outcomes were mortality at 90 days, progression to electroencephalographically (EEG) confirmed status epilepticus, refractory status epilepticus on day 1, "super-refractory" status epilepticus (resistant to general anesthesia), and functional sequelae on day 90. RESULTS: A GOS score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group and in 56 of 130 (43%) in the control group (adjusted common odds ratio, 1.22; 95% confidence interval [CI], 0.75 to 1.99; P=0.43). The rate of progression to EEG-confirmed status epilepticus on the first day was lower in the hypothermia group than in the control group (11% vs. 22%; odds ratio, 0.40; 95% CI, 0.20 to 0.79; P=0.009), but there were no significant differences between groups in the other secondary outcomes. Adverse events were more frequent in the hypothermia group than in the control group. CONCLUSIONS: In this trial, induced hypothermia added to standard care was not associated with significantly better 90-day outcomes than standard care alone in patients with convulsive status epilepticus. (Funded by the French Ministry of Health; HYBERNATUS ClinicalTrials.gov number, NCT01359332 .).

Electroencephalographic patterns of lithium poisoning: a study of the effect/concentration relationships in the rat.

OBJECTIVES: Lithium overdose may result in encephalopathy and electroencephalographic abnormalities. Three poisoning patterns have been identified based on the ingested dose, previous treatment duration and renal function. Whether the severity of lithium-induced encephalopathy depends on the poisoning pattern has not been established. We designed a rat study to investigate lithium-induced encephalopathy and correlate its severity to plasma, erythrocyte, cerebrospinal fluid and brain lithium concentrations previously determined in rat models mimicking human poisoning patterns. METHODS: Lithium-induced encephalopathy was assessed and scored using continuous electroencephalography. RESULTS: We demonstrated that lithium overdose was consistently responsible for encephalopathy, the severity of which depended on the poisoning pattern. Acutely poisoned rats developed rapid-onset encephalopathy which reached a maximal grade of 2/5 at 6 h and disappeared at 24 h post-injection. Acute-on-chronically poisoned rats developed persistent and slightly fluctuating encephalopathy which reached a maximal grade of 3/5. Chronically poisoned rats developed rapid-onset but gradually increasing life-threatening encephalopathy which reached a maximal grade of 4/5. None of the acutely, 20% of the acute-on-chronically and 57% of the chronically lithium-poisoned rats developed seizures. The relationships between encephalopathy severity and lithium concentrations fitted a sigmoidal Emax model based on cerebrospinal fluid concentrations in acute poisoning and brain concentrations in acute-on-chronic poisoning. In chronic poisoning, worsening of encephalopathy paralleled the increase in plasma lithium concentrations. CONCLUSIONS: The severity of lithium-induced encephalopathy is dependent on the poisoning pattern, which was previously shown to determine lithium accumulation in the brain. Our data support the proposition that electroencephalography is a sensitive tool for scoring lithium-related neurotoxicity.

Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol combination play a worsening role in overdose?

Poisoning with opioid analgesics including tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate tramadol-related neurotoxicity, consequences of diazepam/tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon-Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of tramadol and diazepam/tramadol combination did not significantly differ, although time-to-death was longer with combination (P=0.04). Tramadol induced dose-dependent sedation (P<0.05), early-onset seizures (P<0.001) and increase in inspiratory (P<0.01) and expiratory times (P<0.05). The diazepam/tramadol combination abolished seizures but significantly enhanced sedation (P<0.01) and respiratory depression (P<0.05) by reducing tidal volume (P<0.05) in addition to tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced tramadol-induced seizures. Our study shows that diazepam/tramadol combination does not worsen tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.

Out-of-hospital cardiac arrest from brain cause: epidemiology, clinical features, and outcome in a multicenter cohort*.

OBJECTIVES: Although sudden cardiac death has been broadly studied, little is known on cerebrovascular events revealed by out-of-hospital cardiac arrest. We aimed to describe clinical features and prognosis of these patients and identify characteristics that could suggest a cerebrovascular etiology of the out-of-hospital cardiac arrest. DESIGN: Retrospective review (1999-2012) of databases of three regional referral ICU centers for out-of-hospital cardiac arrest. SETTING: Patients admitted to ICU for management of successfully resuscitated out-of-hospital cardiac arrest. PATIENTS: Patients were included when subarachnoid hemorrhage, intracranial hemorrhage, ischemic stroke, sub/epidural hematoma, or cerebral thrombophlebitis was identified as the primary cause of out-of-hospital cardiac arrest. Traumatic or infectious causes were excluded. Patients were compared with a group of out-of-hospital cardiac arrest of nonneurological origin. INTERVENTIONS: All medical records of the three prospective ICU databases, registered according to the Utstein style, were reviewed. MEASUREMENTS AND MAIN RESULTS: Among 3,710 patients admitted for out-of-hospital cardiac arrest, 86 were included (mainly subarachnoid hemorrhage, n = 73). Prodromes were mostly neurological but falsely evoked a cardiac origin in six patients. Electrocardiogram displayed abnormalities in 64% of patients, with 23% of pseudoischemic pattern (ST-segment elevation or left bundle branch block). Mortality rate was 100%, with brain death as the leading cause. In comparison with the nonneurological out-of-hospital cardiac arrest group, female gender, onset of neurological prodromes, lack of other prodromes, initial nonshockable rhythm, and unspecific electrocardiogram repolarization abnormalities were independent predictive factors of a primary cerebrovascular etiology. When present, the combination of these elements displayed an area under the receiver operating characteristic curve of 0.86 (95% CI, 0.81-0.91). CONCLUSIONS: Presentation of cerebrovascular event complicated with out-of-hospital cardiac arrest may mimic coronary etiology, but several clinical elements may help to identify brain causes. Even if survival is null, the high proportion of brain deaths provides opportunity for organ donation.

Influence of α-stat and pH-stat blood gas management strategies on cerebral blood flow and oxygenation in patients treated with therapeutic hypothermia after out-of-hospital cardiac arrest: a crossover study.

OBJECTIVES: In patients treated with therapeutic hypothermia after out-of-hospital cardiac arrest, two blood gas management strategies are used regarding the PaCO2 target: α-stat or pH-stat. We aimed to compare the effects of these strategies on cerebral blood flow and oxygenation. DESIGN: Prospective observational single-center crossover study. SETTING: ICU of University hospital. PATIENTS: Twenty-one therapeutic hypothermia-treated patients after out-of-hospital cardiac arrest more than 18 years old without history of cerebrovascular disease were included. INTERVENTIONS: Cerebral perfusion and oxygenation variables were compared in α-stat (PaCO2 measured at 37 °C) versus pH-stat (PaCO2 measured at 32-34 °C), both strategies maintaining physiological PaCO2 values: 4.8-5.6 kPa (36-42 torr). MEASUREMENTS AND MAIN RESULTS: Bilateral transcranial middle cerebral artery flow velocities using Doppler and jugular vein oxygen saturation were measured in both strategies 18 hours (14-23 hr) after the return of spontaneous circulation. Pulsatility and resistance indexes and cerebral oxygen extraction were calculated. Data are expressed as median (interquartile range 25-75) in α-stat versus pH-stat. No differences were found in temperature, arterial blood pressure, and oxygenation between α-stat and pH-stat. Significant differences were found in minute ventilation (p = 0.006), temperature-corrected PaCO2 (4.4 kPa [4.1-4.6 kPa] vs. 5.1 kPa [5.0-5.3 kPa], p = 0.0001), and temperature-uncorrected PaCO2 (p = 0.0001). No differences were found in cerebral blood velocities and pulsatility and resistance indexes in the overall population. Significant differences were found in jugular vein oxygen saturation (83.2% [79.2-87.6%] vs. 86.7% [83.2-88.2%], p = 0.009) and cerebral oxygen extraction (15% [11-20%] vs. 12% [10-16%], p = 0.01), respectively. In survivors, diastolic blood velocities were 25 cm/s (19-30 cm/s) versus 29 cm/s (23-35 cm/s) (p = 0.004), pulsatility index was 1.10 (0.97-1.18) versus 0.94 (0.89-1.05) (p = 0.027), jugular vein oxygen saturation was 79.2 (71.1-81.8) versus 83.3% (76.6-87.8) (p = 0.033), respectively. However, similar results were not found in nonsurvivors. CONCLUSIONS: In therapeutic hypothermia-treated patients after out-of-hospital cardiac arrest at physiological PaCO2, α-stat strategy increases jugular vein blood desaturation and cerebral oxygen extraction compared with pH-stat strategy and decreases cerebral blood flow velocities in survivors.

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.

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.

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.

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.

Tuberculosis in the intensive care unit: A retrospective descriptive cohort study with determination of a predictive fatality score.

BACKGROUND: Despite effective treatments, tuberculosis-related mortality remains high among patients requiring admission to the intensive care unit (ICU). OBJECTIVE: To determine prognostic factors of death in tuberculosis patients admitted to the ICU, and to develop a simple predictive scoring system. METHODS: A 10-year, retrospective study of 53 patients admitted consecutively to the Hôpitaux de Paris, Hôpital Lariboisière (Paris, France) ICU with confirmed tuberculosis, was conducted. A multivariate analysis was performed to identify risk factors for death. A predictive fatality score was determined. RESULTS: Diagnoses included pulmonary tuberculosis (96%) and tuberculous encephalomeningitis (26%). Patients required mechanical ventilation (45%) and vasopressor infusion (28%) on admission. Twenty patients (38%) died, related to direct tuberculosis-induced organ failure (n=5), pulmonary bacterial coinfections (n=14) and pulmonary embolism (n=1). Using a multivariate analysis, three independent factors on ICU admission were predictive of fatality: miliary pulmonary tuberculosis (OR 9.04 [95% CI 1.25 to 65.30]), mechanical ventilation (OR 11.36 [95% CI 1.55 to 83.48]) and vasopressor requirement (OR 8.45 [95% CI 1.29 to 55.18]). A score generated by summing these three independent variables was effective at predicting fatality with an area under the ROC curve of 0.92 (95% CI 0.85 to 0.98). CONCLUSIONS: Fatalities remain high in patients admitted to the ICU with tuberculosis. Miliary pulmonary tuberculosis, mechanical ventilation and vasopressor requirement on admission were predictive of death.

HISTORIQUE: Malgré des traitements efficaces, la mortalité liée à la tuberculose demeure élevée chez les patients qui doivent être hospitalisés à l'unité de soins intensifs (USI). OBJECTIF: Déterminer les facteurs pronostiques de décès chez les patients tuberculeux admis à l'USI et élaborer un système d'indice prédictif simple. MÉTHODOLOGIE: Les chercheurs ont mené une étude rétrospective d'une durée de dix ans auprès de 53 patients hospitalisés consécutivement à l'USI de l'Hôpital Lariboisière des Hôpitaux de Paris, en France, en raison d'une tuberculose confirmée. Ils ont procédé à une analyse multivariée pour déterminer les facteurs de risque de décès et ont établi un indice prédictif de fatalité. RÉSULTATS: Les diagnostics incluaient une tuberculose pulmonaire (96 %) et une encéphaloméningite tuberculeuse (26 %). Les patients avaient besoin d'une ventilation mécanique (45 %) et d'une perfusion de vasopresseur (28 %) à l'admission. Vingt patients (38 %) sont décédés en raison d'une insuffisance organique liée directement à la tuberculose (n=5), de co-infections bactériennes pulmonaires (n=14) et d'une embolie pulmonaire (n=1). Selon l'analyse multivariée, trois facteurs indépendants à l'admission à l'USI étaient prédictifs d'une fatalité : une tuberculose miliaire (RRR 9,04 [95 % IC 1,25 à 65,30]), une ventilation mécanique (RRR 11,36 [95 % IC 1,55 à 83,48]) et des besoins vasopressifs (RRR 8,45 [95 % IC 1,29 à 55,18]). Un indice conforme à la somme de ces trois variables indépendantes était efficace pour prévenir la fatalité, avec une zone sous la courbe ROC de 0,92 (95 % IC 0,85 à 0,98). CONCLUSIONS: Les décès demeurent élevés chez les patients tuberculeux admis à l'USI. La tuberculose miliaire, la ventilation mécanique et les besoins vasopressifs à l'admission sont prédictifs d'un décès.

[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.

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.

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.

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.

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.

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.

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.