Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN: COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS: The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA: - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO2/FiO2 < 300 and PEEP > 5 cmH2O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO2/FiO2 values over the preceding 24 hours are available; NON-INCLUSION CRITERIA: - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR: Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH2O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH2O), neuromuscular blockers if necessary, prone position if PaO2/FiO2 < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES: The primary outcome is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from "severe" to "moderate" or from "moderate" to "mild". RANDOMISATION: All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS: Protocol version number 2, April 29th, 2020. Recruitment is ongoing. The trial started recruitment on the 21st April 2020. We estimate recruitment will finish August 21st 2020. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This Letter serves as a summary of the key elements of the full protocol.

Early successful reperfusion after endovascular therapy reduces malignant middle cerebral artery infarction occurrence in young patients with large diffusion-weighted imaging lesions.

BACKGROUND AND PURPOSE: Malignant middle cerebral artery infarction (MMI) is a severe complication of acute ischaemic stroke (AIS). The aim of our study was to assess whether successful reperfusion after endovascular therapy (EVT) in AIS with clinical and imaging predictors of MMI decreased its occurrence. METHODS: Data were collected between January 2014 and July 2018 in a monocentric prospective AIS registry of patients treated with EVT. Patients selected were <65 years old with severe anterior circulation AIS with a National Institutes of Health Stroke Scale score >15, baseline Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score ≤ 6 and baseline diffusion-weighted imaging lesion volume >82 mL within 6 h of symptom onset. Successful reperfusion was defined as a Thrombolysis in Cerebral Ischemia score ≥ 2b. Occurrence of MMI was the primary endpoint. RESULTS: A total of 66 EVT-treated patients were included in our study. MMI occurred in 27 patients (41%). In unadjusted analysis, successful reperfusion was associated with fewer MMIs (31.8% vs. 65.0%; P = 0.015) and with more favorable outcome at 3 months (50% vs. 20%; P = 0.023). In multivariate analysis, successful reperfusion was associated with an adjusted odds ratio (95% confidence intervals) of 0.35 (0.10-1.12) for MMI and 2.77 (0.84-10.43) for 3-month favorable outcome occurrence. CONCLUSIONS: Early successful reperfusion performed in patients with AIS with clinical and imaging predictors of MMI was associated with decreased MMI occurrence. Reperfusion status might be considered in evaluating the need for craniectomy in patients with early predictors of MMI.

Emergence of Ceftriaxone Resistance during a Case of Pneumococcal Meningitis with Fatal Evolution.

We report a case of a 62-year-old man treated for Streptococcus pneumoniae meningitis by ceftriaxone and dexamethasone. After neurological improvement, neurological degradation by vasculitis occurred, despite effective concentrations of ceftriaxone in the serum and cerebrospinal fluid (CSF). S. pneumoniae with increased MICs to third-generation-cephalosporins (3GC) was isolated from the ventricular fluid 10 days after the isolation of the first strain. Isolate analysis showed that a mutation in the penicillin-binding protein 2X (PBP2X) has occurred under treatment.

Intrathecal hematoma and arachnoiditis mimicking bacterial meningitis after an epidural blood patch.

We present a case of arachnoiditis and an intrathecal hematoma after an epidural blood patch. A 24-year-old parturient underwent an epidural blood patch three days after an accidental dural puncture during epidural labor analgesia. Four days later, the patient developed severe lower back pain, bilateral leg pain, persistent headache and fever. Bacterial meningitis was initially suspected and antibiotics started. Lumbar magnetic resonance imaging was performed and showed an intrathecal hematoma, with no blood in the epidural space. This report briefly reviews the few cases in the literature of arachnoiditis caused by an intrathecal hematoma and discusses the mechanism which resulted in blood in the subarachnoid space.

[Antiepileptic prophylaxis for elective neurosurgery]. / Prophylaxie antiépileptique en neurochirurgie réglée.

In tumoral surgery, the risk factors for perioperative epilepsy can be roughly grouped into two categories: those related to the preoperative patient's conditions (type and location of the tumors, their impact on the surrounding brain…) and those specifically related to surgery (cerebral edema, parenchymal hematoma, surgical approach, complete or incomplete resection...). The first category is supposed to be responsible for preoperative and late postoperative epilepsy, while the second would be more related to the risk of epilepsy in the first postoperative week (or may be even in the first 48hours). It is well accepted (but not always respected) by the neuro-oncologists that there is no indication for preventive antiepileptic drugs (AED) in a patient with a brain tumor that has never presented seizure. However, every seizure crisis must be treated medically. Neurosurgical procedure (which is also a key factor for controlling epilepsy when it occurs. The AED should then be maintained as appropriate. In the absence of preoperative treatment, it has never been shown that prophylactic AED significantly decreases the incidence of postoperative seizures, early or late. Yet, the opposite has not been shown neither, and many groups use AED despite the risk of side effects and an uncertain risk-benefit ratio. Currently, postoperative epilepsy is much less frequent than it was 20 or 30years ago, and the risk of AED side effects also decreases with the latest generation of molecules (such as levetiracetam). So, AED risks and benefits tend to diminish in parallel, but their relationship is still to be assessed. In practice, a modern attitude would restrict prophylactic AED use to the higher risk patients (preoperative epilepsy, temporal astrocytoma, the extent of edema and mass effect...). A drug of last generation should be used, starting one week before surgery. The duration of the treatment should be limited to one week postoperatively in the absence of seizure.

[Anaesthesia of epileptic patient]. / Anesthésie du patient épileptique.

Although surgery of brain tumors and epilepsy are restricted to few specialized centers, anaesthesia for a patient with epilepsy is commonly encountered. Surgical treatments of epilepsy are currently soaring due to the lack of significant progress about effectiveness of antiepileptic drugs (AEDs). Theoretical principles for the anaesthesiologist are quite complex, involving interactions between physiological and pharmacological anaesthesia and AEDs, such as enzyme induction with the first generation molecules mainly (phenytoin, carbamazepin, phenobarbital). The latest generation AEDs (levetiracetam, lamotrigine, gabapentin, oxcarbazepin, vigabatrin, lacosamide...) are better tolerated and induce fewer drug interactions. Practically, the risk of severe perioperative complications is low, provided that the administration of AEDs is kept as close as possible to its usual dosage, and that metabolic disturbances are prevented. The main anaesthetic drugs to avoid are alfentanil, remifentanil and sevoflurane, although their contraindication are only relative, since the clinical benefit might be clear and the doses should remain moderate.

[Electroencephalography in status epilepticus: Glossary, protocol and interpretation]. / Electroencéphalographie dans les états de mal épileptiques : glossaire, protocole et interprétation.

Electroencephalography is a useful tool in the diagnosis and management of status epilepticus (SE) and it can also give prognostic information. It can help to confirm that an episode of SE has ended. It can identify the patients who have unsuspected subclinical seizures. There is a wide range of presentations of SE. Nearly all types of seizures have the potential of occurring in a repeated or continuous form. The polymorphic EEG patterns in SE reflect this wide variety. But controversial patterns also exist in the form of periodic epileptiform discharges. While some authors considered these patterns to be interictal or postictal, others postulate that these patterns are ictal. In these cases, clinical features are very important in order to conclude. Generalized convulsive SE is a medical emergency and the EEG is not necessary to make a diagnosis. Convulsive generalized SE requires immediate treatment and in this case, EEG is used in guiding treatment especially in refractory SE that may evolve into subtle SE. In non-convulsive SE, diagnosis is not obvious on the basis of clinical signs and symptoms alone and the diagnosis must be confirmed by urgent EEG. EEG can also be used to distinguish SE from psychogenic seizures, movement disorders and in patients who have causes of persistent loss of consciousness (metabolic encephalopathy, postanoxic encephalopathy). This article proposes a protocol for the use of the EEG in SE, guidelines and simple vocabulary for a good interpretation and comprehension of the EEG.

[The electroencephalogram in status epilepticus]. / Place de l'électroencéphalogramme dans l'état de mal épileptique.

Recordings of the electroencephalogram (EEG) play a major role in the management of patients with status epilepticus (SE). The EEG contributes to the diagnosis of SE, can be used to identify differential and syndromic diagnoses, and sometimes provides the etiologic diagnosis. EEG is helpful in monitoring therapeutic management and is an essential component of the follow up. The interpretation of the EEG in a patient with refractory SE is difficult, requiring clinical experience in this domain. We discuss the different modalities of EEG recording and their indications in emergency situations.

[Pathophysiologic basis of status epilepticus]. / Bases physiopathologiques des états de mal épileptiques.

The mechanisms that induce epileptic activity and make it durable, leading to status epilepticus (SE), are poorly known. They probably result from an imbalance between the activating systems of neuronal depolarisation (excitatory amino acids release with postsynaptic N-methyl-d-aspartate [NMDA] receptor activation, spreading depolarisation following abnormal progression) and the inhibiting systems (GABAergic synapses). Status epilepticus leads to many direct and indirect cerebral disorders, as well as systemic disorders, with intertwined mechanisms and consequences. These disorders are more frequent in case of convulsive SE with generalized tonic-clonic seizures. Direct neuronal damage (selective neuronal loss and epileptogenesis) results mostly from excitotoxicity, which arises from enhanced and extended neuronal activation. Indirect neuronal damage results from the inability of the circulatory system to supply sufficient oxygen and glucose contribution compared to the high metabolism level of the highly depolarized and synchronized neurons. This energetic deficit is usually patent after 30 minutes of SE, when systemic compensation mechanisms (cardiac output increase) are exhausted. Understanding these pathophysiologic aspects is essential for effective treatment of SE.

[Non specific treatment of status epilepticus]. / Prise en charge non spécifique de l'état de mal épileptique convulsif.

The systemic consequences of status epilepticus occur in two stages: the first stage is a hyperadrenergic period (high blood pressure, tachycardia, arrhythmia, hyperventilation, hypermetabolism, hyperthermia), the second stage a collapsus period, sometimes with acute circulatory failure, and hypoxemia. Symptomatic resuscitation aimed at restoring vital functions should be undertaken. Resuscitation must be started immediately before hospital transfer, by a trained emergency team. Respiratory care includes at least oxygen intake, but it can also require oral intubation (crash induction) and mechanical ventilation. The arterial blood gas objectives are SaO(2)> or =95%, and 35mmHg< or =PaCO(2)< or =40mmHg. Fluid and electrolyte care includes intravenous infusion of normal saline, with control of sodium and calcium levels as well as blood pH within normal limits. Heart rate and blood pressure must be monitored. Mean blood pressure must be kept between 70 and 90mmHg, first by means of plasma volume expansion, and then norepinephrine if necessary. Hyperthermia must be corrected to prevent further neuronal damage. Cerebromeningeal sepsis should be ruled out. Capillary glucose (most often elevated) must be corrected using a pre-established insulin infusion algorithm. Rhabdomyolysis is rare, but can result in hyperkaliemia, acidosis, and acute renal failure. In case of associated intracranial hypertension (traumatic, vascular or infectious injury), status epilepticus is considered as a secondary insult for the brain, that can worsen neuronal damage. Numerous compounds have experimental neuroprotective properties, but none have proven significant efficacy in clinical conditions. Nevertheless, convulsion cessation is considered as a neuroprotective measure.

[Therapeutic hypothermia]. / L'hypothermie thérapeutique.

The benefit of therapeutic hypothermia after severe head injury is highly controversial. However, hypothermia is still used and studied in this context for multiple reasons. Efficacy of hypothermia is demonstrated after cerebral ischemia in numerous animal studies and after cardiac arrest in human studies. Hyperthermia is a major independent factor of outcome after cerebral ischemic or traumatic brain injury. Moreover, ICP is related to core temperature, and hypothermia may be used to decrease intracranial hypertension. However, many questions are still unresolved and can explain discrepancies between clinical studies: direct measurement of cerebral temperature, relationship between ICP, temperature and PaCO(2), level and duration of hypothermia and precise methods for cooling and particularly for rewarming.

Intrathecal baclofen for severe tetanus in a pregnant woman.

A 6-months pregnant woman suffering from severe tetanus was successfully treated with intrathecal baclofen. She delivered a premature but healthy neonate, and was safely discharged home 40 days after the onset of symptoms of tetanus. Specific aspects of intrathecal baclofen therapy in the pregnant woman are discussed.

Dynamic cerebral microcirculatory changes in transient forebrain ischemia in rats: involvement of type I nitric oxide synthase.

The diameter of surface microvessels and the erythrocyte velocity and flux through intraparenchymal capillaries in the parietal cortex were measured during transient global cerebral ischemia and reperfusion using laser-scanning confocal fluorescence microscopy in anesthetized rats. The role of nitric oxide (NO) from neurons in the microcirculatory changes was also investigated using 7-nitro-indazole (7-NI, 25 mg/kg, i.p.). Wistar rats (4 per group) equipped with a closed cranial window were given fluorescein isothiocyanate (FITC)-Dextran and FITC-labeled erythrocytes intravenously to respectively visualize the microvessels and the erythrocytes in the capillaries. Experiments were videorecorded on-line. Forebrains were made ischemic for 15 minutes and then reperfused for 120 minutes under the microscope. Ischemia was associated with a flattened EEG, a low persistent blood flow, and a transient leakage of fluorescein across the arteriole wall. Unclamping the carotid arteries led to immediate high blood flow in the arterioles, but it was not until 5 minutes later that the arterioles dilated significantly (181% +/- 27%) and erythrocyte velocity in the capillaries increased significantly (460% +/- 263%). Neither nonperfused capillaries nor erythrocyte capillary recruitment occurred. 7-Nitro-indazole significantly reduced the arteriole dilatation and prevented the increase in erythrocyte velocity and flux through capillaries in early reperfusion. 7-Nitroindazole had no influence on the fluorescein leakage. The current study suggests a partial role for NO released from neurons in the postischemic microcirculatory changes and provides new findings on the timing of arteriole dilatation and blood-brain barrier opening, and on erythrocyte capillary circulation in global ischemia.

[Value of intrathecal baclofen in the treatment of severe tetanus in the tropical milieu]. / Place du baclofene intrathecal dans le traitement du tetanos grave en milieu tropical.

Tetanus continues to be a cause of high mortality in developing countries, where resources for muscle relaxation and respiratory support are not readily available. Baclofen, a GABAB receptor agonist, directly restores physiologic inhibition of alpha motoneuron, that is blocked by tetanus toxin. Its use has been suggested at high dosage by intrathecal (i.t.) route, as part of the treatment of tetanus-induced contractures, and to limit the need for general anesthesia and for tracheal intubation in afflicted patients. This review reports personal experience and focuses on published data about i.t. baclofen for severe tetanus. Although statistical analysis are difficult to perform, i.t. baclofen appears to be effective in resolving muscle rigidity and in avoiding the need for deep sedation and for tracheal intubation, thus achieving lower mortality. Nevertheless, i.t. baclofen has a narrow therapeutic range, and a large interindividual pharmacodynamic variability. Thus, its use should be reserved for patients who would have been intubated without it. I.t. baclofen is a fairly simple and cost-effective modality, with significant advantages for management of severe tetanus, especially in tropical environment.

[Physiopathology of cerebral ischemia]. / Physiopathologie de l'ischémie cérébrale.

This article reviews the most currently used experimental models of cerebral ischaemia. Mechanisms involved in ischaemic neuronal death are considered at the tissue, cellular and molecular levels. The various steps of the excitotoxic cascade induced by anoxic depolarization in conditions of energy failure are analyzed, from excessive glutamate release to intracellular calcium accumulation, massive calcium-dependent enzyme activation, and the formation of oxygen radicals. Apoptotic neuronal death is also discussed, which leads one to distinguish between genes whose expression is beneficial or deleterious in ischaemic conditions. Finally, the putative causes of contradictory results obtained from pharmacological studies in animals and humans are discussed.