Michael Kassirer

Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment.

Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain damage. Our objectives were to investigate whether OP-induced SE leads to the emergence of spontaneous recurrent seizures (SRSs), the hallmark of chronic epilepsy, and if so, to assess the efficacy of benzodiazepine therapy following SE onset in preventing the epileptogenesis. We also explored early changes in hippocampal pyramidal cells excitability in this model. Adult rats were poisoned with the paraoxon (450μg/kg) and immediately treated with atropine (3mg/kg) and obidoxime (20mg/kg) to reduce acute mortality due to peripheral acetylcholinesterase inhibition. Electrical brain activity was assessed for two weeks during weeks 4-6 after poisoning using telemetric electrocorticographic intracranial recordings. All OP-poisoned animals developed SE, which could be suppressed by midazolam. Most (88%) rats which were not treated with midazolam developed SRSs, indicating that they have become chronically epileptic. Application of midazolam 1min following SE onset had a significant antiepileptogenic effect (only 11% of the rats became epileptic; p=0.001 compared to non-midazolam-treated rats). Applying midazolam 30min after SE onset did not significantly prevent chronic epilepsy. The electrophysiological properties of CA1 pyramidal cells, assessed electrophysiologically in hippocampal slices, were not altered by OP-induced SE. Thus we show for the first time that a single episode of OP-induced SE in rats leads to the acquisition of chronic epilepsy, and that this epileptogenic outcome can be largely prevented by immediate, but not delayed, administration of midazolam. Extrapolating these results to humans would suggest that midazolam should be provided together with atropine and an oxime in the immediate pharmacological treatment of OP poisoning.

Imaging blood–brain barrier dysfunction as a biomarker for epileptogenesis

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.

Early brain magnetic resonance imaging can predict short and long- term outcomes after organophosphate poisoning in a rat model

INTRODUCTION Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post-poisoning cognitive dysfunction. METHODS Sprague-Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1 - no central antidotal treatment (n=10); group 2 - treated with midazolam (MID) at 30 min after poisoning (n=9), group 3 - treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n=9) and controls (n=6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel (1)H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetyl-aspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. RESULTS All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID+SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3h after exposure (1.1 ± 0.07 and 1.42 ± 0.05 in ATOX and control groups, respectively) and remained lower compared to non-poisoned animals even 24h after poisoning. MID and MID+SCOP prevented much of the 3h NAA/Cr decrease (1.22 ± 0.05 and 1.32 ± 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4-0.75 (p<0.05). CONCLUSIONS MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with clinical consequences of organophosphate poisoning and could be potentially used in the future to predict long-term prognosis of poisoned casualties.

Airway control in case of a mass toxicological event: superiority of second-generation supraglottic airway devices.

INTRODUCTION Early respiratory support and airway (AW) control with endotracheal intubation (ETI) are crucial in mass toxicology events and must be performed while wearing chemical personal protective equipment (C-PPE). AIM The aim of this study is to evaluate the efficiency of AW control by using second-generation supraglottic AW devices (SADs) as compared with ETI and first-generation SAD while wearing C-PPE. METHODS This is a randomized crossover trial involving 117 medical practitioners. Four AW management devices were examined: endotracheal tube, the first-generation SAD, laryngeal mask AW unique and 2 second-generation SAD, the laryngeal tube suction disposable, and supreme laryngeal mask AW (SLMA). Primary end point measured were success or failure, number of attempts, and time needed to achieve successful device insertion. Secondary end point was a subjective appraisal of the AW devices by study population. RESULTS More attempts were required to achieve AW control with endotracheal tube, with and without C-PPE (P<.001). Time to achieve AW control with ETI was, on average, 88% longer than required with other devices and improved with practice. The mean times to achieve an AW were longer when operators were equipped with C-PPE as compared with standard clothing. Subjectively, difficulty levels were significantly higher for ETI than for all other devices (P<.0001). CONCLUSIONS When compared with ETI, the use of SADs significantly shortened the time for AW control while wearing C-PPE. Second-generation SAD were superior to laryngeal mask AW unique. These finding suggest that SADs may be used in a mass toxicology event as a bridge, until definite AW control is achieved.

The association between self-perceived proficiency of personal protective equipment and objective performance: An observational study during a bioterrorism simulation drill

Highlights:We compared between self‐perceived proficiency of PPE use and objective performance.• There was no correlation between comfort and objective performance scores.• Clinics personnel performed better than hospital personnel.• Self‐perceived proficiency is a poor predictor of appropriate PPE use. Background The recent Ebola virus disease outbreak emphasized the potential misuse of personal protective equipment (PPE) by health care workers (HCWs) during such an event. We aimed to compare self‐perceived proficiency of PPE use and objective performance, and identify predictors of low compliance and PPE misuse. Methods: An observational study combined with subjective questionnaires were carried out during a bioterror simulation drill. Forty‐two observers evaluated performance under PPE. Mistakes were recorded and graded using a structured observational format and were correlated with the subjective questionnaires and with demographic parameters. Results: One hundred seventy‐eight HCWs from community clinics and hospitals were included. The mean self‐perceived proficiency was high (6.1 out of 7), mean level of comfort was moderate (4.0 out of 7), and mean objective performance was intermediate (9.5 out of 13). There was no correlation between comfort and objective performance scores. Self‐perceived proficiency was in correlation with donning and continuous performance with PPE but not with doffing. Clinic personnel performed better than personnel in hospitals (40.3% vs 67.8% with 3 or more mistakes, respectively; P = .001). Demographic characteristics had no correlation with objective or self‐perceived performance. Conclusions: Self‐perceived proficiency is a poor predictor of appropriate PPE use. The results suggest poor awareness of the possibility of PPE misuse.

Toxins as biological weapons for terror—characteristics, challenges and medical countermeasures: a mini-review

Toxins are hazardous biochemical compounds derived from bacteria, fungi, or plants. Some have mechanisms of action and physical properties that make them amenable for use as potential warfare agents. Currently, some toxins are classified as potential biological weapons, although they have several differences from classic living bio-terror pathogens and some similarities to manmade chemical warfare agents. This review focuses on category A and B bio-terror toxins recognized by the Centers for Disease Control and Prevention: Botulinum neurotoxin, staphylococcal enterotoxin B, Clostridium perfringens epsilon toxin, and ricin. Their derivation, pathogenesis, mechanism of action, associated clinical signs and symptoms, diagnosis, and treatment are discussed in detail. Given their expected covert use, the primary diagnostic challenge in toxin exposure is the early detection of morbidity clusters, apart from background morbidity, after a relatively short incubation period. For this reason, it is important that clinicians be familiar with the clinical manifestations of toxins and the appropriate methods of management and countermeasures.

Estimated prevalence of smallpox vaccine contraindications in Israeli adolescents

BACKGROUND Routine smallpox vaccination for military recruits was discontinued in Israel in 1996. However, Israeli guidelines recommend post-event mass-vaccination. This study aimed to estimate the rate of Israeli adolescents at risk of severe adverse events after vaccination during 1998-2013. METHODS The study population included adolescents screened before military service in 1998-2013. Medical parameters correlating with contraindications to smallpox vaccination were retrieved from army databases, and were categorized by severity according to the Israeli post-event strategy. RESULTS Of 1,180,964 individuals, 1.86% had vaccination contraindications in a post-event scenario. An additional 1.24% had contraindications in a pre-event scenario. There was an increase in the percentage of contraindications over time, attributed to the rising incidence of atopic-dermatitis. CONCLUSIONS Only a small percentage of the adolescent population is ineligible to receive the smallpox vaccine currently in use. This group may be protected by herd-immunity, or by new-generation vaccines designed to prevent severe adverse events.

Using the skin protective lotion IB1 as a substitute for chemical protective gloves

We aimed to evaluate the performance of medical personnel in using the IB1 topical protective lotion on their hands and wrists together with standard disposable medical gloves, compared to standard-issued medical chemical protective gloves. This randomized cross-over study included 144 medical personnel. Primary endpoints were time-to-completion of autoinjection; success rate, number of attempts, and time-to-achieve successful endotracheal intubation; time-to-achieve satisfactory tube fixation; time-to-draw and inject the content of an ampoule; and the total time-to-perform all medical procedures. Secondary endpoints included the subjective assessment of convenience to perform these four procedures with each protective measure. Mean time was significantly shorter using IB1 compared to chemical protective gloves for tube fixation, ampoule drawing, and the total time-to-perform all procedures (58.6±22.7 seconds vs. 71.7±29.7; 31.5±21.8 vs. 38.2±19.4; 137.4±56.1 vs. 162.5±63.6, respectively; P<.001 for all). For all medical procedures, the use of IB1 was reported as significantly more convenient than the use of chemical protective gloves (P<.001 for all comparisons). IB1 with standard medical gloves significantly shorten the time-to-perform medical procedures requiring fine motor dexterities and is subjectively more convenient than chemical protective gloves. IB1 should be considered as an appropriate alternative for medical teams in a chemical event.

Treatment of Chemical Warfare Agent Casualties: Retention of Knowledge and Self-Perceived Competency Among Military Physicians and Paramedics

OBJECTIVE Specialized training of medical teams for chemical warfare agent (CWA) events is important to save lives. We aimed to evaluate the retention of knowledge (ROK) and self-perceived competency (SPC) of military medical personnel in delivering treatment during CWA events. METHODS A questionnaire and a multiple-choice examination were sent to military physicians and paramedics, evaluating their CWA, ROK, and SPC (study group [SG]). Their assessment was compared to medical personnel immediately post training (reference group [RG]). SG was subdivided into two groups: G1 ≤ 1 year and G2 > 1 year, past training. RESULTS Overall, 135 participants responded (35-RG, 65% physicians). Self-reported ROK and SPC were significantly higher in RG compared to SG and in G1 compared to G2. Test scores were higher in RG compared to SG, but similar in G1 and G2 groups. SPC was lower compared to ROK in the entire cohort and subgroups. A moderate correlation was found between the self-and test-assessed scores (Pearson correlation coefficient 0.45, p < 0.001). Physicians received significantly (p = 0.01) higher test scores in RG compared with paramedics. CONCLUSIONS ROK and SPC among military medical personnel for treatment of CWA casualties deteriorate significantly as early as 1 year post training, SPC > ROK. Thus, we recommend CWA refresher training at least every year.