Association of the COVID-19 pandemic on stroke admissions and treatment globally: a systematic review.

OBJECTIVES: The COVID-19 pandemic has highlighted insufficiencies and gaps within healthcare systems globally. In most countries, including high-income countries, healthcare facilities were over-run and occupied with too few resources beyond capacity. We carried out a systematic review with a primary aim to identify the influence of the COVID-19 pandemic on the presentation and treatment of stroke globally in populations≥65 years of age. DESIGN: A systematic review was completed. In total, 38 papers were included following full-text screening. DATA SOURCES: PubMed, MEDLINE and Embase. ELIGIBILITY CRITERIA: Eligible studies included observational and real-world evidence publications with a population who have experienced stroke treatment during the COVID-19 pandemic. Exclusion criteria included studies comparing the effect of the COVID-19 infection on stroke treatment and outcomes. DATA EXTRACTION AND SYNTHESIS: Primary outcome measures extracted were the number of admissions, treatment times and patient outcome. Secondary outcomes were severity on admission, population risk factors and destination on discharge. No meta-analysis was performed. RESULTS: This review demonstrated that 84% of studies reported decreased admissions rates during the COVID-19 pandemic. However, among those admitted, on average, had higher severity of stroke. Additionally, in-hospital stroke treatment pathways were affected by the implementation of COVID-19 protocols, which resulted in increased treatment times in 60% of studies and increased in-hospital mortality in 82% of studies by 100% on average. The prevalence of stroke subtype (ischaemic or haemorrhagic) and primary treatment methods (thrombectomy or thrombolysis) did not vary due to the COVID-19 pandemic. CONCLUSIONS: During the COVID-19 pandemic, many populations hesitated to seek medical attention, decreasing hospital admissions for less severe strokes and increasing hospitalisation of more severe cases and mortality. The effect of the pandemic on society and healthcare systems needs to be addressed to improve stroke treatment pathways and prepare for potential future epidemics. PROSPERO REGISTRATION NUMBER: CRD42021248564.

Motor patterning, ion regulation and spreading depolarization during CNS shutdown induced by experimental anoxia in Locusta migratoria.

Anoxia induces a reversible coma in insects. Coma onset is triggered by the arrest of mechanisms responsible for maintaining membrane ion homeostasis in the CNS, resulting in a wave of neuronal and glial depolarization known as spreading depolarization (SD). Different methods of anoxia influence the behavioural response but their effects on SD are unknown. We investigated the effects of CO2, N2, and H2O on the characteristics of coma induction and recovery in Locusta migratoria. Water immersion delayed coma onset and recovery, likely due to involvement of the tracheal system and the nature of asphyxiation but otherwise resembled N2 delivery. The main difference between N2 and CO2 was that CO2 hastened onset of neural failure and SD and delayed recovery. In the CNS, this was associated with CO2 inducing an abrupt and immediate decrease of interstitial pH and increase of extracellular [K+]. Recording of the transperineurial potential showed that SD propagation and a postanoxic negativity (PAN) were similar with both gases. The PAN increased with ouabain treatment, likely due to removal of the counteracting electrogenic effect of Na+/K+-ATPase, and was inhibited by bafilomycin, a proton pump inhibitor, suggesting that it was generated by the electrogenic effect of a Vacuolar-type ATPase (VA). Muscle fibres depolarized by ~20 mV, which happened more rapidly with CO2 compared with N2. Wing muscle motoneurons depolarized nearly completely in two stages, with CO2 causing more rapid onset and slower recovery than N2. Other parameters of SD onset and recovery were similar with the two gases. Electrical resistance across the ganglion sheath increased during anoxia and at SD onset. We provisionally attribute this to cell swelling reducing the dimensions of the interstitial pathway from neuropil to the bathing saline. Neuronal membrane resistance decreased abruptly at SD onset indicating opening of an unidentified membrane conductance. Consideration of the intracellular recording relative to the saline suggests that the apical membrane of perineurial glia depolarizes prior to neuron depolarization. We propose that SD is triggered by events at the perineurial sheath and then propagates laterally and more deeply into the neuropil. We conclude that the fundamental nature of SD is not dependent on the method of anoxia however the timing of onset and recovery are influenced; water immersion is complicated by the tracheal system and CO2 delivery has more rapid and longer lasting effects, associated with severe interstitial acidosis.

Inhibition of ATP-sensitive potassium channels exacerbates anoxic coma in Locusta migratoria.

Under extreme environmental conditions, many insects enter a protective coma associated with a spreading depolarization (SD) of neurons and glia in the central nervous system (CNS). Recovery depends on the restoration of ion gradients by mechanisms that are not well understood. We investigated the effects of glybenclamide, an ATP-sensitive K+ (KATP) channel inhibitor, and pinacidil, a KATP activator, on the mechanisms involved in anoxic coma induction and recovery in Locusta migratoria. KATP channels allow for the efflux of K+ when activated, thereby linking cellular metabolic state to membrane potential. In intact locusts, we measured the time to enter a coma after water immersion and the time to recover the righting reflex after returning to normoxia. In semi-intact preparations, we measured the time to SD in the metathoracic ganglion after flooding the preparation with saline or exposing it to 100% N2 gas, and the time for the transperineurial potential to recover after removal of the saline or return to air. Glybenclamide decreased the time to coma induction, whereas pinacidil increased induction times. Glybenclamide also lengthened the time to recovery and decreased the rate of recovery of transperineurial potential after SD. These results were not the same as the effects of 10-2 M ouabain on N2-induced SD. We conclude that glybenclamide affects the CNS response to anoxia via inhibition of KATP channels and not an effect on the Na+/K+-ATPase.NEW & NOTEWORTHY We demonstrate the involvement of ATP-sensitive K+ (KATP) channels during recovery from spreading depolarization (SD) induced via anoxic coma in locusts. KATP inhibition using glybenclamide impaired ion homeostasis across the blood-brain barrier resulting in a longer time to recovery of transperineurial potential following SD. Comparison with ouabain indicates that the effects of glybenclamide are not mediated by the Na+/K+-ATPase but are a result of KATP channel inhibition.

Role of adenosine in functional recovery following anoxic coma in Locusta migratoria.

When exposed to prolonged anoxia insects enter a reversible coma during which neural and muscular systems temporarily shut down. Nervous system shut down is a result of spreading depolarization throughout neurons and glial cells. Upon return to normoxia, recovery occurs following the restoration of ion gradients. However, there is a delay in the functional recovery of synaptic transmission following membrane repolarization. In mammals, the build-up of extracellular adenosine following spreading depolarization contributes to this delay. Adenosine accumulation is a marker of metabolic stress and it has many downstream effects through the activation of adenosine receptors, including the inhibition of cAMP production. Here we demonstrate that adenosine lengthens the time to functional recovery following anoxic coma in locusts. Caffeine, used as an adenosine receptor antagonist, decreased the time to recovery in intact animals and lengthened the time to recovery in semi-intact animals. A cAMP inhibitor, NKH 477, delayed recovery time in male animals. Our results show that the rate of recovery in insect systems is affected by the presence of adenosine.