Effect of drug interventions on cerebral haemodynamics in ischaemic stroke patients

The ischaemic penumbra is sensitive to alterations in cerebral perfusion. A myriad of drugs are used in acute ischaemic stroke (AIS) management, yet their impact on cerebral haemodynamics is poorly understood. As part of the Cerebral Autoregulation Network led INFOMATAS project ( Identifying New Targets for Management and Therapy in Acute Stroke), this paper reviews some of the most common drugs a patient with AIS will come across and their potential influence on cerebral haemodynamics with a particular focus being on cerebral autoregulation (CA). We first discuss how compounds that promote clot lysis and prevent clot formation could potentially impact cerebral haemodynamics, before focusing on how the different classes of antihypertensive drugs can influence cerebral haemodynamics. We discuss the different properties of each drug and their potential impact on cerebral perfusion and CA. With emerging interest in CA status of AIS patients, either during or soon after treatment when timely reperfusion and salvageable tissue is at its most critical, the properties of these pharmacological agents may be relevant for modelling cerebral perfusion accuracy and for setting individualised treatment strategies.

The ischemic penumbra: From concept to reality

The discovery that brain tissue could potentially be salvaged from ischaemia due to stroke, has led to major advances in the development of therapies for ischemic stroke. In this review, we detail the advances in the understanding of this area termed the ischaemic penumbra, from its discovery to the evolution of imaging techniques, and finally some of the treatments developed. Evolving from animal studies from the 70s and 80s and translated to clinical practice, the field of ischemic reperfusion therapy has largely been guided by an array of imaging techniques developed to positively identify the ischemic penumbra, including positron emission tomography, computed tomography and magnetic resonance imaging. More recently, numerous penumbral identification imaging studies have allowed for a better understanding of the progression of the ischaemic core at the expense of the penumbra, and identification of patients than can benefit from reperfusion therapies in the acute phase. Importantly, 40 years of critical imaging research on the ischaemic penumbra have allowed for considerable extension of the treatment time window and better patient selection for reperfusion therapy. The translation of the penumbra concept into routine clinical practice has shown that “tissue is at least as important as time.”

Diagnosis and management of acute ischaemic stroke

Acute ischaemic stroke is a major public health priority and will become increasingly relevant to neurologists of the future. The cornerstone of effective stroke care continues to be timely reperfusion treatment. This requires early recognition of symptoms by the public and first responders, triage to an appropriate stroke centre and efficient assessment and investigation by the attending stroke team. The aim of treatment is to achieve recanalisation and reperfusion of the ischaemic penumbra with intravenous thrombolysis and/or endovascular thrombectomy in appropriately selected patients. All patients should be admitted directly to an acute stroke unit for close monitoring for early neurological deterioration and prevention of secondary complications. Prompt investigation of the mechanism of stroke allows patients to start appropriate secondary preventative treatment. Future objectives include improving accessibility to endovascular thrombectomy, using advanced imaging to extend therapeutic windows and developing neuroprotective agents to prevent secondary neuronal damage.

Mild fever as a catalyst for consumption of the ischaemic penumbra despite endovascular reperfusion

Cerebrovascular ischaemia is potentiated by hyperthermia, and even mild temperature elevation has proved detrimental to ischaemic brain. Infarction progression following endovascular reperfusion relates to multiple patient-specific and procedural variables; however, the potential influence of mild systemic temperature fluctuations is not fully understood. This study aims to assess the relationship between systemic temperatures in the early aftermath of acute ischaemic stroke and the loss of at-risk penumbral tissues, hypothesizing consumption of the ischaemic penumbra as a function of systemic temperatures, irrespective of reperfusion status. A cross-sectional, retrospective evaluation of a single-institution, prospectively collected endovascular therapy registry was conducted. Patients with anterior circulation, large vessel occlusion acute ischaemic stroke who underwent initial CT perfusion, and in whom at least four-hourly systemic temperatures were recorded beginning from presentation and until the time of final imaging outcome were included. Initial CT perfusion core and penumbra volumes and final MRI infarction volumes were computed. Systemic temperature indices including temperature maxima were recorded, and pre-defined temperature thresholds varying between 37°C and 38°C were examined in unadjusted and adjusted regression models which included glucose, collateral status, reperfusion status, CT perfusion-to-reperfusion delay, general anaesthesia and antipyretic exposure. The primary outcome was the relative consumption of the penumbra, reflecting normalized growth of the at-risk tissue volume ≥10%. The final study population comprised 126 acute ischaemic stroke subjects (mean 63 ± 14.5 years, 63% women). The primary outcome of penumbra consumption ≥10% occurred in 51 (40.1%) subjects. No significant differences in baseline characteristics were present between groups, with the exception of presentation glucose (118 ± 26.6 without versus 143.1 ± 61.6 with penumbra consumption, P = 0.009). Significant differences in the likelihood of penumbra consumption relating to systemic temperature maxima were observed [37°C (interquartile range 36.5 − 37.5°C) without versus 37.5°C (interquartile range 36.8 − 38.2°C) with penumbra consumption, P = 0.001]. An increased likelihood of penumbra consumption was observed for temperature maxima in unadjusted (odds ratio 3.57, 95% confidence interval 1.65 − 7.75; P = 0.001) and adjusted (odds ratio 3.06, 95% confidence interval 1.33 − 7.06; P = 0.009) regression models. Significant differences in median penumbra consumption were present at a pre-defined temperature maxima threshold of 37.5°C [4.8 ml (interquartile range 0 − 11.5 ml) versus 21.1 ml (0 − 44.7 ml) for subjects not reaching or reaching the threshold, respectively, P = 0.007]. Mild fever may promote loss of the ischaemic penumbra irrespective of reperfusion, potentially influencing successful salvage of at-risk tissue volumes following acute ischaemic stroke.

108 Endovascular clot retrieval beyond 24 hours for top of the carotid occlusion

IntroductionSub-clinoid proximal occlusion is defined by internal carotid artery (ICA) occlusion with intact Circle of Willis flow. We hypothesise that such cases of large vessel occlusion provide collateral blood flow to preserve the ischaemic penumbra and may benefit from endovascular clot retrieval (ECR) beyond 24 hours.MethodWe retrospectively searched the stroke database from 2018 at Calvary Hospital, Canberra, Australia for ECR cases performed beyond 24 hours from symptom onset.ResultsTwo patients were identified from the registry data.64-year-old man awoke with left hemiparesis and was last seen well 9.5 hours prior. ECR for ICA occlusion was not initially performed due to rapidly improving National Institute of Health Stroke Scale (NIHSS) of three to zero. ECR was later performed at 38.5 hours for clinical deterioration. Stroke aetiology was atrial fibrillation. At 90-day NIHSS and modified Rankin Scale (mRS) were three.75-year-old man awoke with left hemiparesis and was last seen well 10 hours prior. Baseline NIHSS was four. Off-label thrombolysis was administered based on salvageable penumbra on CTP, however ECR for ICA occlusion was not performed as neurointervention was unavailable. After 24 hours his NIHSS score improved to one but hemispheric hypoperfusion persisted on CTP. At 36 hours he underwent ECR with carotid stenting. Stroke aetiology was large-vessel atherosclerosis. At 90 days his NIHSS and mRS were zero.ConclusionAcute sub-clinoid proximal carotid occlusion requires tissue viability assessment with imaging to guide decision of ECR beyond 24 hours and may be of benefit.