Dear Editor,

Time is brain in the treatment of acute stroke. Minimizing time to treatment with intravenous thrombolysis and/or endovascular treatment (EVT) for ischemic stroke is a priority because faster treatment increases the chance of achieving functional independence by a large margin: on average, every 30-min reduction in onset to needle time is associated with nearly 2% increase in chances of excellent functional outcome, and every 60-min reduction in onset-to-groin puncture is associated with a 6–10% increase in chances of functional improvement at 90 days [1‒3]. Ultra-early treatment – “golden-hour thrombolysis” (intravenous thrombolysis within 60 min of symptom onset) – is known to be associated with twice the odds of an excellent functional outcome [4].

While time is brain as a dictum has been used for ischemic stroke alone, it likely holds true for intracerebral hemorrhage as well [5]. A recent secondary analysis from the “Transfer to the Closest Local Stroke Centre versus Direct Transfer to Endovascular Stroke Centre of Acute Stroke Patients with Suspected Large Vessel Occlusion in the Catalan Territory” (RACE-CAT) trial showed that patients with a final diagnosis of intracerebral hemorrhage who were transferred directly to EVT-capable centers, bypassing the nearest local stroke center, had a longer time from stroke onset to neuroimaging and worse functional outcomes [6]. Possible reasons for this observation include delays in initiating prompt intracerebral hemorrhage management with blood pressure reduction and reversal of anti-thrombotics. Because time to treatment is such an essential and modifiable factor in determining patient outcomes, it seems intuitive to say that the biggest future stroke research efforts should be made in the pre-hospital epoch.

While in-hospital stroke workflows continue to be optimized with various time metrics targets recommended in current guidelines [7], the field of pre-hospital stroke triage remains understudied. Pre-hospital stroke triage is essential in the prompt diagnosis of acute stroke, initiating hyper-acute treatment/management and optimizing transport to primary or comprehensive stroke centers according to the likelihood of EVT eligibility. However, pre-hospital stroke triage remains highly variable and context-specific. It depends on geography, loco-regional infrastructure, the availability of human workforce, financial resources, and the wider context of the roles of emergency medical services (EMS) responders and their expected responses in different healthcare systems. EMS responder approaches can vary based on either protocolized methods learned through vocational training or through advanced assessment skills from professional diploma or degree qualifications [8]. Despite the successes of recent pre-hospital stroke trials, conducting pre-hospital stroke research remains in its infancy compared to other aspects of stroke research and management [9‒12]. High-level evidence in pre-hospital stroke care remains limited, despite the potential to exploit various opportunities available in improving an important pathway in overall stroke management. Key issues to improving pre-hospital stroke care and implementing pre-hospital stroke trials, for diagnostic and therapeutic purposes, were highlighted at the recent 5T stroke conference in September 2023 (Table 1).

Table 1.

List of challenges and recommendations of pre-hospital stroke triage and research

ChallengesRecommendations
Clinical diagnosis and training 
 1. Inadequate knowledge and lack of standardized education content in detection of stroke among EMS responders 1. Uniformity of training provided should consider the heterogeneity in skill sets and the fields of interest among EMS providers. 
 2. Capability to upskill and maintain specialized knowledge in various triage techniques 2. NIHSS as a screening tool may be feasibly used following training of EMS providers. 
 3. Lack of formalized training in research, research mentorship, and funding opportunities 3. Increase opportunities and support for EMS providers’ involvement in research or education by in-hospital medical and allied staff. 
Use of technology 
 1. Limited small, simple, and affordable mobile devices to reliably detect acute stroke 1. Transcranial Doppler ultrasound or point-of-care blood biomarker testing to detect LVO, VIPS to detect changes in the bioimpedance of brain tissue, or EEG to detect changes in brain electrophysiology in acute stroke. 
 2. High stroke mimic rates and inclusion of non-targeted cohorts of enrolled patients in pre-hospital stroke trials causing inflated sample sizes 2. Implementation of MSU in healthcare systems to (i) aid the diagnosis of acute stroke, (ii) stratifying stroke type, and in turn (iii) reducing the sample size required in pre-hospital stroke trials, and (iv) facilitating further research in simpler and cheaper acute stroke detection, all while considering the financial costs of running an MSU. 
Clinical information and consent opportunities 
 1. Limited clinical history and lack of immediate access to previous hospital attendances or investigations readily available to EMS providers. 1. Improving communication between the EMS and in-hospital stroke teams via high-speed data connection and video recordings allows instant connectivity to stroke neurologists at base hospitals to (i) aid in the decision making process or troubleshooting of complications and (ii) patient or proxy consent for recruitment into trials. 
 2. Emergently consenting patients or their next of kin for treatment and enrollment in pre-hospital trials 2. Pragmatic AI-based software as an alternative to aid EMS teams in the triage and emergent data capture or transfer of clinical information. 
3. Automated pre-hospital transportation alerts and feedback loops may facilitate simultaneous preparation of the in-hospital stroke team to receive and transfer patients. 
ChallengesRecommendations
Clinical diagnosis and training 
 1. Inadequate knowledge and lack of standardized education content in detection of stroke among EMS responders 1. Uniformity of training provided should consider the heterogeneity in skill sets and the fields of interest among EMS providers. 
 2. Capability to upskill and maintain specialized knowledge in various triage techniques 2. NIHSS as a screening tool may be feasibly used following training of EMS providers. 
 3. Lack of formalized training in research, research mentorship, and funding opportunities 3. Increase opportunities and support for EMS providers’ involvement in research or education by in-hospital medical and allied staff. 
Use of technology 
 1. Limited small, simple, and affordable mobile devices to reliably detect acute stroke 1. Transcranial Doppler ultrasound or point-of-care blood biomarker testing to detect LVO, VIPS to detect changes in the bioimpedance of brain tissue, or EEG to detect changes in brain electrophysiology in acute stroke. 
 2. High stroke mimic rates and inclusion of non-targeted cohorts of enrolled patients in pre-hospital stroke trials causing inflated sample sizes 2. Implementation of MSU in healthcare systems to (i) aid the diagnosis of acute stroke, (ii) stratifying stroke type, and in turn (iii) reducing the sample size required in pre-hospital stroke trials, and (iv) facilitating further research in simpler and cheaper acute stroke detection, all while considering the financial costs of running an MSU. 
Clinical information and consent opportunities 
 1. Limited clinical history and lack of immediate access to previous hospital attendances or investigations readily available to EMS providers. 1. Improving communication between the EMS and in-hospital stroke teams via high-speed data connection and video recordings allows instant connectivity to stroke neurologists at base hospitals to (i) aid in the decision making process or troubleshooting of complications and (ii) patient or proxy consent for recruitment into trials. 
 2. Emergently consenting patients or their next of kin for treatment and enrollment in pre-hospital trials 2. Pragmatic AI-based software as an alternative to aid EMS teams in the triage and emergent data capture or transfer of clinical information. 
3. Automated pre-hospital transportation alerts and feedback loops may facilitate simultaneous preparation of the in-hospital stroke team to receive and transfer patients. 

EMS, emergency medical services; LVO, large vessel occlusion; VIPS, volumetric impedance phase-shift spectroscopy; EEG, electroencephalography; MSU, mobile stroke unit; AI, artificial intelligence.

The introduction of pre-hospital stroke and EVT triage protocols in the stroke workflow has been shown to increase access to EVT by fourfold compared to healthcare systems without such protocols in place [13]. However, current pre-hospital stroke and EVT triage relies on clinical tools both for the diagnosis of stroke and to assess stroke severity by the EMS responders in the field [14]. A recent survey identified inadequate knowledge and training in detection of stroke due to large vessel occlusion (LVO), stroke severity scales, and stroke center levels among EMS responders in the USA [15]. Up to a third of respondents did not receive any training in stroke severity or stroke due to LVO assessment, while the lack of standardized educational content provided was identified as a limitation among those who did [15]. Because the number of dispatches for suspected stroke represent a small proportion of paramedic practice, the capability to upskill and maintain specialized knowledge in various triage techniques remains a challenge. However, such a feat of training paramedics in Norway to use the National Institutes of Health Stroke Scale (NIHSS) as a screening tool has been shown to be feasible in the “Paramedic Norwegian Acute Stroke Prehospital Project” (ParaNASSP) trial. While it is now being implemented across the entire country, its effectiveness in improving patient care or system efficiency remains uncertain [12]. Nevertheless, uniformity of training provided should also consider the heterogeneity in skill sets and fields of interest among the EMS providers, which can range from experienced medical physicians to medical technicians [8]. Increasing the skill set and active involvement of EMS providers in pre-hospital-based research have been beset by the lack of formalized training in research, research mentorship, and funding opportunities. Perhaps, to ensure continued engagement of EMS providers in pre-hospital stroke trials, opportunities for EMS providers’ involvement in research or education should be created and their efforts supported by hospital-based staff including physicians, in more formal ways, while improving research collaborations between academic institutions and their EMS counterparts. Additional ideas include the development of a brief “observership or exchange program” which would facilitate paramedics in being involved in the entire in-hospital stroke care at an EVT-capable center; understanding the entire chain of care may improve their engagement and motivation at the front end. This is a tough challenge that may be achievable in only a few well-developed health systems. More foundational work is still needed in low- and middle-income countries who have the largest burden of stroke and are limited by resources with already stretched emergency services.

The use of mobile stroke units (MSU) equipped with a non-contrast computed tomography (CT) head and even CT angiography has advantages by aiding in the diagnosis of acute stroke (vs. stroke mimics) and stratifying stroke type, accelerating the initiation of hyper-acute stroke management, as well as facilitating further research into simpler and cheaper acute stroke detection methods [9, 16, 17]. Specificity of diagnosis, in particular, is an essential element in sample size efficiency for pre-hospital stroke trials. While MSUs may be an attractive option, the cost to purchase and maintain the specialized equipment, the requirement for on-board trained physicians or paramedics, and restricted geographical coverage due to the paucity of available MSUs have been a critical factors in preventing its adoption in various healthcare systems [18]. Furthermore, the minimal clinically effective time (and hence distance) for dispatch for suspected stroke to be deemed superior to current simpler triage methods remains undetermined.

There are ongoing efforts to develop smaller, less sophisticated, and more affordable mobile devices to reliably detect acute stroke. These include transcranial Doppler ultrasound to detect LVO, volumetric impedance phase-shift spectroscopy (VIPS) to detect changes in the bioimpedance of brain tissue, or electroencephalography (EEG) to detect changes in brain electrophysiology in acute stroke, all of which have shown promise and may be increasingly used in future trials [19‒22]. Furthermore, point-of-care testing using blood-based biomarkers is being investigated to reliably detect and differentiate hemorrhagic and ischemic stroke types [23]. High stroke mimic rates and inclusion of non-targeted cohorts of enrolled patients are clear limitations of pre-hospital stroke trials. For example, the “Prehospital Transdermal Glyceryl Trinitrate in Patients with Ultra-Acute Presumed Stroke” (RIGHT-2) pre-hospital stroke trial which primarily utilized the face-arm-speech-time (FAST) score as assessed by paramedics to identify eligible patients, resulted in a high rate of stroke mimics of approximately 30% and hence an increase in sample size following the interim analysis [10]. On the other hand, poorer functional outcome was demonstrated among patients with underlying intracerebral hemorrhage who were inadvertently enrolled and bypassed local stroke centers in the RACE-CAT trial, which was primarily designed to evaluate the effectiveness of direct transfer to EVT-capable centers for patients with suspected LVO ischemic stroke [6]. If proven effective and safe in larger trials, portable stroke detection devices, such as EEG helmets, transcranial ultrasound or VIPS headbands, or point-of-care blood biomarker testing, could be translated into the real-world setting within the next few years. These promising technologies, in addition to current triage techniques, could reduce the need for inflated sample sizes, reduce the associated costs, and invariably improve the precision of recruitment of the target population to be studied in pre-hospital clinical therapeutic trials. However, implementation of any pre-hospital stroke pharmacological or non-pharmacological intervention methods will need to be balanced with the optimization of the already limited storage space in current ambulances or emergency response vehicles. Overall, successful large-scale application of pre-hospital stroke trials utilizing these varying triage methods will certainly require adequate and repeated training to ensure the EMS team in the field is capable of feasibly using such methods to make rapid triage decisions. Importantly, early and sustained engagement with EMS providers in the design of pre-hospital trials may also improve the delivery and the compliance of EMS responders in pragmatically integrating the trialed intervention with their current workflow.

Not infrequently, there is limited clinical history readily available to EMS providers, along with a lack of immediate access to previous hospital attendances or investigations. This increases the challenge and complexity of making rapid and accurate diagnoses and consenting patients or their next of kin for treatment and enrollment in clinical trials, particularly for study designs and in healthcare systems that do not support deferred or full waiver of consent. Improving communication between the EMS and in-hospital stroke teams may improve diagnostic accuracy and hence treatment appropriateness by allowing instant connectivity to stroke neurologists at the base hospital to aid in the decision making process, patient or proxy consent and recruitment into trials, and the delivery or troubleshooting of complications of the proposed intervention. Having this level of support with adequate infrastructure and connectivity via high-speed data connections and video recordings may also indirectly increase the confidence and engagement of EMS providers in conducting future pre-hospital trials while reducing their overall burden and responsibility in the pre-hospital stroke care [8]. For instance, the “Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pre-hospital stroke trial which investigated the effectiveness of magnesium sulfate as a neuroprotective agent in acute stroke utilized a two-stage screening process to identify eligible patients for enrollment [11]. This included a brief modified Los Angeles Prehospital Stroke Screen (LAPSS) score used by paramedics, followed by further assessment by a hospital-based physician-investigator, which resulted in recruitment of a lower than expected overall rate of stroke mimics (3.9%) [11]. Well-designed, pragmatic AI-based software could also be alternatives to aid EMS teams in the triage and emergent data capture or transfer of relevant clinical information required in routine clinical practice and in stroke trials. Automated pre-hospital transportation alerts may also facilitate simultaneous preparation of the in-hospital stroke team to receive and transfer patients directly for any further imaging workup and EVT treatment [24]. In similar light, automated feedback loops could be useful in alerting EMS responders of the diagnostic and treatment outcomes of the patients they had triaged, invariably maximizing their learning opportunities, and improving future patient care.

The ability to obtain earlier diagnoses and implement hyper-acute treatment for acute ischemic stroke patients opens up avenues for further research into neuroprotective or adjunctive therapy trials, involving both pharmacological and non-pharmacological interventions that aim to reduce infarct growth and cerebral edema, prior to eventual more definitive treatment, such as EVT [25, 26]. Further work in shifting the balance of the overall workload from the hospital to the pre-hospital setting by improving the overall education and training of EMS providers in acute stroke detection and management and exploiting current technological advancements to optimize pre-hospital stroke detection and communication methods should be prioritized. These strategies will invariably aid in the conduct of more robust pre-hospital stroke trials, which are needed to generate high-level evidence in pre-hospital stroke care at a faster pace. Updating current research priorities with adequate distribution of research funding in pre-hospital stroke care should be strongly considered. The “LetsGetProof” platform is an example of an excellent avenue to create working groups to develop new studies and encourage further discussion while fund raising for proposed trials [27]. Engagement with all stakeholders, including the EMS team, emergency physicians, stroke neurologists, neurointerventionists, as well as the policymakers, is required in order to further develop and improve pre-hospital stroke triage pathways while accounting for the cost-effectiveness of each strategy, which may differ according to the local healthcare systems.

We thank all participating members that were involved in and contributed to the discussion on the various topics covered at the 5T Stroke Conference 2023.

J.M.O. is a consultant for NICOLab. M.G. reports receiving an unrestricted institutional grant from Medtronic; he received a grant from Stryker and consulting fees from Stryker, MicroVention, and Mentice; he holds patent rights in systems and methods for acute stroke diagnosis with GE Healthcare. M.D.H. reports unrestricted grant funding for the ESCAPE trial to the University of Calgary from Covidien/Medtronic and active/in-kind support consortium of public/charitable sources (Heart and Stroke Foundation, Alberta Innovates Health Solutions, Alberta Health Services) and the University of Calgary (Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, and Calgary Stroke Program); grant funding from Boehringer Ingelheim, NoNo Inc., and Stryker; personal fees from Merck; and nonfinancial support from Hoffmann-La Roche Canada. M.D.H. also has a submitted patent for triaging systems in ischemic stroke and owns stock in Calgary Scientific, a company that focuses on medical imaging software. No other disclosures or competing interests declared by the remaining authors.

No specific funding was sought for this study.

Drafting of the manuscript: Permesh Singh Dhillon and Nishita Singh. Critical revision of the manuscript: Permesh Singh Dhillon, Nishita Singh, Johanna Maria Ospel, Bob Roozenbeek, Mayank Goyal, and Michael D. Hill. All authors approved the final version of the manuscript.

No new data generated or analyzed. All data are available within the original publications of included studies.

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