American Journal of Emergency Medicine

American Journal of Emergency Medicine xxx (2013) xxx–xxx

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Review

Prehospital stroke diagnosis and treatment in ambulances and helicopters—a concept paper Thilo Hölscher MD a,⁎, James V. Dunford MD e, Felix Schlachetzki MD d, Sandra Boy MD d, Thomas Hemmen MD, PhD b, Brett C. Meyer MD b, John Serra MD c, Jeff Powers PhD f, Arne Voie PhD a a

Department of Radiology, Brain Ultrasound Research Laboratory (BURL), University of California, San Diego, CA, USA Department of Neurosciences, University of California, San Diego, CA, USA Department of Emergency Medicine, University of California, San Diego, CA, USA d Department of Neurosciences, University of Regensburg, Regensburg, Bavaria, Germany e City of San Diego Division of Emergency Medical Services, San Diego, CA, USA f Philips Ultrasound, Bothell, WA, USA b c

a r t i c l e

i n f o

Article history: Received 29 August 2012 Received in revised form 18 December 2012 Accepted 28 December 2012 Available online xxxx

a b s t r a c t Stroke is the second common cause of death and the primary cause of early invalidity worldwide. Different from other diseases is the time sensitivity related to stroke. In case of an ischemic event occluding a brain artery, 2 000 000 neurons die every minute. Stroke diagnosis and treatment should be initiated at the earliest time point possible, preferably at the site or during patient transport. Portable ultrasound has been used for prehospital diagnosis for applications other than stroke, and its acceptance as a valuable diagnostic tool “in the field” is growing. The intrahospital use of transcranial ultrasound for stroke diagnosis has been described extensively in the literature. Beyond its diagnostic use, first clinical trials as well as numerous preclinical work demonstrate that ultrasound can be used to accelerate clot lysis (sonothrombolysis) in presence as well as in absence of tissue plasminogen activator. Hence, the use of transcranial ultrasound for diagnosis and possibly treatment of stroke bares the potential to add to current stroke care paradigms significantly. The purpose of this concept article is to describe the opportunities presented by recent advances in transcranial ultrasound to diagnose and potentially treat large vessel embolic stroke in the prehospital environment. © 2013 Published by Elsevier Inc.

1. Introduction The need to improve upon disparities that restrict rapid identification and treatment of acute stroke is obvious. Stroke is both the second most common cause of death and the leading cause of early invalidity worldwide [1]. In the United States, nearly 800 000 people suffer an acute stroke every year, and globally, stroke accounts for 5.5 million deaths per year. Tissue plasminogen activator (tPA) is the accepted criterion standard of stroke current stroke therapy and the only drug approved by the US Food and Drug Administration (FDA) [2]. Innovative neurointerventional techniques provide new treatment options by mechanical removal of the vessel occluding thrombus [3-6]. 1.1. Limitations of current stroke treatment Because of delays in access and lack of effective stroke systems, the number of patients currently receiving tPA ranges between 1.6% [7] ⁎ Corresponding author. E-mail address: [email protected] (T. Hölscher).

and 9% [8] with an average of 3% to 4% of the global stroke population. The number of tPA-treated stroke victims who do show an improved outcome after 3 months varies between 30% [9] and 60% [10], depending on the literature cited. Two major limitations restricting the use of tPA are the time window (up to 4.5 hours after known onset of stroke symptoms) and the exclusion of an intracranial hemorrhage using cranial computer tomography (CT). The latter is the main reason why tPA can only be administered in the hospital because mobile CT units are not available. Exception of this rule is the mobile stroke unit, introduced by investigators at the Charité hospital in Berlin, Germany [11]. This unit carries a CT scanner, besides clinical chemistry capabilities, enabling the administration of tPA in the field. The concept of a mobile stroke unit, however, is rather cumbersome, expensive, requires greater manpower, and is not necessarily widely applicable, mainly because of the costs. Neurointerventional techniques designed to mechanically retrieve vessel-occluding blood clots show great promise but are limited to highly specialized medical centers with on-call trained interventionalists. By far, major limitation, however, is the lack of recognition of stroke symptoms and the delayed presentation after acute stroke onset.

0735-6757/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajem.2012.12.030

Please cite this article as: Hölscher T, et al, Prehospital stroke diagnosis and treatment in ambulances and helicopters—a concept paper, Am J Emerg Med (2013), http://dx.doi.org/10.1016/j.ajem.2012.12.030

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T. Hölscher et al. / American Journal of Emergency Medicine xxx (2013) xxx–xxx

1.2. Stroke care—a question of time and location Effective stroke care is much more likely in large metropoles where prehospital transportation commonly averages 15 minutes or less [12]. According to a recent publication 80% of the US population is within 60 minutes of a stroke center for air medical transport [13]. Stroke victims in rural communities may encounter transports that take hours. The odds of good outcomes are significantly higher in industrialized countries where state-of-the-art care can be quickly accessed [14]. However, 85% of all strokes occur in low- to middleincome countries where 85% of the world's population resides [15]. The risk of stroke rises with increasing age. By 2025, more than 800 million senior citizens (age ≥ 65 years) will reside in developing countries, predominantly in Asia and Latin America [15]. Clearly, most of the world's stroke victims would benefit from quick, simple, and effective interventions. In an effort to limit the time-dependent loss of brain tissue, any delay in diagnosis and treatment should be avoided and ideally started once the emergency call has been dispatched. In ischemic stroke, nearly 2 million neurons die every minute [16]. The purpose of this article is to describe the opportunities presented by recent advances in transcranial ultrasound to diagnose and potentially treat ischemic strokes in the prehospital environment. 2. Prehospital transcranial ultrasound The body of literature demonstrating the use of portable ultrasound devices for early diagnostic assessment at the emergency scene or during transport is rapidly increasing [17-22]. Yet, their use is far from being accepted or even considered as a standard tool for prehospital personnel. The range of potential diagnostic indications for prehospital ultrasound now includes focused sonographic assessment in trauma [22-25], cardiac arrest [26-28], chest examination [29-31], or placement of intravenous catheters [32]. Recently, the feasibility of prehospital transcranial ultrasound to diagnose large vessel embolic stroke has been demonstrated [33,34]. In 2011, a case report of a 49-year-old man, diagnosed and treated with transcranial ultrasound at an altitude of 5900 m, was published suggesting that portable ultrasound could be used in the prehospital arena to enable early diagnosis of thrombotic stroke [35]. In 2008, the first pilot study demonstrated the feasibility of prehospital transcranial ultrasound to assess intracranial arteries in a prehospital environment [33]. Non–contrast-enhanced transcranial duplex ultrasound studies were performed by emergency neurologists either on-site (eg, private home) or upon transfer of potential stroke patients to a medical helicopter (Fig. 3) or ambulance. Visualization and Doppler flow measurements of both middle cerebral arteries (MCA) could be adequately assessed in 20 (80%) of 25 patients. In the remaining 5 cases, intracranial vessels could not be visualized due to insufficient quality of the temporal bone window. The average delay from arrival at the scene to completion of the ultrasound study was 12 minutes, which included first aid provided by the physician. The average task time to complete the transcranial ultrasound study was 2 minutes. A recent follow-up study demonstrated the diagnostic accuracy and time requirement for transcranial duplex ultrasound-assisted assessment of stroke patients in the prehospital setting [34]. After dispatch to “911 stroke code” calls, neurologists with expertise in ultrasonography rendezvoused with paramedic teams at the site of the emergency. After brief neurologic assessment, patients underwent a transcranial ultrasound study either on-site or in an ambulance. An ultrasound contrast microbubble agent was administered in cases of insufficient temporal bone windows. As a microbubble agent, SonoVue (BRACCO Imaging, Italy) was used. Depending on the individual quality of the temporal bone window, 0.5 to 2.0 mL of the microbubble solution was administered via a peripheral cubital or

Fig. 1. Visualization of the Circle of Willis in standard color Doppler mode. Red indicates flow toward the ultrasound probe; blue indicates flow away from it. PCA, posterior cerebral artery; CS, contralateral skull.

forearm vein. In a meta-analysis, the results of 113 patients were analyzed. Middle cerebral artery occlusion was diagnosed in 10 patients by either CT angiography or magnetic resonance tomographic angiography. In 9 of these 10 patients, MCA occlusion could be visualized in the prehospital setting using contrast-enhanced or non– contrast-enhanced transcranial duplex ultrasound. Overall, the sensitivity of a “field diagnosis” of MCA occlusion was 90%, whereas the specificity was 98%. The mean time between arrival at the site of the emergency and the transcranial ultrasound examination was 5.6 minutes. The authors reported that the use of contrast agent microbubbles was beneficial in cases with insufficient temporal bone windows. The use contrast microbubbles also shortened the examination time, increased diagnostic confidence, and was found useful during difficult examinations. Limitation of both studies mentioned above is that they were performed in physician-staffed ambulances or helicopters, which is not the case in other countries, such as the United States.

Fig. 2. Presentation of an ipsilateral MCA/ACA occlusion in standard color Doppler mode. The missing color Doppler signal of the MCA and ACA (_) is indicative for no flow in these supply areas. Red indicates flow toward the ultrasound probe; blue indicates flow away from it. PCA, posterior cerebral artery; CS, contralateral skull.



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absent flow contralateral to a patient's hemiplegic arm/leg was suggestive of an acute stroke. An example of a MCA/anterior cerebral artery (ACA) occlusion as it presents on the screen of the ultrasound device is given in Fig. 2. 3. Current state of transcranial ultrasound for stroke treatment 3.1. Macrovasculature

Fig. 3. Ultrasound experienced neurologist performing a transranial ultrasound study inside the helicopter.

2.1. Use of wireless technology for stroke care The use of wireless technology to enhance stroke care in the prehospital setting can be provided in numerous ways. The overall goal is improved stroke evaluation by use of real-time image/video data transfer to a dedicated stroke center. In recent years, real-time assessment by stroke neurologists via remote telecommunication has been shown to significantly improve stroke care [36-41]. Telemedicine has provided remarkable improvement in appropriate use of tPA in stroke victims cared for in nonstroke certified hospitals [37]. Most current telemedicine projects are based upon remote communication between hospitals. However, studies assessing telecommunication between emergency vehicles and expert staffed medical facilities are now underway. The latter could 1 day significantly improve the triage of stroke victims to primary and comprehensive stroke centers. Recently, Liman et al [42] used live video streaming from ambulance to the hospital to assess stroke symptoms using a well-established stroke scale (National Institute of Health Stroke Scale). The authors concluded that remote assessment of the National Institute of Health Stroke Scale in a moving vehicle was clinically feasible in only 40% of cases due to limitations including loss of connection and difficulties in performing a sophisticated remote clinical assessment. 2.2. Prehospital transcranial ultrasound and wireless technology Currently, University of California, San Diego, stroke researchers and City of San Diego paramedics are initiating a trial to transmit ultrasound image/video data from a portable duplex ultrasound device to a regional stroke center for real-time evaluation during patient transport. In collaboration with Philips Ultrasound, a high-end duplex ultrasound device has been modified using 4G bandwidth for wireless data transfer. The technical feasibility to transmit image/ video data within seconds over short (urban) or long (west-east USA) distances has been demonstrated (unpublished data). The approximate start date of this clinical project, which is sponsored by the MedEvac Foundation International, is December 2012. As phase one of this project, a 4-hour voluntary training program for emergency physicians, paramedics, and EMTs was held for the first time in May 2012. Students received instruction in cranial anatomy including recognition of bony and vascular landmarks (Fig. 1) and identification of temporal bone windows that permit adequate signal transmission. During a 4-hour sessions, 45 students achieved competency in identifying and calculating bilateral middle cerebral artery flow. Students were taught that bilateral equal Doppler-quantified MCA flow was inconsistent with large-vessel stroke, whereas weak or

It is known that ultrasound has the capability to mechanically disaggregate the fibrin network of a blood clot. The prothrombolytic effect of ultrasound in combination with tPA has been demonstrated [43-47], leading to a first clinical trial in humans in 2004. Alexandrov et al [48] showed that the time to MCA recanalization was significantly decreased when tPA was used in combination with 2 hours of continuous transcranial ultrasound exposure. In this study, diagnostic ultrasound devices were used. All devices fulfilled the FDA safety standards for transcranial ultrasound. During the last 8 years several additional studies have shown the potential benefit of tPA in combination with diagnostic ultrasound [49-51]. Recently, it has been demonstrated that the combined effect of tPA and ultrasound might be further enhanced when combined with ultrasound microbubbles. Microbubbles were introduced in the early 1990s to enhance diagnostic imaging with ultrasound. The effect of microbubble signal enhancement is very different from conventional radiological contrast agents based upon their specific acoustic properties in a sound field. With regard to thrombolysis, microbubbles enhance the mechanical impact of the ultrasound wave on the blood clot due to oscillation and/or bubble disruption [52,53]. Despite the excitement about this potential therapeutic approach, the overall number of stroke victims who might benefit from it is currently limited by the small number of patients who are eligible for tPA treatment. Hence, it has been postulated that the combination of ultrasound and microbubbles alone, in absence of tPA, might have a beneficial effect on thrombolysis [54-58]. In vitro as well as in vivo studies confirm this hypothesis, suggesting a potential benefit of combinational therapy for stroke victims who are not eligible for tPA or neurointervention or as a pretreatment or treatment initiation. 3.2. Microvasculature In addition to re-establishing blood flow in large vessels, the combination of ultrasound and microbubbles has been shown to have a beneficial effect on the microcirculation in presence of an ischemic event. Initial studies performed in rabbit thigh muscles demonstrated that the exposure to ultrasound and microbubbles led to a significantly reduced ischemic area even if the main feeding vessel, which caused the ischemia, could not be recanalized [59]. Similar results were reported in a cardiac ischemic model showing significantly reduced ischemic areas after ultrasound treatment [60]. Very recently, similar results were reported for ischemic brain tissue using a rabbit stroke model [61]. The mechanisms regarding how ultrasound in combination with microbubbles confers neuroprotective/ tissue-protective effect are not sufficiently understood. One current hypothesis is that microbubbles in combination with ultrasound cause mechanical sheer on the endothelial layer, leading to the release of nitric oxide, a potent vasodilator. Improved perfusion of collaterals that supply blood to the penumbra or tissue at risk in the ischemic zone can limit the expansion of the core infarct. 4. Future directions 4.1. Potential use of ultrasound for prehospital stroke treatment The ultimate goal of definitive stroke care is the initiation of beneficial treatment at the earliest time possible. Based on


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preliminary data, ultrasound treatment could be initiated in as little as 10 minutes following the arrival of prehospital personnel. Confirmation or exclusion of a major vessel occlusion using transcranial ultrasound should not take longer than 2 minutes in most suspected stroke victims. Whether treatment might be initiated using the same diagnostic ultrasound device or a dedicated treatment system is part of ongoing investigations. The latter includes innovative approaches to use transcranial ultrasound in combination with microbubbles in a safe manner without either causing intracranial hemorrhages or increasing already existing bleeds. If this could be accomplished, dedicated ultrasound treatment devices might be used simply based on the clinical symptom presentation of a potential stroke victim. All potential treatment approaches share the common goal of recanalizing the culprit vessel and improving brain tissue perfusion based upon the mechanical effects of ultrasound (with or without microbubbles) in absence of tPA. Stroke is a devastating disease. Its socioeconomic impact on both the victim and society is very significant. Unfortunately, the incidence of stroke is increasing worldwide. The armory of today's treatment options is limited to only 1 FDA-approved drug (tPA) and a small number of clot retrieval devices. The principal that “time is brain” is now indisputable, and all medical care providers recognize that stroke should be diagnosed and treated at the earliest time moment to improve long-term outcome. Until now, a key metric of quality has been to minimize the “door-to-needle” time, which describes the interval between the patient's arrival in the emergency department and the initiation of treatment. Similar to the management of STelevation myocardial infarction, it may be that a better metric of stroke care will 1 day seeking to minimize the “EMS-to-Transcranial Ultrasound” time as well.

4.2. Limitations of transcranial ultrasound Critically, it has to be addressed that the establishment of a prehospital stroke system, including diagnostic ultrasound devices, the potential use of microbubbles, the technical requirements for wireless data transfer, the training of emergency medical services personal, the introduction of potential ultrasound treatment devices, and others, requires a fairly sophisticated work force and financial efforts. Both will not be negligible and might be a limiting factor to some extent. This might be of concern especially in developing countries and rural areas where resources are limited. A reasonable discussion on this topic might be initiated by the question what the current standard of stroke care, for example, in developing countries is. Tissue plasminogen activator treatment and, more so, neurointerventional approaches, which might be accepted as standard of care in industrialized countries, are costly and simply not affordable in lowincome countries. The stroke burden, however, might be the same or even higher in comparison with industrialized countries. Consequently, there is a high demand for cost-efficient strategies specifically in those countries where standard stroke care is either too expensive or simply not available. If the concept of prehospital stroke care, as suggested in the present article, should prove to be efficacious, however, the long-term gain medically as well as socioeconomically would outweigh by far the initial investments. The prehospital use of ultrasound for therapeutic purposes should be viewed as “treatment initiation” that in no way excludes patients from established stroke therapies. The hope would be that ultrasound can serve to “precondition” the culprit clot to increase its therapeutic sensitivity to tPA or neurointervention while providing neuroprotection for tissue at risk. Research in this regard must follow strict safety requirements to assure that prehospital, ultrasound-based treatment neither causes nor exacerbate intracranial bleeding or harms patients who do not have an embolic stroke as the cause for their symptoms.

In other words, the concept of prehospital ultrasound stroke diagnosis and pretreatment should be viewed as augmenting established paradigms of care. 5. Conclusion Time remains the most important denominator for successful stroke treatment. Yet, few strategies address stroke before the patient arrives at the hospital. The current curriculum stresses attention to basic life support activities (airway, breathing, and circulation), assessing blood glucose and administering supplemental oxygen, establishing an intravenous access, and expediting transport to a designated stroke center if one exists. Novel approaches have been either cumbersome and costly (such as the “mobile stroke unit,” at the Charité Hospital in Berlin/Germany) [11] or technologically challenging, such as the wireless telecommunication project described by Liman et al [42]. The use of prehospital transcranial ultrasound to diagnose ischemic strokes, performed by trained emergency medical services personnel, including physicians, paramedics, and EMTs and linked via wireless technology for rapid evaluation by stroke and ultrasound specialists, could significantly improve stroke care. The initiation of stroke treatment in the prehospital scenario via transcranial ultrasound would advance this technology far beyond its diagnostic capabilities. Only large randomized trials will provide the answer as to whether prehospital stroke diagnosis and treatment using ultrasound is a valuable “first aid” strategy for millions of stroke victims. Acknowledgment The Prehospital Transcranial Stroke Diagnosis Using Ultrasound And Wireless Technology project at the University of California, San Diego, has been supported by the MedEvac Foundation International. Philips Ultrasound, Bothell/Washington, USA, provides the portable duplex ultrasound device, equipped with 4G wireless capability, for the aforementioned project. The Bavaria California Technology Center (BaCaTec) provides travel funds for the ongoing joint project between the University of Regensburg, Germany, and the University of California San Diego, USA. References [1] Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 2008;371(9624): 1612–23. [2] Zivin JA. Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA). Ann Neurol 2009;66(1):6–10. [3] Broussalis E, Trinka E, Hitzl W, Wallner A, Chroust V, Killer-Oberpfalzer M. Comparison of stent-retriever devices versus the merci retriever for endovascular treatment of acute stroke. AJNR Am J Neuroradiol 2012. [4] Noorian AR, Gupta R, Nogueira RG. Acute stroke: techniques and results with the Merci retriever. Tech Vasc Interv Radiol 2012;15(1):47–52. [5] Dorn F, Stehle S, Lockau H, Zimmer C, Liebig T. Endovascular treatment of acute intracerebral artery occlusions with the solitaire stent: single-centre experience with 108 recanalization procedures. Cerebrovasc Dis 2012;34(1):70–7. [6] Soize S, Kadziolka K, Estrade L, Serre I, Bakchine S, Pierot L. Mechanical thrombectomy in acute stroke: prospective pilot trial of the solitaire FR device while under conscious sedation. AJNR Am J Neuroradiol 2012. [7] Reed SD, Cramer SC, Blough DK, Meyer K, Jarvik JG. Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals. Stroke 2001;32(8):1832–40. [8] Grotta JC, Burgin WS, El-Mitwalli A, et al. Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000. Arch Neurol 2001;58(12):2009–13. [9] Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333(24):1581–7. [10] Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60(5):508–17.


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