Prehospital stroke care: telemedicine, thrombolysis and neuroprotection.

Review

Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nyu Medical Center on 06/27/15 For personal use only.

Prehospital stroke care: telemedicine, thrombolysis and neuroprotection Expert Rev. Neurother. 15(7), 753–761 (2015)

Joachim Weber*1, Martin Ebinger1,2 and Heinrich J Audebert1,2 1 Department of Neurology, Charite-Universita¨tsmedizin Berlin, Berlin, Germany 2 Center for Stroke Research Berlin (CSB), Charite – Universita¨tsmedizin Berlin, Berlin, Germany *Author for correspondence: Tel.: +49 304 50543524 Fax: +49 308 4454264 [email protected]

Over the last 15 years, new approaches regarding neuroprotective and thrombolytic strategies in stroke management have been evaluated in the prehospital setting. These efforts have provided exciting new potentials of hyperacute stroke care. Trials have shown that the use of specialized stroke ambulances increases the proportion of patients receiving intravenous thrombolysis and shortens alarm-to-treatment time by approximately half an hour compared to standard care. Intravenous thrombolysis within the ultra-early time window of the ‘golden hour’ has become a realistic scenario. However, direct effects of prehospital stroke care on functional outcome have yet to be shown and other approaches such as neuroprotective treatments could not demonstrate clinical benefit so far. There is a clear need for systematic research in the prehospital field to test the clinical effectiveness and cost–effectiveness of new therapeutic strategies. It will be necessary to test various components of prehospital stroke care alone and in combination. KEYWORDS: endovascular treatment . hemorrhagic stroke . ischemic stroke . neuroprotection . prehospital stroke care .

stroke ambulance . thrombolysis

Acute stroke treatment experienced a revolutionary paradigm change in recent years. Prehospital stroke management now offers the opportunity to improve the efficacy of wellestablished treatments as well as to implement new strategies. Although great efforts have been made over the last years in avoiding in-hospital treatment delays [1–3], this approach only tackles part of the problem. Time from onset to treatment is a compound of the time from appearance of first stroke symptoms to seeking medical help, the time from emergency call to hospital arrival and the in-hospital time interval (the so-called door-to-needle time) [4]. Exclusively focusing on the latter has only a limited potential in time saving [5]. This is particularly relevant given the fact that the chance of a successful recovery from ischemic stroke depends strongly on the time between the onset of symptoms and the administration of effective therapies [6,7]. Recent studies suggest that treatment of ischemic stroke in the first 60 min after the onset of symptoms is associated with improved outcomes, but in standard care, only a small proportion of patients is

informahealthcare.com

10.1586/14737175.2015.1051967

treated with tissue plasminogen activator (tPA) in this ‘golden hour’ of stroke [8]. The relevance of precise diagnostic as well as swift action is emphasized through the corresponding results of a number of studies regarding early intra-arterial treatment in case of large artery occlusion [9–12]. A similar situation applies to patients suffering from intracerebral hemorrhage. It is well-known that during the first hours after onset, hematoma growth is common and associated with poor clinical outcome [13]. The prehospital detection of intracerebral hemorrhage allows immediate start of antihypertensive treatment [14] and subsequent transport to specialized facilities where patients can receive intensive care management and – if needed – neurosurgical intervention [15]. Even in subarachnoid hemorrhage, the use of neuroprotective agents such as albumin may also have a potential to improve outcome [16]. For these reasons, a rethinking of the rescue chain in stroke management has started, which no longer insists on waiting for the patient to arrive in the hospital but rather on optimizing processes already at the dispatcher level and bringing diagnostic tools and treatment to the patient.

Ó 2015 Informa UK Ltd

ISSN 1473-7175

753

Review

Weber, Ebinger & Audebert

597 citations matched the search criteria 549 articles excluded after screening title and abstract


48 articles

19 articles excluded after screening full texts

29 articles

7 articles in optimizing dispatcher algorithm

8 articles in ‘telestroke’

8 articles in diagnostic and thrombolysis

6 articles in ‘neuroprotection’

Figure 1. Study selection process flow chart for review.

Methods Data sources & searches

The authors performed a systematic review of prehospital stroke care with a focus on telemedicine, thrombolysis and neuroprotection. The search was applied to Pubmed for publications starting from 1 January 2004 (data search date: 15 March 2015) using the search terms ‘stroke AND (prehospital OR ambulance) AND (thrombolysis OR treatment OR neuroprotection OR telemedicine OR telestroke OR telecommunication OR dispatcher)’. Further information was retrieved through a manual search of references from recent reviews and other relevant published studies. Selection of studies

Title, keywords and abstracts of the identified citations were initially screened. Studies were excluded if they were irrelevant, with decision-making based on title and abstract. The authors selected publications after obtaining the full texts of the remaining articles. Disagreement was resolved through consensus. The relevant information was finally extracted by two of the authors (HJA and JEW). Criteria for inclusion & exclusion

The authors considered original works in the form of randomized as well as quasi-randomized controlled trials, nonrandomized clinical studies, before and after studies, uncontrolled observational studies or any published description. Reviews as well as theoretical topics without clinical implementation, studies of low quality, approaches in non-acute settings and pure technical topics were excluded (FIGURE 1). Dispatcher & EMS level–maximizing accuracy, minimizing delays

The rapid recognition of stroke symptoms on the dispatcher level, as well as the efficient and purposeful transport to a 754

stroke unit are the major factors with respect to potential delays of the prehospital part of standard stroke care (TABLE 1) [17]. De Luca et al. reported an improved accuracy of stroke identification by using the Cincinnati Prehospital Stroke Scale during telephone dispatch interviews [18]. It is, however, noteworthy that the standard criterion to test accuracy was the diagnosis of paramedics at the scene. Information about the final diagnosis in hospital was not given. In another study, Krebes et al. developed a new dispatcher identification algorithm for stroke emergencies that was informed by a retrospective analysis of emergency calls [19]. Based on the new algorithm, the dispatcher was allowed to assign the stroke code in case of only one typical stroke symptom (e.g., speech problems, unilateral neurological deficits) or if an atypical stroke symptom was identified – after a positive Face Arm Speech Test [20]. By use of the new algorithm, more than half of the patients with an acute stroke (according to the final diagnosis in hospital) were identified with a positive predictive value of 0.48. This is within the upper range of studies evaluating the computer-based Advanced Medical Priority Dispatch System used at the dispatcher level [21,22]. The next link in the rescue chain is the emergency medical System (EMS) system. In two studies, the implementation of stroke-specific, clearly defined processes was evaluated. In a randomized controlled trial (RCT), it was shown that a higher priority level for stroke alarms already leads to shorter alarm-totreatment time as well as substantially higher rate of thrombolysis [23]. Furthermore, in a large retrospective multicenter cohort study, patients with suspected stroke were transported to the nearest primary stroke center instead of the next hospital [24]. Together with additional training of EMS personnel, this measure resulted in a significant increase in the thrombolysis rate and shortened the onset-to-treatment time. In a very recent study, the National Institutes of Health Stroke Scale (NIHSS) was obtained by helicopter emergency medical Expert Rev. Neurother. 15(7), (2015)


[18]

POT (a) n.a./n.a. 87/51 67/24 n.a. 3038/3224 2010/2011 Da Luca et al.

4976/16,784

2010/2011 Prabhakaran et al.

POT: Prospective observational trial; PPV: Positive predictive value; RCT: Randomized controlled trial; tPA: Tissue plasminogen activator.

2009/2010 Krebes et al.

n.a.

n.a.

1172/1075

n.a.

53 48 131 n.a.

2009 Cacares et al.

274

n.a. n.a. 52,282

2008 Berglund et al.

27,566

n.a. 243/229 n.a.

2006/2007 Deakin et al.

470/430

n.a./n.a.

[24]

Retrospective multicenter cohort study (b) 10/4

97

n.a.

POT (c)

[17]

POT (c) n.a.

[23]

RCT (a) 24/10

[21]

POT (c) n.a. 99 48 49 126 n.a.

POT (c) n.a. 83 42 367 n.a. 2005 Ramanujam

882

Hospital Scene Dispatch

With/without (a) / pre/after (b) / without (c) intervention for stroke

n.a.

tPA (%) Specificity (%) Sensitivity (%) PPV (%)

Year(s) of implementation

Stroke cases

Review

Project

Table 1. Trials at the dispatcher level.


Telestroke – communication with obstacles

122

Ref. Study design

services in the prehospital setting and the in-hospital stroke team physicians subsequently [25]. Based on the positive predictive value of 84% in predicting large-vessel occlusions, the study implies that use of NIHSS could be helpful to increase the triage to the appropriate hospital. This contrasts with previous studies by Maas et al. and Cooray et al. reporting only limited sensitivity and specificity for predicting proximal artery occlusion [26,27].

With improving technology of mobile telecommunication, the concept of telemedicine for prehospital stroke assessment has been developed over the last years. The reviewed studies tested the feasibility, validity and reliability of the remote assessment of telemedicine in patients with acute ischemic stroke (AIS) (TABLE 2) [28–35]. In Telemedicine for the Brain Attack Team (TeleBAT), an array of four parallel 2G connections was used to increase data throughput, compared to a single connection [28]. Actors mimicked stroke scenarios and the neurologic examination of these simulations was transferred via the TeleBAT-system. Independent hospital-based raters scored the transferred examinations. TeleBAT did not use a real-time transfer of the data, but video images were captured and subsequently sent in 2 s intervals. In addition, data of a simulated ambulance transport and the consecutive diagnostic assessment were compared to the data of a control group of stroke patients whose diagnosis was completed and who were treated with tPA. On the basis of this simulation, the authors stated that TeleBAT seems to be a valid and reliable instrument with the potential to shorten time to treatment [28]. Gonzalez et al. used a simplified version of the NIHSS to assess a standardized patient via a cellular video phone with 3G connectivity technology. Results of these assessments did not differ significantly compared to a bedside evaluation, but the remote examination took around 15% longer [29]. In addition, it should be noted that the video-based remote assessment was conducted in a hospital room and not in an ambulance. Studies using real-time audio–video data transfer based on 3G connectivity led to inconsistent results. In a Korean pilot study, the clinical face-to-face evaluation of five patients (two normal and three stroke patients) using the Cincinnati Prehospital Stroke Scale was compared to the rating provided by a mobile telemedicine system with 3G connectivity [30]. In about 92% of the measurements, clinically acceptable data transfer rates of video and audio data were provided and ratings of the Cincinnati Prehospital Stroke Scale were reliable. By contrast, mobile real-time audio–video streaming was less reliable in a German project testing telemedicine devices in an ambulance. In >50% of the evaluated ambulance scenarios (in different locations), the NIHSS could not be assessed by the hospital-based neurologists due to transmission problems [31]. Another German project used four parallel data channels from different network providers with 3G connectivity [32]. Not only audio and video data but also monitoring as well as ECG data were transmitted to the teleconsultant. A group of 18 patients with AIS managed in the

[22]

Prehospital stroke care: telemedicine, thrombolysis and neuroprotection

755

Review


Table 2. Telemedicine studies on prehospital stroke diagnosis. Project

Connectivity

Subjects

Cases

TIA/AIS-cases

Study design

Ref.

La Monte et al. (TeleBAT)

2G

Actors/patients

12/15

12/15

Feasibility study (a)

[28]

Kim et al.

2.5G

Actors

5/-

3/-

Pilot study (b)

[30]

Liman et al.

3G

Actors

30/-

30/-

Feasibility study (b)

[31]

Bergrath et al.

3G

Patients/patients

289/650

19/47

Controlled intervention (a)

[32]

Gonzalez et al.

3G

Standardized patient

1

1


[29]

Van Hooff et al.

3.9G

Volunteers

41/-

41/-


[33]

Wu et al.

4G

Actors

40/-

40/-


[34]

Yperzeele et al.

4G

Patients/patients

41/134

3/9

Controlled intervention (a)

[35]


With/without (a) / with (b) intervention

AIS: Acute ischemic stroke; TIA: Transient ischemic attack.

telemedicine ambulance was compared to a control group of 46 patients treated in standard care. Despite some minor technical failures, multifunctional prehospital teleconsultation was feasible, but it neither shortened the time intervals from on-scene to imaging nor improved the diagnostic accuracy [32]. The implementation of 4G connectivity with bandwidths up to 1 GBit/s including a high-upload bandwidth as well as the possibility of prioritized channels constitutes a quantum leap in the development of telemedicine applications. Three recent studies used 4G technologies with respect to patients with AIS [33,34,36]. Van Hooff et al. were able to demonstrate the feasibility of a telemedicine system with 4G technology, as well as the high reliability of the Unassisted TeleStroke Scale by using stroke scenarios simulated by volunteers [33]. Similarly, Wu et al. could show that remote prehospital evaluation of actors simulating AIS patients is feasible and reliable [34]. An additional recent study compared the deployment of an ambulance-based multimodal telemedicine technology with a standard ambulance system with regard to unselected emergency patients [35]. The authors concluded that broadbandbased prehospital bidirectional real-time telemedicine was safe and feasible. Due to the low percentage of patients with AIS, the study did not examine the process times of diagnostics and treatment.

Specialized stroke ambulances – bringing the hospital to the patient

In the two previous sections, the authors have described strategies to optimize conventional parts of the rescue chain. This section deals about a new approach to speed up the treatment of stroke patients (TABLE 3). Joux et al. reported the deployment of a mobile medical team (service d’aide medicale d’urgence [SAMU]) predominantly required for stroke code patients [37]. SAMU included an emergency physician specifically trained in stroke recognition and options to prenotify the emergency department as well as the radiological department. The impact of SAMU on the time parameters of stroke treatment and thrombolysis rates was compared to the capacity of standard ambulances. The authors concluded that the onset-to-treatment time and, particularly, the door-to-treatment time were decreased. In addition, the rate of tPA treatment was increased from 28 to 42%. The first study that evaluated the feasibility of bringing stroke-specific equipment to the patient was carried out by Schlachetzki et al. [38,39]. Neurosonography was performed on patients with suspected stroke. It was shown that transcranial color-coded sonography in the prehospital setting was not only feasible [38], but also offered high sensitivity, specificity and positive predictive value regarding the detection of major artery

Table 3. Trials using stroke-specific ambulances. Project

Years of implementation

Cases

TIA/AIS

ODT (min)

OTT (min)

Thrombolysis (%)

Study design

Ref.

With/without (a) / with (b) intervention Joux et al.

2007/2009

n.a.

193/120

89/82

215/234

37/25

RCT (a)

[37]

Schlachetzki et al.

2010/2011

113/-

73/-

65/n.a.

n.a.

12/n.a.

POT (b)

[38,39]

Walter et al.

2008/2011

53/47

29/25

n.a.

56/104

23/17

RCT (a)

[40,41]

Ebinger et al.

2011/2013

1804/4378

614/1497

n.a.

80.5/105

32.6/22.0

RCT (a)

[42,44,45]

AIS: Acute ischemic stroke; ODT: Onset-to-door time; OTT: Onset-to-treatment time; POT: Prospective observational trial; RCT: Randomized controlled trial; TIA: Transient ischemic attack.

756

Expert Rev. Neurother. 15(7), (2015)


Review

Table 4. Prehospital trials to treat an acute stroke with antihypertensive drugs or neuroprotective agents. Project

Year

Cases

Stroke

Study design

Ref.

Ankolekar et al. (RIGHT)

2010–2012

25/16

22/14

Pilot RCT

[60]

Shaw et al. (PILFAST)

2010/2011

6/8

13 (n.a./n.a.)

Pilot RCT

[61]

Saver et al. (FAST-MAG)

2005–2012

857/843

827/805

RCT

With/without intervention

[55,57–59]


n.a.: Not applicable; RCT: Randomized controlled trial.

occlusions, in particular, middle cerebral artery occlusions [39]. As the evaluation was an uncontrolled study, time parameters of stroke treatment were not compared to a control group. A further step forward consisted of employing the full equipment to differentiate AIS from intracranial bleeding (CT scanner) and to check criteria for exclusion from intravenous thrombolysis in the ambulance (point-of-care laboratories). This concept was implemented in different ways. First, in the Mobile Stroke Unit (MSU) project of the University of Saarland/Germany, a truck was exclusively designed as an emergency unit with the above-mentioned diagnostic equipment, and a neuroradiologist, a stroke physician and a paramedic on board [40,41]. The MSU was deployed in addition to a standard ambulance and a vehicle staffed with an emergency physician. The effects were assessed in an RCT using weeks with and without MSU availability, which showed that time from call to treatment decision could substantially be reduced compared to regular care (Alarm to therapy decision 35 [31–39] vs 76 [63–94]). Second, the Stroke Emergency Mobile project in Berlin/ Germany was designed as a fully operational ambulance with additional diagnostic and therapeutic facilities [42]. The Stroke Emergency Mobile team consists of a paramedic, a radiology technician and a neurologist with additional training in emergency medicine. CT scanning and reading was performed via teleradiology instead of having a radiologist aboard the vehicle. In a large-scale trial using alternating weeks with and without Stroke Emergency Mobile availability, it was shown that the alarm-to-treatment time in patients who received intravenous thrombolysis could be reduced by 25 min [43,44]. In addition, both the thrombolysis rate and the proportion of patients receiving thrombolysis within the ‘golden hour’ were substantially increased. The latter was related to better short-term outcome in terms of discharge home from acute inhospital care [45]. It has been shown that prehospital stroke care can be operated in a responsible way even in health-economic dimensions [46,47]. It should be noted that the final proof of a better longterm outcome is missing due to the design of the studies so far. Two more initiatives have been recently started to ‘bring the hospital to the patient’: the Houston MSU and the Cleveland mobile stroke treatment unit [48]. First experiences in the Cleveland project support the results described above [49]. Neuroprotective & antihypertensive approaches

The only treatment approach in AIS patients that has been proven effective is based on recanalization strategies of the blocked artery [7,11,50,51]. In practice, there are various informahealthcare.com

implementation problems. This is due to the short time window for the use of recanalisation therapy, especially for the use of tPA, as well as for the loss of efficacy of both treatments even within accepted time windows. In addition, endovascular therapy is usually offered in specialized centers only. As a consequence, only a minority of patients receive adequate therapy [52]. Therefore, other approaches should be considered (TABLE 4). There is a wide variety of neuroprotective or neuroreparative concepts in acute stroke. Based on the complexity of the pathophysiological cascade induced by the damage to cerebral tissue, a large number of molecules have been identified with potentially neuroprotective properties. So far, however, most strategies have been successfully tested in animals only [53]. Although neuroprotective agents are often safe and potentially useful in both ischemic as well as hemorrhagic stroke, the translation from bench to bedside has failed thus far. A number of reasons could be attributed for the discrepancies between experimental and clinical studies. Among others, the substantial delay to therapy in human trials in contrast to animal tests could play a significant role [54]. This consideration appears to be justified, as neuroprotective agents are most effective in rodent and primate focal stroke models during the first 2 h. Based on this assumption, the first prehospital trial testing a potentially neuroprotective agent was initiated after the Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial had failed [55,56]. In the IMAGES trial, magnesium sulfate, a neuroprotective agent protecting against excitotoxicity, was tested in a 12 h time window after the onset of an acute stroke, and neither primary nor secondary outcomes showed any treatment effect [56]. Saver et al. then conducted the Field Administration of Stroke Therapy – Magnesium (FASTMAG) trial, an RCT aiming to demonstrate that intravenous infusion of magnesium sulfate within 2 h after symptom onset improves long-term functional outcome of stroke patients [55,57,58]. Of note, >74% of the patients received the study medication within the ‘golden hour’. Although this placebo-controlled trial failed to show differences in disability outcome [59], it demonstrated for the first time that prehospital neuroprotection trials are feasible. Another approach for starting early treatment for acute stroke is evaluated in two studies of antihypertensive treatment initiated by paramedics [60,61]. Ankolekar et al. concluded that the use of glyceryl trinitrate by paramedics in case of an acute stroke was safe and that systolic blood pressure was reduced [60]. The second trial was designed as a small proof of concept to test the opportunity of conducting an RCT of antihypertensive treatment with lisinopril [61]. It was concluded that this approach seems to be feasible. 757


Review


In various animal experiments (including primates), it has been shown that NA-1 (also called Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, is neuroprotective [62]. In a first clinical study in patients with iatrogenic stroke after endovascular therapy of ruptured or unruptured aneurysms, it was suggested that NA-1 is safe and effective in reducing ischemic brain damage [63]. NA-1 is going to be tested in the prehospital setting in Canada [69]. In a recent analysis of the efficacy of neuroprotective treatments for ischemic stroke, Minnerup et al. identified 46 Phase III studies with neuroprotective agents [64]. Only one Phase III study was positive, but was followed by a larger negative study [65,66]. Discussion

In recent years, prehospital stroke care has started to shift paradigms. This is reflected by a number of new approaches. The success of this new strategy in acute stroke management is built on several pillars. Improvements at the dispatcher level by means of more accurate algorithms for decision-making serve as a basis for a specific deployment of targeted emergency services. These measures are easy to establish and can be widely used. Connectivity issues within the framework of telemedicine applications have successfully been solved and other teething troubles have been overcome to a large extent. The latest 4G technology enables stroke specialists to be involved in hyperacute care. The combination of these communication tools with ambulances upgraded with a diagnostic setup supports therapeutic decisions directly onsite without any delay. As a consequence, new therapeutic regimes can be investigated and triage decisions with transports to most appropriate hospitals can be made. This may improve the care of specific groups of patients whose treatment can only take place in specialized medical departments, for example, endovascular therapy in case of a proximal arterial occlusion. A reasonable basis for the use of neuroprotective agents in the prehospital phase should follow the recommendations of Stroke Therapy Academic Industry Roundtable for preclinical animal tests (for details see [67]). The time–effectiveness relationship and the search for relevant biomarker endpoints seem to be of particular importance for the prehospital setting. However, a wide range of issues has still not been answered, including the effects of prehospital stroke care on clinical outcomes in the acute phase and after a longer period of time and its definite cost–effectiveness. Before the new technology

can enjoy widespread use, further studies should clarify these questions. Expert commentary

Developments in the field of prehospital stroke care are characterized by use of the latest communication technology as well as miniaturization of medical equipment. The key element is to bring the best expertise to the patient in the least amount of time. Currently, the concept of mobile stroke ambulances has the greatest influence on optimizing crucial parameters of treatment, in particular, time to treatment and prehospital triage. For this reason, the concept should be expanded and used as a research platform to bring innovative diagnostics and treatments into the field. At the same time, other approaches, in particular, telemedicine technologies should be integrated. This will improve the economic efficiency of such ambulances and consequently enable their international implementation. Five-year view

Communication technology will be developed to such an extent that ambulances with telemedicine equipment will be the norm. Specialized stroke ambulances with diagnostic equipment on board will be based in more densely populated areas and will be able to treat patients not only with tPA but, at the same time, also with neuroprotective agents. Depending on local and national regulations, paramedics in these ambulances may be supported by stroke physicians using telemedicine equipment. Compared with the current situation, a significantly higher proportion of patients will receive medical care in the ‘golden hour’ and can be treated with tPA in case of AIS. In addition, specialized stroke ambulances help to optimize prehospital triage [68]. Patients can be transported to specialized hospitals as fast as possible, for example, in case of a large vessel occlusion or intracranial hemorrhage. Financial & competing interests disclosure

HJ Audebert has received speakers honoraria from BMS, Lundbeck Pharma, Pfizer, Sanofi, EVER Neuropharma and Boehringer Ingelheim. HJ Audebert has served as a consultant/advisor for Roche Diagnostics, Lundbeck Pharma and Bayer Vital. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed..

Key issues .

Research on prehospital stroke care focuses on optimizing the dispatcher algorithm, establishing telemedicine techniques, implementing specialized stroke ambulances and evaluating new treatment approaches.

.

Telemedicine approaches require reliable real-time connections.

.

Specialized stroke ambulances were evaluated in two independent studies which showed a significant improvement of the onset-totreatment time and thrombolysis rate.

.

The use of new drugs with neuroprotective effects requires a standardized transfer process from bench to bedside following the Stroke Therapy Academic Industry Roundtable recommendations.

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Caceres JA, Adil MM, Jadhav V, et al. Diagnosis of stroke by emergency medical dispatchers and its impact on the prehospital care of patients. J Stroke Cerebrovasc Dis 2013;22(8):e610-14 De Luca A, Giorgi Rossi P, Villa GF. The use of cincinnati prehospital stroke scale during telephone dispatch interview increases the accuracy in identifying stroke and transient ischemic attack symptoms. BMC Health Serv Res 2013;13:513 Krebes S, Ebinger M, Baumann AM, et al. Development and validation of a dispatcher identification algorithm for stroke emergencies. Stroke 2012;43(3):776-81 Nor AM, McAllister C, Louw SJ, et al. Agreement between ambulance paramedicand physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients. Stroke 2004;35(6):1355-9

21.

Deakin CD, Alasaad M, King P, Thompson F. Is ambulance telephone triage using advanced medical priority dispatch protocols able to identify patients with acute stroke correctly? Emerg Med J 2009;26(6): 442-5

22.

Ramanujam P, Guluma KZ, Castillo EM, et al. Accuracy of stroke recognition by emergency medical dispatchers and

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35.


Yperzeele L, Van Hooff RJ, De Smedt A, et al. Feasibility of AmbulanCe-Based Telemedicine (FACT) study: safety, feasibility and reliability of third generation in-ambulance telemedicine. PLoS One 2014;9(10):e110043

36.

Yperzeele L, Van Hooff RJ, De Smedt A, et al. Prehospital stroke care: limitations of current interventions and focus on new developments. Cerebrovasc Dis 2014;38(1): 1-9

37.

Joux J, Olindo S, Girard-Claudon A, et al. Prehospital transfer medicalization increases thrombolysis rate in acute ischemic stroke. A French stroke unit experience. Clin Neurol Neurosurg 2013;115(9):1583-5

38.

Holscher T, Schlachetzki F, Zimmermann M, et al. Transcranial ultrasound from diagnosis to early stroke treatment. 1. Feasibility of prehospital cerebrovascular assessment. Cerebrovasc Dis 2008;26(6):659-63

39.

40.

Schlachetzki F, Herzberg M, Holscher T, et al. Transcranial ultrasound from diagnosis to early stroke treatment: part 2: prehospital neurosonography in patients with acute stroke: the Regensburg stroke mobile project. Cerebrovasc Dis 2012;33(3):262-71

Walter S, Kostpopoulos P, Haass A, et al. Bringing the hospital to the patient: first treatment of stroke patients at the emergency site. PLoS One 2010;5(10): e13758

42.

Ebinger M, Rozanski M, Waldschmidt C, et al. PHANTOM-S: the prehospital acute neurological therapy and optimization of medical care in stroke patients - study. Int J Stroke 2012;7(4):348-53

43.

44.

45.

..

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47.

Ebinger M, Winter B, Wendt M, et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA 2014;311(16):1622-31 Weber JE, Ebinger M, Rozanski M, et al. Prehospital thrombolysis in acute stroke: results of the PHANTOM-S pilot study. Neurology 2013;80(2):163-8 Ebinger M, Kunz A, Wendt M, et al. Effects of golden hour thrombolysis: a prehospital acute neurological treatment and optimization of medical care in stroke

760

This study stresses the importance to treat patients with AIS as fast as possible and reports a better short-term outcome for use of tPA in the golden hour.

Saver JL, Starkman S, Eckstein M, et al. Methodology of the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) Phase 3 trial: Part 1 - rationale and general methods. Int J Stroke 2014;9(2):215-19

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Gyrd-Hansen D, Olsen KR, Bollweg K, et al. Cost-effectiveness estimate of prehospital thrombolysis: Results of the PHANTOM-S Study. Neurology 2015; 84(11):1090-7

Muir KW, Lees KR, Ford I, et al. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet 2004; 363(9407):439-45

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Dietrich M, Walter S, Ragoschke-Schumm A, et al. Is prehospital treatment of acute stroke too expensive? an economic evaluation based on the first trial. Cerebrovasc Dis 2014;38(6):457-63

Saver JL, Starkman S, Eckstein M, et al. Methodology of the field administration of stroke therapy - magnesium (FAST-MAG) Phase 3 trial: Part 2 - prehospital study methods. Int J Stroke 2014;9(2):220-5

58.

Saver JL, Kidwell C, Eckstein M, Starkman S. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial. Stroke 2004;35(5):e106-8

59.

Saver JL, Starkman S, Eckstein M, et al. Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med 2015;372(6):528-36

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Although this randomized controlled trial failed with respect to its primary hypothesis, it constitutes an important milestone for the prehospital trials of neuroprotective drugs.

60.

Ankolekar S, Fuller M, Cross I, et al. Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the rapid intervention with glyceryl trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824). Stroke 2013;44(11):3120-8

61.

Shaw L, Price C, McLure S, et al. Paramedic initiated lisinopril for acute stroke treatment (PIL-FAST): results from the pilot randomised controlled trial. Emerg Med J 2014;31(12):994-9

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Cook DJ, Teves L, Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 2012;483(7388): 213-17

63.

Hill MD, Martin RH, Mikulis D, et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a Phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2012;11(11):942-50

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In this randomized controlled trial the translation of a neuroprotective agent from primates to humans has been successfully shown.

48.

Parker SA, Bowry R, Wu TC, et al. Establishing the first mobile stroke unit in the United States. Stroke 2015;46(5): 1384-91

49.

Gomes JA, Ahrens CL, Hussain MS, et al. Prehospital reversal of warfarin-related coagulopathy in intracerebral hemorrhage in a mobile stroke treatment unit. Stroke 2015;46(5):e118-20

50.

Fransen PS, Beumer D, Berkhemer OA, et al. MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial. Trials 2014;15:343

Walter S, Kostopoulos P, Haass A, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012;11(5):397-404

41.

55.

(phantom-s) substudy. JAMA Neurol 2015; 72(1):25-30

51.

52.

53.

Campbell BC, Mitchell PJ, Yan B, et al. A multicenter, randomized, controlled study to investigate extending the time for thrombolysis in emergency neurological deficits with intra-arterial therapy (EXTEND-IA). Int J Stroke 2014;9(1): 126-32 Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 min. Circulation 2011; 123(7):750-8 Moretti A, Ferrari F, Villa RF. Neuroprotection for ischaemic stroke: Current status and challenges. Pharmacol Ther 2015;146:23-34

54.

Sutherland BA, Minnerup J, Balami JS, et al. Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke 2012;7(5):407-18

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This study gives a good overview over neuroprotective approaches as well as the difficulties in translation from animal models into clinical practice.



64.

Minnerup J, Wersching H, Schilling M, Schabitz WR. Analysis of early phase and subsequent Phase III stroke studies of neuroprotectants: outcomes and predictors for success. Exp Transl Stroke Med 2014; 6(1):2 Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. N Engl J Med 2006;354(6):588-600

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Shuaib A, Lees KR, Lyden P, et al. NXY-059 for the treatment of acute

67.

Fisher M. New approaches to neuroprotective drug development. Stroke 2011;42(1 Suppl):S24-7

68.

Wendt M, Ebinger M, Kunz A, et al. Improved prehospital triage of patients with stroke in a specialized stroke ambulance: results of the pre-hospital acute neurological therapy and optimization of medical care in stroke study. Stroke 2015;46(3):740-5

69.

Safety and Efficacy Study of a Single Dose of NA-1 in Patients Undergoing Endovascular Repair of Ruptured Aneurysms (ENACT-2). Available from: https://clinicaltrials.gov/ct2/show/ NCT02056574


65.

ischemic stroke. N Engl J Med 2007; 357(6):562-71

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761

Using telemedicine in stroke care.

Prehospital use of magnesium sulfate as neuroprotection in acute stroke.

Logistical problems in prehospital thrombolysis.

Prehospital thrombolysis in acute myocardial infarction.

[Prehospital thrombolysis in acute myocardial infarct].

Prehospital thrombolysis: a manual from Berlin.

Smartphone-assisted prehospital medical information system for analyzing data on prehospital stroke care.

Cost-effectiveness of optimizing acute stroke care services for thrombolysis.

Application of Telemedicine System to Prehospital Medical Control.

Stroke neuroprotection: targeting mitochondria.

[Mobile stroke unit for prehospital stroke treatment].

Thrombolysis in acute stroke.

Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale.

Thrombolysis in acute stroke.

Affordable Care Act and telemedicine.

Prehospital delay and stroke-related symptoms.

Prehospital and hospital coronary care.

Non-Coding RNAs in Stroke and Neuroprotection.

Thrombolysis in pediatric stroke study.

Neuroprotection in stroke: past, present, and future.

Attention to prehospital care.

Comment: Telemedicine training during stroke fellowship.

Prehospital stroke care: limitations of current interventions and focus on new developments.

How can we improve stroke thrombolysis rates? A review of health system factors and approaches associated with thrombolysis administration rates in acute stroke care.