To date, intravenous (i.v.) tissue-type plasminogen activator (tPA) is still the unique pharmacological treatment approved for acute ischemic strokes (AIS). This thrombolytic therapy remains little used all over the world, mainly because of excessive prehospital and in-hospital delays and lack of stroke center coverage [1–3]. As a result, thrombolytic therapy is available for less than 5% of the patients [4,5]. The factors influencing prehospital delay are related to the patient (recognition of stroke symptoms and decision to seek medical attention) and to the management of a suspected stroke victim by medical and paramedical personnel . The recommended 3-h time window from symptom onset [7,8] is certainly the major issue, which limits the use of i.v. tPA to trained stroke physicians. Since 2008, on the basis of the results of European Cooperative Acute Stroke Study 3 , the therapeutic window bas been extended to 4.5 h. Although these findings imply that more patients may benefit from thrombolytic therapy, patients should be treated as early as possible to maximize the gain [10,11]. Other than time to treatment, most recent data suggest that shortening the time from symptom onset to recanalization should be the main goal (i.e. reopen the artery as fast as possible) [12•]. All the above-mentioned factors represent opportunities to improve prehospital and in-hospital care. We present the factors influencing time intervals from stroke onset to the decision to seek medical attention, from first medical contact to hospital admission, and from hospital door to treatment. We also describe strategies which have been successful in reducing prehospital delay and increasing access to acute stroke treatment.
Stroke awareness, symptom recognition, and treatment-seeking process
It has been demonstrated worldwide that patients and bystanders should immediately seek medical attention and use ambulance transport directly to hospital as soon as stroke symptoms occur in order to reduce prehospital delay [13–16]. Contact with a general physician is associated with delayed admission in several studies [16–19], whereas activation of Emergency Medical Services (EMS) and transport by EMS is associated with early admission and increased chances of transfer to a hospital offering acute stroke therapy [13,20]. A prospective analysis [21•] of 262 consecutive Spanish patients with AIS has shown that patients arriving directly at the stroke center via EMS also receive neurologic attention sooner, are more frequently treated with tPA, and have better clinical outcome than those patients who are first taken to a community hospital.
Unfortunately, stroke awareness remains limited in the general public, not only in terms of stroke symptoms awareness but also in terms of appropriate response when symptoms occur [22,23]. It has been shown that in about 40–50% of patients with stroke, EMS attention is not sought [18,20,24]. An Australian study  has shown that factors independently associated with a rapid call for an ambulance were recognition of a speech problem, patient not being alone at the onset of symptoms, and the caller having a family history of stroke. In this study, only 22% of all callers recognized the problem as stroke and called within 1 h from the onset of symptoms. An important variable in the treatment-seeking process is the role played by bystanders, in particular, in patients with aphasia, neglect, and altered consciousness. Living alone increases admission delay in acute stroke [16,26]. Mosley et al.  showed that one-third of acute stroke patients were found to be unable to think, act, or communicate, and patients only called an ambulance for themselves 3% of the time. Another study  has shown that the recognition of symptoms by bystanders significantly shortened the admission delay, and that patients whose symptoms were recognized by bystanders were more than two times more likely than patients who recognized their symptoms themselves to be transported by EMS. A recent nationwide study  performed in the Czech Republic has shown fair knowledge about stroke but poor response to warning signs in the general population. The predictors of a correct response to stroke were secondary school education, knowing that stroke is a serious disease, and knowing that stroke is treatable. Regarding acute stroke treatment awareness, a recent survey  of 4724 adults conducted in Michigan, USA has shown that only one-third of the public were aware of tPA as a treatment for stroke and only one in six was aware of the time window for tPA. Awareness of tPA was higher among middle-aged adults, women, whites, and those with higher education and income.
Continuous television advertising has been associated with significant increases in the knowledge of the warning signs of stroke [29,30] and in the mean number of emergency department (ED) visits for stroke within 2.5 h . However, another study  has failed to find a relationship between stroke symptoms knowledge and admission delay. A German educational multimedia campaign  has shown differential effects on public stroke knowledge and care-seeking behavior. An increase of stroke knowledge was observed but this did not immediately transfer into a change of intended behavior in the acute situation. Although the majority of respondents indicated that they would call emergency care if they witnessed someone having a stroke, no significant difference was observed before and after the campaign concerning this issue. A ceiling effect may be responsible for these findings, as a high percentage of respondents (81%) stated they would seek an ambulance in this study even before the educational intervention. Overall, these data indicate that public educational campaigns should be designed to improve not only the awareness of stroke warning signs but also the optimal way to react (‘call EMS immediately’) and the awareness of tPA treatment per se. Mass media campaigns can change awareness and behavior if they concentrate on single efficacious and clear messages and have prolonged exposure . Clearly, further research is needed to better elucidate the behavior of people if they experience or witness stroke symptoms.
Prehospital delays by the medical system
Studies [13,20,26] have demonstrated a correlation between increasing stroke severity and shorter prehospital delay. Studies [20,26,32] have reported an association between stroke severity and reduced time from symptom onset to first call for medical help and transport by the EMS. A recent population-based American cohort study [33•] has shown an increase in the likelihood of seeking care with the number of stroke symptoms in which 46.4% of those experiencing a single symptom sought care as compared with 58.0% of those experiencing two symptoms and 54.3% for those experiencing three or more symptoms. All patients should be encouraged to seek immediate medical attention whatever their initial clinical severity because of the significant potential risk of early and marked progression of mild/moderate stroke symptoms . In the setting of acute pediatric stroke, a similar impact of clinical severity on admission delay has recently been demonstrated. A Canadian study  has evaluated the factors influencing prehospital delay in 209 children with AIS. The median prehospital delay was 1.7 h (interquartile range 49 min to 8.1 h). The main predictors of longer prehospital delay were a milder stroke severity as assessed by the Pediatric National Institute of Health Stroke Scale and the parent's help-seeking action [patients not brought directly to the Emergency Department (ED)].
For patients with intracerebral hemorrhage (ICH), a German study  of 157 patients has shown that clinically more severely affected patients were also admitted to hospital earlier. The presence of intraventricular hemorrhage also predicted early hospital admission in the multivariate logistic regression model. The authors emphasize the need to get less severely affected patients admitted earlier, as they might be ideal candidates for hemostatic innovative treatments in the future.
Emergency medical dispatchers play an important role in optimizing stroke care by accurately identifying acute cerebrovascular disease. Previous experiences have shown that only 30–50% of stroke calls are accurately identified by EMS dispatchers [37,38]. A variety of systems have been developed to aid emergency medical technicians and paramedics in successfully identifying patients with stroke. The American Stroke Association recommends EMS use algorithms such as the Los Angeles Prehospital Stroke Scale or the Cincinnati Prehospital Stroke Scale for this purpose [39,40], but data assessing their performance when used by EMS personnel in the field remain limited . A recent study  was undertaken in California, USA, to assess the diagnostic accuracy of the current national protocol guiding dispatcher questioning of 911 callers to identify stroke. Dispatcher recognition of stroke calls using the widely employed Medical Priority Dispatch System algorithm was suboptimal, with failure to identify more than half of stroke patients as likely stroke. The authors conclude that revisions to the current national dispatcher structured interview and symptom identification algorithm for stroke may facilitate more accurate recognition of stroke by emergency medical dispatcher. Revision of the algorithm to emphasize asymmetrical motor deficits and de-emphasize altered level of consciousness likely would improve accurate identification of acute stroke patients in the field . At the University of Texas in Houston, a multilevel educational program directed at EMS personnel resulted in better diagnostic accuracy, increased proportion of stroke patients arriving within 2 h of onset, and increased frequency of i.v. thrombolytic therapy .
The hospital prenotification of the arrival of a suspected stroke victim by EMS is of paramount importance in order to reduce time of medical assessment, delay to brain imaging, and door-to-needle time (DNT). It has been shown that paramedic stroke recognition and hospital prenotification are associated with shorter prehospital times and in-hospital times from hospital arrival to first medical assessment . A study  performed in Finland showed that an intervention consisting of moving the computed tomography (CT) scanner to the ED and instituting a protocol for routine prehospital notification of the stroke team (moving the triage step to the prehospital phase) significantly reduced door-to-CT interval and DNT, and markedly increased access to thrombolysis.
The reorganization of in-hospital systems is an important topic, as studies have shown that in-hospital delays may account for more than 50% of the symptom-to-needle time in some hospitals. A before-and-after study  has demonstrated that a training program for ED staff (rapid triage and urgent CT scanning) may be effective in reducing in-hospital delay from diagnosis to tPA administration and increasing the proportion of AIS patients receiving tPA.
Successful strategies for reducing prehospital delays
Remote, rural, and suburban hospitals commonly do not have a stroke unit, or even a stroke physician. Stroke patients admitted to these hospitals are not usually considered for tPA therapy, even if they are eligible. Some patients are transferred to a stroke unit, but commonly miss the 3-h time window because of the transfer duration. Evidences have shown that a video conferencing system could help remote stroke specialists to guide ED staff to administer tPA to patients in a rural setting. These data have been collected by several networks of telemedecine developed in different countries : Telemedical Pilot Project for Integrative Stroke Care (TEMPiS) in Germany , Telemedicine in Stroke in Swabia (TESS) , telemedicine for remote collaboration with urgentists for stroke-tPA treatment trial in France , and Remote Evaluation for Acute Ischemic Stroke in the United States [46,47].
One of them, the TEMPiS program, consisted of the set-up of specialized local stroke wards, with telemedical consultation for acute stroke patients by two stroke centers. In this program, five community hospitals were compared with five matched control hospitals without specialized stroke facilities or telemedicine support. A total of 2.4% (115 of 4727) of stroke patients admitted to one of the community hospitals received telemedicine-based i.v. tPA [48••]. The rate of in-hospital mortality was low (3.5 vs. 4.5%), and the rate of symptomatic ICH was not statistically different (7.8 vs. 2.7%). At 3 months, 44% of patients treated in network hospitals vs. 54% treated in control hospitals had a poor outcome (P < 0.0001). The patient management with the telestroke expertise independently reduced the probability of a poor outcome [odds ratio (OR) 0.62, 95% confidence interval (CI) 0.52–0.74, P < 0.0001] [48••]. The long-term results at 12 and 30 months , including 3060 patients (1938 in TEMPiS and 1122 in control hospitals), were consistent with the initial results. The TEMPiS program was associated with a significant reduction of ‘death and dependency’ at 12 months (OR 0.65, 95% CI 0.54–0.78, P < 0.01) and 30 months (OR 0.82, 95% CI 0.68–0.98, P = 0.031). These data suggest a benefit of a telemedicine network in the management of stroke patients (i.e. improvement of i.v. tPA access and general care).
Telestroke expertise may be performed with telephone or video conferencing consultation. Meyer et al.  showed that telethrombolysis should be preferred to telephone consultation. In this study, 222 stroke patients were randomized (111 in each arm) in a remote hospital to be managed by video conferencing (i.e., telemedicine) or telephone consultation.
Telemedecine appeared to be more accurate than telephone consultation for the tPA decision-making process. A correct treatment decision was made in 98% (n = 108) of patients randomized to telemedecine vs. 82% (n = 91) of patients randomized to telephone consultation (P = 0.0009). However, the 90-day functional outcomes were similar. It is important to remember that neither video conferencing nor telephone consultation was shown to be equivalent to the gold standard of immediate transfer of eligible patients for i.v. tPA therapy given in a stroke unit. For this reason, telestroke expertise is not level Ia but IIb recommendation according to the European Stroke Organisation .
Telemedecine to increase access to stroke care
Although senior emergency medicine physicians can diagnose most strokes and select eligible patients for i.v. tPA, some physicians who are less familiar with stroke diagnosis and treatment could benefit from a video conferencing system for supervision by a vascular neurologist. Diagnoses of posterior circulation stroke or basilar artery occlusions need specialized skills. Apart from diagnosis, telestroke expertise might help emergency medicine physicians in triage, with the selection of the most appropriate treatment. Patients no more eligible for i.v. tPA may be good candidates for endovascular therapy (e.g. patients with middle cerebral artery occlusion after 4.5 h of symptoms onset). Furthermore, patients with medical conditions unfavorable to i.v. tPA (i.e. proximal occlusions such as extracranial carotid occlusion or intracranial carotid ‘T’ occlusion) may benefit from centers with endovascular therapy facilities, which may not the case for stroke patients without large-vessel occlusion. In this setting, triage is critical, and telemedicine should play a fundamental role. Drawbacks of telemedicine should also be considered: incorrect application of recommended procedures by the remote physician and the absence of transfer in a stroke unit facility (which decreases the likelihood of recovery ) may impact the outcome of the patients.
Importance of time to recanalization
Recanalization is a powerful predictor of stroke outcome after tPA or endovascular approach [12•]. Furthermore, the time from symptom onset to recanalization seems to be a crucial factor . Spontaneous recanalization in patients with AIS is a well known phenomenon; therefore, shortening the time to recanalization should be the main goal. In the REcanalisation using Combined intravenous Alteplase and Neurointerventional ALgorithm for acute Ischemic StrokE (RECANALISE) study [12•], it was shown that a systematic i.v.–endovascular approach as compared with an i.v.-only approach allows more recanalization (87 vs. 52%, OR 1.49, 95% CI 1.21–1.84, P = 0.0002) in cases of AIS seen within 3 h of symptom onset and with documented intracranial arterial occlusion. The sooner the recanalization was obtained, the higher the number of cured patients at 3 months either for i.v. or i.v. and i.v.–intraarterial tPA. For example, if recanalization was obtained within 3 h and 30 min, 93% of the patients were cured at 24 h and at 3 months (OR 2.30, 95% CI 121–436, P = 0.01, and OR 2.20, 95% CI 124–388, P = 0.007, respectively). Each 30-min delay to recanalization was followed by 20% fewer patients cured at 3 months. Data from the Interventional Management of Stroke pilot trials confirmed that good clinical outcome following angiographically successful reperfusion was significantly time dependent . These data argue for an ‘as fast as possible’ prehospital stroke care, emphasizing the importance of the rapidity of treatment administration, and of the triage to avoid time loss.
Future development may extend to video conferencing with the patient in the ambulance on the way to the hospital with the possibility of a pre-ED triage. However, the image quality of personal digital assistants and cell phones is insufficient at present to be used for video conferencing. Although, the benefit of telethrombolysis vs. the gold standard (i.v. tPA) to improve the percentage of cured patients at 3 months remains to be proven, the development of telemedicine for improved access to tPA therapy in stroke patients is needed and can be reasonably used when transfer to a stroke center is not possible. The goal for prehospital stroke care is to increase the access to stroke ‘gold standard’ treatments (i.v. tPA and stroke units) to all eligible patients. To achieve this aim, we need to change people's awareness of and behavior to stroke symptoms, need accurate triage for every stroke patient, and need to recanalize the artery as fast as possible.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 90).
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