I think it makes a whole lot of sense to enable i.v. thrombolysis beyond stroke centers. A whole lot more patients will benefit from the treatment and potentially be spared the sequelae of stroke. However, establishing some safeguards and precautions are in order.

Certainly not. It may be applicable in developed nations where stroke centres may be available widely. But when a world wide view is taken this is not the scenario. IV thrombolysis may be the only treatment option available in many centres and hence should be used in all centres where a neurologist is available. My only word of caution is that it should be within guidelines. No heroic - beyond guideline thrombolysis should be attempted in centres other than specialised stroke centres.

This question was addressed in a recent study downloadable from RearchGate [1]. Its main conclusion was that on-site treatment is more effective than referral to another hospital (number of patients with favorable neurological outcome 45.3% vs 41.3%). In patients seen within 45 min of the onset of symptoms, for every 10 patients transferred there was an additional case with an unfavorable neurological outcome that could have been avoided with on-site thrombolysis.

[1] J Latour-Pérez, P Galdos Anuncibay . [Thrombolysis in acute ischemic stroke in centers lacking a stroke unit: referral to reference center or on-site treatment?]. Med Intensiva 2012; 36 (5): 324-328

The current issue of JAMA contains an important study about this issue:

Saver JL, Fonarow GC, Smith EE, et al. Time to Treatment With Intravenous Tissue Plasminogen Activator and Outcome From Acute Ischemic Stroke. JAMA 2013;309(23):2480-2488. doi:10.1001/jama.2013.695

Dear Dr. Latour-Perez, thank you very much for this interesting study. As you state, the available evidence does not support the recommendations of the national stroke strategy or some regional plans that discourage the administration of thrombolysis in hospitals without stroke units. It would be interesting to know, if the benefit was still seen among patients admitted later (>45min) and if your findings are supported by external studies with different cohorts - an essential way to increase evidence for recommendations.

With proper training and always within guidelines I think IV thrombolysis should be available in all ER´s.

Specially in undeveloped countries where the burden of stroke is increasing.

If we want to introduce thrombolysis in time in rural and scattered areas, we need to use the emergency physicians. Neurologist is not necessary, only specific training personal in acute isquemic stroke. It is also interesting to use tele medicine for difficult diagnostic. The experience in Galicia (Spain) is well known and the results in the emergency department the same that when a neurologist attend the patient. Different things are the specific stoke units. We are talking about thrombolysis in adequate time.

Dr. Cameron is right when he says that the JAMA study is not a randomized study. However, the dose-response association detected in this study reinforces the credibility of the results. On the other hand, we now have high-quality randomized trials and meta-analysis of individual data [1] that support the effectiveness of early thrombolysis in ischemic stroke.

In my opinion, the current debate is not focused on the efficacy of thrombolysis but how to apply it safely and efficiently to benefit the greatest number of patients.

[1] Lees KR, Bluhmki E, von Kummer R et al. ,Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375: 1695–703

Dear Dr. Sutter, thank you very much for your comments and for your important question.

In our study [1], the benefit of on-site treatment was maintained throughout the time window, but was decreasing with time (figure 2). Accordingly, the number needed to treat varied from 10 (45 min after onset symptoms) to 44 (270 min).

The effectiveness data of our model are based on the meta-analysis of Lees et al. [2], but are supported by observational studies conducted in the "real world" as the SIT-MOST study [3], conducted with non-specialists in treating stroke patients.

References

[1] J Latour-Pérez, P Galdos Anuncibay . [Thrombolysis in acute ischemic stroke in centers lacking a stroke unit: referral to reference center or on-site treatment?]. Med Intensiva 2012; 36 (5): 324-328

[2] Lees KR, Bluhmki E, von Kummer R et al. ,Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375: 1695–703

[3] Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-82.

I would like to highlight Juan Marquez-Romero. Keeping in mind the under developed countries where the Stroke Unit is almost hard to be available, a guideline should be made and proper training should be provided to health professional and then Thromobolytics should be made available.

I think IV thrombolysis should be available in all ER´s where a neurologist is available.

I think the first major step is to identifiy a focal neurological deficit which needs neurological expertise. The neurological examination needs a lot of expericence and skills. These skills are not always present in ERs. Although we know from register studies that thrombolysis is pretty save in stroke mimics, there is still the general risk of intracranial bleeding around 5-6% (RCT data).

Telestroke networks are in my opinion are a good way to give thrombolyis to more people (esp. in rural areas) and to slove the problem of lacking neurological expertise. The telestroke network in Helskinsi and some centers in Germany (SOS-NET,...) show good results.

But then there comes another problem. What to do with the patients who got thrombolysis? Leave them and at the rural hospital or bring them all to the stroke center? In my opinion if it is possible they should all be brought to a stroke unit near by. A highly organised stroke unit is the best treatment in stroke medicine, its NNT is even higher than iv-thrombolyis.

I agree with Dr. Angermaier. In studies regarding thrombolysis outside stroke units it would also be important to focus on the differences in management of complications such as intracerebral hemorrhage (ICH) or rt-PA related orolingual edema and if there are different outcomes especially in patient with these complications. This would answer the question if the availability of specialized monitoring and neurosurgery for rapid craniotomy for large ICH etc. leads to more frequent and earlier interventions and better long-term outcome. However, I completely agree that a neurologist has to be on site, as acute neurological deficits can be very subtle or may be misinterpreted by untrained caregivers such as for example aphasia which can be interpreted as delirium or confusion.

Many hospitals are not staffed with a neurologist 24 hours a day but do have physicians properly trained in acute stroke care. So perhaps the core of the problem lies not on the academic level, but on the adequacy of expertise.

I have not found evidence that clinical outcomes of initial treatment by a neurologist are better than the results obtained by a properly trained emergency physician, alone or with expert help through telemedicine. At the contrary, some studies indicate that initial care by a neurologist is not associated with better neurological outcomes [1].

Regarding the risk of cerebral hemorrhage, there is evidence that thrombolysis in patients without signs of bleeding in the scanner is safe [2]. Furthermore, the delay in treatment (eg the delay associated with the transfer to the stroke unit) carries an increased risk of cerebral hemorrhage [3]. Therefore, early on-site treatment may be safer than late treatment in a stroke unit.

REFERENCES

[1] Gillum LA, Johnston SC. Influence of physician specialty on outcomes after acute ischemic stroke. J Hosp Med 2008;3:184-192.

[2] Chernyshev O, Martin-Schild S, Albright K, Barreto A, Misra V, Acosta I, Grotta J, Savitz S. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology 2010;74:1340.

[3] Fonarow GC, Smith EE, Saver JL, Reeves MJ, Bhatt DL, Grau-Sepulveda MV, Olson DM, Hernandez AF, Peterson ED, Schwamm LH. 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 minutes. Circulation 2011;123:750-758

Although in the last answers only neurologists were mentioned, I completely agree with Dr. Latout-Perez that trained non-neurologists are a valuable alternative depending on the level of training and experience.

Regarding ICH, I am not aware of studies that focus on differences in outcome of patients who develop a intracerebral bleed after thrombolysis in and outside stroke units - a question which is not answered by the study of Chernyshev et al. but has certain impact in the current debate...

Regarding the last comment of Dr. Sutter, in Spain ICH are usually managed in intensive care units (in close collaboration with Neurosurgery), not in stroke units.

In Berlin, they have set up a prehospital thrombolysis system where a specialized ambulance equipped with a CT scanner, teleradiology system, and point-of-care testing, and staffed with a neurologist, EMT and radiographer. Their first results suggest that this approach lowers the time to thrombolysis without increasing risks (admittedly, the number of enrolled patients is small yet). By analogy, maybe thrombolysis could be initiated at smaller hospitals and patients could then systematically be transferred to stroke centers.

Weber JE, Ebinger M, Rozanski M, Waldschmidt C, Wendt M, Winter B, Kellner P, Baumann A, Fiebach JB, Villringer K, Kaczmarek S, Endres M, Audebert HJ; STEMO-Consortium. Prehospital thrombolysis in acute stroke: results of the PHANTOM-S pilot study. Neurology. 2013 Jan 8;80(2):163-8.

http://dx.doi.org/10.1212/WNL.0b013e31827b90e5

Thank you Dr. Mégevand. It seems that I.V. thrombolysis is on its way to be introduced in smaller care centers. An important question that comes to mind is how guidelines should be established for patients with thrombolysis related complications outside tertiary care centers. Are there any such guidelines in Berlin?

So far as I understood it, in Berlin they start the thrombolysis in their mobile thrombolysis truck-cum-CT-scanner and bring back the patients to a high-level stroke center.

I used to work in a regional hospital in Switzerland that had no neuroradiology or neurosurgery specialists. We had an iv thrombolysis protocol in place but I did not get to use it (the 2 stroke patients that i saw as part of the pre-hospital response team I sent directly to a tertiary stroke center from the site). I remember that the guidelines regarding complications were not extremely detailed; they called for stopping the thrombolysis if it was still ongoing, redoing a CT scan to assess hemorrhage, and getting a neurosurgery consult or transferring the patient emergently if required.

i think fibrinolytics will be better to use than just thrombolytics.thrombolytics are used in acs.

According to German law there has to be a neurologist on the truck who is also trained in emergency medicine. This approach saves up to 20 min in adminstration time for iv rtpa but is in my opinion suitable for large cities which several stroke units in the area. At my hospital which we have a helicopter which brings us the patient asap.

Considering the fact 1/that for many countries, many cities, it will be impossible to have a thrombolysis-CT-Scan truck with a neurologist; 2/ that time is the main problem for ischemic stroke treatment: “time is brain”, i perfectly agree with the proposition that each Emergency Department (ED) should have the authorization to thrombolysis a patient suffering from ischemic stroke according to the international guidelines and counter-indications, telemedicine should helpful in case of doubt. When I was responsible of the ED of a university hospital of Paris ‘area (in the late 1990 and the beginning of 2000’s), I saw too much stroke ischemic patients which should have received thrombolysis, if we had the authorization. In France, neurologists associated with authorities recommended that stroke patients should be directly admitted to a stroke center, and that hospital without a stroke unit should not receive any more stroke patients. But in the real life, ED continues to receive patients transferred by their practitioner’s or pre-hospital care!

THE BEST should be a public awareness raising campaign to improve response and limit the delay between onset and first medical assistance. In 1995, being in the USA, I was surprised by the Californian campaign against stroke. In each newspapers, in each room hotel TV, you have a page concerning Stroke Diagnosis (10 major messages) and then Call 911 ! With this campaign, Californian patients reached ED in less than three hours versus at least twelve…. This debate is similar to the cardiologists’ discussion about myocardial necrosis and the authorization of thrombolysis…

Thus, I believe that each ED should have the authorization for stroke thrombolysis, patients being evaluated immediately (STROKE CODE for nurses, physicians, radiologists, laboratories…). Stroke centers should receive all stroke patients treated or not with thrombolysis… but for the very old patients ???

“Time is brain”, the chain of survival should be effective, even if we can now enroll patients within 4.5 hours of onset of ischaemic stroke.

The number of well-trained neurologists in developing country like Thailand are extremely limited. It is not possible to have the stroke center with eligible neurologists covered the whole country. Not even talk about Ambulace-CT things! take forever? to have this kind of thing! If that's the case, most of the stroke patients have a very little chance to reach thrombolysis. So train ED or internal medicine physicians to know how to treat with thrombolysis should be the better way to go for Thailand.

AHA recommends a stroke center.As u said , it would be better if a hospital with a ct scan and the licence to give fibrinolytic therapy would be the best...

@Sombat that case is not only in Thailand, but also in Nepal or many other nations. I too support your idea of training the ED/Internal Medicine physicians.

I agree with Dr. varsou. It is ideal to give thrombolysis in a stroke centre. But in a country like India, where Neurologists to population ratio is low, it may be a nice idea to give thrombolysis throgh teleneurology consult.

The question relates to which centers should provide thrombolysis for acute ischaemic stroke. It is common practice around the world to NOT limit this time critical service to neurosurgical centres only. The Drip-and-Ship model of giving the "juice" wherever the diagnosis is made and then transferring the patient to a stroke unit is becoming more common, especially with telemedical backup.

It might be debated whether the teleconsultation would even require a video component. A solid history and well read CT scans are crucial and after that it boils down to making a judgement call on the expected benefits vs. risks, which can be done over the phone. 

The quality of the clinical examination might not always be superior in stroke centres. You might have the best clinician consultants in the world, but in most centres they would not go down into the ED, only provide their advice to the residents over the phone.

Finally, on the question of neurosurgery, even if a patient bleeds (ca. 1:20) they rarely receive surgery. Either the bleed is all over the place and there is no prognosis irrespective of surgery, or the bleed is small and deep and would not benefit from surgery. The vast majority of haemorrhagic transformations are managed medically.

So to sum up, I would not believe on-site neurosurgical services or even a stroke unit iscompulsory for delivering thrombolysis for stroke.   

I completely agree with Doctor Atte Meretoja comments and, indeed, we have experienced this “drip and ship” approach in a paper that tested i.v. thrombolysis in ED under experienced supervision (1). The results were similar to those obtained by the NINDS study.

1. Semplicini A, et al. Intravenous thrombolysis in the emergency department for the treatment of acute ischaemic stroke. Emerg Med J. 2008 Jul;25(7):403-6. doi: 10.1136/emj.2007.053033.