Prehospital Thrombolysis: A Manual from Berlin

1Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, 2Klinik und Hochschulambulanz für Neurologie, Charité - Universitätsmedizin Berlin, 3Medical School of the Universität Hamburg, Universitätsklinikum Hamburg - Eppendorf, 4Berliner Feuerwehr, 5STEMO-Consortium
Published 11/26/2013
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Summary

Identification of suspected stroke in the dispatch center of the Berlin Fire Brigade prompts the deployment of a CT-equipped ambulance. If ischemic stroke is confirmed and contraindications are excluded prehospital thrombolysis is applied.

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Ebinger, M., Lindenlaub, S., Kunz, A., Rozanski, M., Waldschmidt, C., Weber, J. E., et al. Prehospital Thrombolysis: A Manual from Berlin. J. Vis. Exp. (81), e50534, doi:10.3791/50534 (2013).

Abstract

In acute ischemic stroke, time from symptom onset to intervention is a decisive prognostic factor. In order to reduce this time, prehospital thrombolysis at the emergency site would be preferable. However, apart from neurological expertise and laboratory investigations a computed tomography (CT) scan is necessary to exclude hemorrhagic stroke prior to thrombolysis. Therefore, a specialized ambulance equipped with a CT scanner and point-of-care laboratory was designed and constructed. Further, a new stroke identifying interview algorithm was developed and implemented in the Berlin emergency medical services. Since February 2011 the identification of suspected stroke in the dispatch center of the Berlin Fire Brigade prompts the deployment of this ambulance, a stroke emergency mobile (STEMO). On arrival, a neurologist, experienced in stroke care and with additional training in emergency medicine, takes a neurological examination. If stroke is suspected a CT scan excludes intracranial hemorrhage. The CT-scans are telemetrically transmitted to the neuroradiologist on-call. If coagulation status of the patient is normal and patient's medical history reveals no contraindication, prehospital thrombolysis is applied according to current guidelines (intravenous recombinant tissue plasminogen activator, iv rtPA, alteplase, Actilyse).

Thereafter patients are transported to the nearest hospital with a certified stroke unit for further treatment and assessment of strokeaetiology. After a pilot-phase, weeks were randomized into blocks either with or without STEMO care. Primary end-point of this study is time from alarm to the initiation of thrombolysis. We hypothesized that alarm-to-treatment time can be reduced by at least 20 min compared to regular care.

Introduction

Thrombolysis with intravenous recombinant tissue Plasminogen Activator (rtPA) is the only proven effective treatment in acute ischemic stroke. The benefits of thrombolysis are time-dependent. Efficacy of thrombolytic therapy for ischemic stroke decreases with time elapsed from symptom onset1. Therefore, delays until initiation of treatment must be avoided. However, there are prehospital and in-hospital reasons for delays in treatment initiation. Patients' decision time to call emergency services and the time from emergency call to arrival at the hospital are factors in the prehospital delay. In hospital, reductions of both the time to CT scanning and of the time between CT scan and start of thrombolysis remain challenging2. Stroke awareness campaigns shorten patient related times to emergency call3, but effects are only temporary and require repetition of such campaigns. While there are successful examples of reducing in-hospital delay 4,5 many centers struggle to remain within the required 60 min from door to needle. One way to avoid these delays may be a start of specific stroke treatment at the emergency site, i.e. prehospital thrombolysis. Until recently, several requirements made this unfeasible. First, only physicians experienced in stroke care are qualified to make acute treatment decisions. Second, computed tomography (CT) is necessary to rule out intracranial hemorrhage. Third, laboratory tests should be available to exclude coagulation disorders6. In order to overcome these challenges, a stroke emergency mobile (STEMO) was constructed. This special ambulance is equipped with a CT scanner, a point-of-care laboratory and an infrastructure for teleradiological support7. It is operated by a highly specialized crew consisting of experienced neurologists, paramedics of the Berlin Fire Brigade, and radiology technicians8. To meet the legal requirements and the requirements of the Berlin Medical Board, each neurologist involved completed an additional training in emergency medicine. Radiology technicians completed a three month formal training in emergency care9. STEMO has been integrated in public emergency medical services (EMS) provided by the Berlin Fire Brigade. For the identification of eligible patients with suspected stroke during the emergency call, a special interview algorithm was developed and integrated at the dispatcher level10. During a three months pilot-study, we demonstrated safety and feasibility11. Our colleagues from Homburg, Germany, recently published their experience with the first 12 prehospital thrombolysis in the Saarland State12. We believe that prehospital stroke care using STEMO can reduce the alarm-to-needle time compared to regular care ultimately leading to improved patients care. However, prior to implementation final results of sufficiently powered studies need to confirm safety and efficacy of this approach. Here we present the methods used in the "prehospital acute neurological therapy and optimization of medical care in stroke patients" study (PHANTOM-S).

Protocol

1. Emergency Response at the Dispatch Center of the Berlin Fire Brigade

  1. Answer an incoming "112" emergency call.
  2. Gather information about the emergency site, such as address, floor, name on the doorbell and phone number. Type the data directly into the worksheet of the computer-controlled emergency dispatch system (called Ignis)
  3. Identify the medical emergency as a stroke emergency, using the newly developed Dispatcher Identification Algorithm for Stroke Emergencies (DIASE).
  4. Verify that the emergency site is within the operating area of STEMO via Ignis.
  5. Communicate alarm to STEMO via a radio-based alarm system. (In Berlin, currently, a regular care ambulance is alarmed simultaneously.) Available information concerning the emergency is automatically transmitted via fax.

2. Receipt of the Alarm Transmission at the Fire Station

  1. A personal pager signals the alert by audible tone. Go immediately to the fax machine and take the fax containing the detailed emergency information.
  2. Go to the STEMO vehicle, press the status button 3 on the on-board radio, thus confirming a receipt for alert to the dispatch center. The GPS-based navigation system has automatically received a routing to the patient's location.
  3. When complete crew is on board (Paramedic, Neurologist and Radiology technician) drive the STEMO vehicle to the emergency site. CAUTION: Approach with blue lights flashing and siren to the scene. Therefore, pay particular attention to other road users and observe the regulations of the German traffic law concerning the use of blue lights and siren.
  4. Upon arrival at the emergency site, press the status button 4 on the on-board radio, thus giving a confirmation to the dispatch center.
  5. Pay extra attention to safety before leaving the STEMO vehicle at the emergency site. CAUTION: Watch out for potential hazards, such as unsecured scene of an accident, violent people, risk of fire, moving traffic or hazardous substances.

3. Examination of the Patient at the Emergency Site

  1. Check consciousness using the Glasgow Coma Scale (GCS).
  2. Follow the structured "ABCDE algorithm" for the initial assessment of the patient's status: Airways, Breathing, Circulation, Disability, Exposure13.
  3. Explore medical history of the patient. If stroke is suspected clinically assess severity of symptoms using the National Institutes of Health Stroke Scale (NIHSS).
  4. Determine the exact onset of symptoms by questioning the patient/witnesses.
  5. Ask for current medication with a main focus on anticoagulation therapy.
  6. Measure and log the vital signs, such as heart rate, blood pressure, blood sugar concentration, and oxygen saturation.

4. Insert a Peripheral Intravenous (IV) Line and Perform Blood Withdrawals

  1. Apply a tourniquet around the upper arm.
  2. Search for a suitable hand, forearm, or antecubital vein. The best choice for the iv line is a vein on the dorsum of the hand.
  3. Disinfect the skin.
  4. Remove needle sheath from the indwelling venous catheter. Ensure needle bevel is upwards.
  5. Apply traction distal to the vein to prevent vein from rolling during cannulation.
  6. Insert the needle into the vein at 20-40°. The flashback of blood confirms that the needle tip is inside the vein. Advance the catheter off the needle into the vein.
  7. Fix the catheter using adhesive tape.
  8. Remove the needle, discard it to a sharps container and connect a plastic adapter containing a shrouded needle, which enables to start with a blood draw from the indwelling venous catheter.
  9. Perform blood draw using several Vacutainer blood test tubes. Some of these blood tubes contain different anticoagulatory additives, such as EDTA, citrate and heparine. The type of blood test tube is color-coded: 1. Purple for complete blood counts; 2. Blue for coagulatory assays; 3. Green for electrolytes, BUN, and other basic blood parameters; 4. Orange for specialized serum analysis.
  10. Push a Vacutainer blood test tube into the plastic holder, so that its rubber cap is pierced by the shrouded needle. (The negative pressure in the Vacutainer tubes forces blood into the blood test tubes.)
  11. Remove the Vacutainer tube after it was filled with blood and repeat this procedure with the other Vacutainer tubes.
  12. After the last Vacutainer tube was filled, remove the tourniquet, flush the indwelling venous catheter with normal saline solution, and close the catheter using a closing cone.

5. Determine the International Normalized Ratio (INR), using a Bedside Point-of-care Analyzer

  1. Take a test strip from its container. Slide it into the guide in the direction indicated by the arrows.
  2. Take a lancet and twist the protective cap off. Press the tip of the lancet against the side of the fingertip and press the trigger button.
  3. Apply the blood sample on the target area of the test strip within 15 sec of sticking the fingertip. After a few seconds the result (INR) is displayed.
  4. Place the used strip and the lancet into containers for biohazards and sharps, respectively.

6. Advanced Diagnostics and Intervention

  1. Immediately transfer the patient into the STEMO vehicle.
  2. Position the patient on a stretcher.
  3. Insert the purple Vacutainer blood test tube into the point-of-care laboratory (Horiba ABX Micros 60). Measure additional blood parameters such as platelet count, total leukocyte count, erythrocyte count, hemoglobin concentration, hematocrit, electrolytes.
  4. Insert the patient's insurance card into the card reader (installed in the control room).
  5. Call the neuroradiologist on-call to discuss the indication for CT scanning and prepare for examination.
  6. Explain benefits and risks of CT scanning to the patient. Afterwards, obtain informed consent from the patient, if possible.
  7. Start the CT. CAUTION: X-ray radiation is released from the CT scanner. Radiology technician has to be in the shielded control room. The rest of the STEMO staff is requested to leave the vehicle during the examination in order to avoid unnecessary exposure to x-ray radiation (STEMO vehicle is lead covered). Furthermore, protective measures (eye protection) should be applied to the patient.
  8. Transmit the CT image via on-board telemetric infrastructure and request teleradiological support for decision making regarding diagnosis and therapy. (Parallel analysis of images in the STEMO by the neurologist.)
  9. Ask the patient for contraindications against thrombolytic therapy using a standardized check list.
  10. Explain benefits and possible risks of thrombolysis. Inform the patient that the treatment is part of a clinical study and obtain informed consent, if possible.

7. Administration of Recombinant Tissue Plasminogen Activator (rtPA or Alteplase)

  1. Calculate the dose of alteplase (trade name: Actilyse) based on the best approximation of bodyweight available. The recommended dose is 0.9 mg/kg bodyweight. Maximum dose is 90 mg6.
  2. Reconstitute the dry solid alteplase using the solvent provided. Use the transfer cannula, which must be introduced vertically into the rubber stopper of the phials and through the mark at its center.
  3. Dissolve the dry solid by gentle agitation.
  4. Initiate thrombolysis by administering 10% of the calculated total dose as a bolus injection over 1 min. Keep record of the point in time, when alteplase bolus is injected. CAUTION: Pay attention to immediate allergic responses following administration. Be prepared to administer antiallergic drugs (i.e. antihistaminics, high-dose glucocorticoids, catecholamines) in case of an acute allergic response. In general, alteplase should be used only by a physician experienced in the treatment of ischemic stroke6.
  5. Inject the remaining dose via an injection pump syringe continuously over 60 min (after evacuation of the tubing to avoid the injection of air bubbles).

8. Transportation of the Patient to a Suitable Hospital

  1. Make an advanced notification to the emergency room of the closest hospital with a certified stroke unit.
  2. Start the transportation immediately. Communicate the selected hospital to the dispatch center via radio.
  3. Monitor neurological deficits and vital signs during transfer to the hospital.
  4. Print out and sign the admission letter (using Vimed software) including diagnosis, history, results of neurological examination, neuroradiological report (sent by the neuroradiologist on call via UMTS), results of laboratory investigations, and description of actions taken. Copy CT-scan on a CD for the hospital.
  5. On arrival at the hospital (press status button 8) provide concise present and past medical histories of the patient to the neurologist on-call and to the primary team in the Emergency Room. Hand over printed report, CD containing CT images (step 8.4), and the blood-filled blue, green and orange Vacutainer blood test tubes (step 4.9).

9. Restoring the Operational Readiness

  1. Clean and disinfect hands and all equipment that has been used during the EMS response.
  2. Report operational stand-by status to the dispatch center using button 1 on the onboard radio. Return to the local fire station.

Representative Results

From February 8 to April 30, 2011, a total of 152 subjects were treated in the STEMO vehicle. Informed consent was obtained from 77 patients. Forty-five patient's (58%) had an acute ischemic stroke and 23 (51%) of these patients received rtPA. The mean alarm-to-needle time using STEMO was 62 min compared to 98 min in a control cohort of 50 consecutive patients thrombolysed in Berlin in 2010. Two (9%) of the rtPA-treated patients suffered a symptomatic intracranial hemorrhage and one of these patients (4%) died in hospital. Technical failures comprised one CT dysfunction and two delayed CT-image transmissions11.

Figure 1
Figure 1. Call-to-needle-time. Comparison of acute ischemic stroke patients who received tissue-Plasminogen Activator (tPA). STEMO-treated patients (n=23) vs. in-hospital treated patients in 2010 (n=50). Boxes show standard deviation (SD) with the line representing the mean call-to-needle time (62 minutes vs. 98 minutes); whiskers indicate the distribution width within 2 x SD. Based on data from Weber et al.11 Click here to view larger figure.

Figure 2
Figure 2. STEMO overall concept. Flow diagram of EMS response with main focus on stroke emergencies responded by STEMO. Modified according to an original design by Audebert, H.J. STEMO (Stroke-Einsatz-Mobil). http://tsb-berlin.de /media/uploads/zukunfsfonds/STEMO_(Stroke-Einsatz-Mobil).pdf. Click here to view larger figure.

Discussion

Prehospital thrombolysis may be able to revolutionize acute specific stroke treatment. However, it is a cost and resource consuming way of treatment delivery. In general, a 'stay-and-play' rather than a 'load-and-go' approach needs to be justified by specific characteristics of the emergency at hand. Ischemic stroke has distinctive features that warrant a 'treat-and-run' compromise: The benefits of acute stroke treatment are enormously time dependent. During an ischemic stroke approximately 2,000,000 neurons die per minute14. Intravenous treatment with rtPA enhances the chances of reperfusion and favorable functional outcome in stroke patients15. Treatment should be started as soon as possible. By now, it is the only evidence-based, effective and approved treatment for acute ischemic stroke. Associated with the risk of severe bleeding, the exclusion of intracranial bleeds and other contraindications is mandatory prior to thrombolysis. STEMO is set up to prove that this specific treatment can be safely administered in a prehospital setting and actually safes time compared to regular care8,11. First results from 12 prehospital thrombolyses in the Saarland State, Germany, seem promising in this respect12. In this study, Walter and colleagues reported that after randomized weeks between November, 2008, and July, 2011 and an interim analysis at 100 of 200 planned patients (53 in the prehospital setting, 47 in the control group), the median time from alarm to therapy decision (primary end-point) was substantially reduced in the 12 cases of prehospital thrombolysis: 35 min (IQR 31-39) versus 76 min, p<0.0001; median difference 41 min (95% CI 36-48 min). Overall, the additional costs have to be weighed against benefits that patients may experience. For this, the final results of the ongoing PHANTOM-S will be crucial. In this prospective study (http://clinicaltrials.gov/ct2/show/ NCT01382862), weeks with and without STEMO on duty are randomized until 228 patients have received iv rtPA in both treatment arms. Primary end-point of the study is time from alarm to thrombolysis. Secondary end-points include modified Rankin Scale score after three months, symptomatic intracranial hemorrhage, mortality and cost effectiveness. Results of this study will help decision makers whether to implement prehospital thrombolysis of acute ischemic stroke patients with specialized ambulances in their emergency systems. Site specific adaptations may be necessary. For instance, in regions with a shortage of neurologists telemedicine may provide the expertise to the emergency physician on board. Similarly, the results of the PHANTOM-S study may help to identify regions with the most likely benefit for patients and cost effectiveness for authorities. So far, it is not known whether prehospital thrombolysis is the most appropriate approach in mega-cities, urban, or rural settings16. Taken together, prehospital thrombolysis seems to be a logical step when the need of shortening time to treatment is taken seriously. Only a sufficiently powered study may provide the evidence of actual benefit to stroke patients.

Disclosures

The authors declare that they have no competing financial interests.

Acknowledgements

We wish to acknowledge all of the funding organizations, the "Technology Foundation Berlin" (TSB) via the "Zukunftsfonds Berlin", the Federal Ministry of Education and Research via the grant CSB (01 EO 0801), the Volkswagen Foundation (Lichtenberg program to Matthias Endres), the EU (EuStroke, ARISE) and the German Research Foundation (NeuroCure, SFB-TR 43).

Materials

Name Company Catalog Number Comments
Drug
Alteplase (rtPA) Boehringer-Ingelheim Licensed drug
Table 1. Alteplase. Alteplase (tissue-Plasminogen Activator) is the only licensed drug for acute ischemic stroke that has proven effectiveness within 4.5 hr of symptom onset in randomized controlled trials.
Device
ABX micros 60 Horiba Medical Point-of-care laboratory
CereTom NeuroLogica CT-Scanner
CoaguChek XSPlus Roche Handheld blood analyzer
EBA 20 HettichLab centrifuge
FastPack System Qualigen Point-of-care immunoassay
i-STAT Abbot Handheld blood analyzer
OptiStat Siemens Contrast agent delivery system
Pilot A2 Fresenius Infusion pump
TGL 12.250 4 x 2 BL MAN Vehicle chassis
Van body Fahrtec Systeme GmbH Custom-built
Vimed COMM MEYTEC GmbH Video communication system
Vimed GATEWAY MEYTEC GmbH Network solution
Vimed STEMO-DOC MEYTEC GmbH Documentation software
Vimed TELEMED MEYTEC GmbH Equipment for telemedicine
Vimed WEB-ENTRY MEYTEC GmbH Teleradiology
Table 2. Table of specific equipment. The software solution used in the ambulance was developed by a partner of the STEMO-consortium, MEYTEC GmbH, Germany. MEYTEC designed and implemented the overall technical solution. The entire system can be obtained from the partner MEYTEC under the name VIMED STEMO.

DOWNLOAD MATERIALS LIST

References

  1. Meretoja, A., Strbian, D., et al. Reducing in-hospital delay to 20 min in stroke thrombolysis. Neurology. 79, (4), 306-313 (2012).
  2. Herlitz, J., Wireklintsundström, B., et al. Early identification and delay to treatment in myocardial infarction and stroke: differences and similarities. Scand. J. Trauma Resusc. Emerg. Med. 18, (48), (2010).
  3. Worthmann, H., Schwartz, A., et al. Educational campaign on stroke in an urban population in Northern Germany: influence on public stroke awareness and knowledge. Int. J. Stroke. (2012).
  4. Köhrmann, M., Schellinger, P. D., et al. Avoiding in hospital delays and eliminating the three-hour effect in thrombolysis for stroke. Int. J. Stroke. 6, 493-497 (2011).
  5. Ford, A. L., Williams, J. A., et al. Reducing Door-to-Needle Times Using Toyota's Lean Manufacturing Principles and Value Stream Analysis. Stroke. (2012).
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  7. Gierhake, D., Weber, J. E., et al. Mobile CT: Technical Aspects of Prehospital Stroke Imaging before Intravenous Thrombolysis. Rofo. (2012).
  8. Ebinger, M., Rozanski, M., et al. PHANTOM-S: the prehospital acute neurological therapy and optimization of medical care in stroke patients - study. Int. J. Stroke. 7, (4), 348-353 (2012).
  9. Körting, E., Notarztdienstverordnung,, et al. Available from: www.berlin.de (2010).
  10. Krebes, S., Ebinger, M., et al. Development and Validation of a Dispatcher Identification Algorithm for Stroke Emergencies (DIASE). Stroke. 43, (3), 776-781 (2012).
  11. Weber, J. E., Ebinger, M., Rozanski, M., et al. Pre-hospital thrombolysis in acute stroke - results of the PHANTOM-S pilot study. Neurology. (2012).
  12. Walter, S., Kostopoulos, P., et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol. 11, (5), 397-404 (2012).
  13. Thim, T., Krarup, N. H., Grove, E. L., Rohde, C. V., Loefgren, B. Initial assessment and treatment with the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach. Int. J. Gen. Med. 5, 117-121 (2013).
  14. Saver, J. L. Time Is Brain - Quantified. Stroke. 37, (1), 263-266 (2006).
  15. Lees, K. R., Bluhmki, E. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 375, (9727), 1695-1703 (2010).
  16. Rothwell, P. M., Buchan, A. M. Mobile acute stroke units: bringing the hospital to the patient. Lancet Neurol. 11, (5), 382-383 (2012).

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