Thrombolysis in acute ischaemic stroke pathway

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INTEGRATED CARE PATHWAYS ORIGINAL ARTICLE

Thrombolysis in acute ischaemic stroke pathway Samuel Chew*, Shahid A Kausar* and Steve Sturman† *Department of Geriatric Medicine; †Department of Neurology, City Hospital, Birmingham, UK ABSTRACT. Thrombolysis of appropriate and selected patients presenting with an acute ischaemic stroke within 3 h of onset with recombinant Tissue Plasminogen Activator (alteplase, r-TPA) can be implemented safely, reduce long-term disability, and is recommended by the National Institute of Health and Clinical Excellence and the Department of Health’s National Stroke Strategy. We have developed an integrated and comprehensive pathway in order to achieve the above aims, which also provide guidelines for nursing in the peri-acute period and management of complications arising from the ischaemic stroke itself, from thrombolysis or from concomitant hyperglycaemia.

INTRODUCTION Stroke can be defined as a clinical syndrome of acute onset and of vascular origin, resulting in focal or global neurological deficit. Eighty-five percent are ischaemic in nature, hence should be assessed and treated in the context of a ‘brain attack’.1 For every minute of delay in treatment, up to 1.9 million neurons are lost permanently.2

BACKGROUND Stroke is the third largest cause of death in England after ischaemic heart disease and cancer.1 There are about 110,000 new strokes in England in a year.1 One in four individuals are expected to have had a stroke by the age of 85.1 However, strokes also affect

Samuel Chew MB BCh MRCP (Edinburgh), Specialist Registrar in Geriatric and Internal Medicine; Shahid A Kausar MD DNB MRCPI, Consultant Physician/ Stroke Specialist, Honorary Senior Clinical Lecturer, Department of Geriatric Medicine; Steve Sturman MB ChB FRCP, Consultant Neurologist, Department of Neurology, City Hospital, Dudley Road, Birmingham B18 7QH, West Midlands, UK Correspondence to: SC Email: [email protected]

the younger population with up to 25% of strokes occurring in patients ,65 years of age.1 Up to one-third of all stroke patients die within one month while another one-third is left with permanent disabilities and lost of independent living.1 The total cost of stroke care is about £7 billion per year; consisting of £2.8 billion in direct costs to the NHS, £2.4 billion in informal care costs paid by the patient’s family and £1.8 billion in lost income due to loss of productivity and disability.1 Despite this high cost, outcomes in the UK compares unfavourably internationally due to high levels of avoidable disability and mortality.3 Less than 1% of patients with ischaemic strokes were thrombolysed in 2006,2 compared with 10% in a leading hospital in Australia.1 It has been estimated that achieving the same rates of thrombolysis in England would result in more than 1500 patients with full recovery and a net savings of .£16 million a year to the NHS.2,4 The efficacy of thrombolysis of selected patients in this group has been reviewed by the National Institute of Health and Clinical Excellence (NICE),5 and this treatment is recommended by the NICE and the Department of Health’s National Stroke Strategy.2

METHODS We undertook a comprehensive review of the available literature on thrombolysis in acute ischaemic stroke

JOURNAL OF INTEGRATED CARE PATHWAYS (2008) 12, 10–22 # The Royal Society of Medicine Press 2008.

DOI: 10.1258/jicp.2008.008004

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INTEGRATED CARE PATHWAYS

and established the evidence base for our pathway.6–11 In particular, we identified that thrombolysis was only effective and safe if performed within 3 h of onset of symptoms. Recent analysis of the National Institute of Neurological Disorders and Stroke data shows that outcomes are even better if thrombolysis can be delivered within a 90 min time-frame.10,12 We have also noted the emerging evidence in the literature that shows a negative correlation between hyperglycaemia and patient outcomes postthrombolysis for acute ischaemic stroke,13–15 and have decided to make glycaemic control a key part of our protocol. Our blood sugar cut-off points are based largely on the European Stroke Initiative recommendations.14 Our protocol is broadly based on the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST), which was carried out in 285 centres in 14 countries in the European Union, involving a total of 6483 patients.6 Using a strictly defined treatment criteria, it has shown that thrombolysis of acute ischaemic stroke with alteplase can be delivered safely and effectively in routine clinical practice in European countries.6 We recognized that successful implementation of a stroke thrombolysis pathway requires the coordinated efforts of many departments, including but not limited to the pre-hospital emergency services, the accident and emergency department, the radiology department and the acute stroke thrombolysis team. The Stroke Association also played an important role in raising awareness in the community and in distributing information on the face arm speech test (FAST), which is a validated tool for identifying the symptoms of stroke in the community.16,17 All stakeholders were consulted and engaged early in the development phase of our pathway. Key parts of the pathway were summarized into single page checklists and reference points in order to ensure high levels of usability in the real-world clinical setting. This would also help reduce user errors, especially with regards to dosing of alteplase for each individual patient. As the pathway requires a multidisciplinary approach in a time-critical situation, we made the role and responsibility of each member explicit in the protocol. Guidelines for the management of hyperglycaemia, intracerebral haemorrhage, severe hypertension, specialized nursing protocol, detailed information needed to facilitate informed consent and where to obtain the most up-to-date ‘Summary of Product Characteristics’ for alteplase are included.

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INTERNAL REVIEW PROCESS The draft protocol was presented to the Accident and Emergency Department, the Stroke Unit, at our hospital’s Grand Round presentations and to the Clinical Governance Board. It was also distributed to all the stakeholders via email for their review and further input. The final draft was then ratified by our Drugs and Therapeutics Committee and sent to the Medicine Divisional Governance Group for final approval by our Trust.

SUMMARY OF THE STROKE THROMBOLYSIS PATHWAY Patients who suspect that they might be having a stroke activate the emergency services by dialling ‘999’. They are then assessed by the paramedic crew using the FAST test. If this is positive, they then activate the ‘Stroke Alert Call’ via the accident and emergency (A&E) department. The patient is then ‘blue-lighted’ to the hospital. In the A&E department, they are rapidly assessed and have an urgent computerized tomography (CT) head scan in the next slot during the day. The on-call stroke thrombolysis will be on hand to review the clinical findings, inclusion/exclusion criteria and the CT head images and radiologist report. If all the criteria for thrombolysis have been met, then the patient will be thrombolysed in a monitored bed in A&E immediately. The dose of alteplase used is 0.9 mg/kg to a maximum of 90 mg. Ten percent of the total dose is given as a bolus with the remaining 90% given over 60 min via a syringe driver pump. Infusion should be stopped if there are any signs or symptoms of anaphylaxis, a decrease in Glasgow Coma Scale of .2 or an increase in NIH Stroke Scale score of .4, an increase of blood pressure .185/110 mmHg or any major systemic bleeding. The patient should then be managed as per protocol with the appropriate supportive management and investigations. The patient will then be transferred to a monitored bed in the Medical Assessment Unit (MAU) for close observations for 24 h, before they are then moved to the acute stroke unit for further care if there are no further complications within this period of time. The content listing of our protocol is illustrated in Box 1. We have included the appendices in full and the detailed descriptions of the contents are available on request.

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Box 1 Thrombolysis in acute ischaemic stroke pathway Contents: (1) Introduction (i) Inclusion criteria (ii) Exclusion criteria (iii) Treatment protocol (2) Preparation of Alteplase (3) Administration (4) Concomitant therapy (i) Hyperglycaemia (ii) Increased blood pressure (iii) Haemorrhage (iv) Overdose (v) Anaphylactic reactions (vi) Precautions (5) Follow-up care (i) Key requirements (ii) Nursing skills required (iii) General management (iv) Monitoring (6) Acute deterioration post Alteplase (7) Active bleeding (8) Acute intracerebral haemorrhage (9) Management of blood pressure (10) Appendices (i) Appendix 1: Roles and responsibilities (ii) Appendix 2: NIH Stroke Scale checklist (iii) Appendix 3: Checklist for thrombolysis for acute ischaemic stroke (iv) Appendix 4: Alteplase weight–dose table (v) Appendix 5: Nursing protocol (vi) Appendix 6: Stroke thrombolysis pathway algorithm (vii) Appendix 7: NIH Stroke Scale in full with picture tools (viii) Appendix 8: Alteplase summary of product characteristics & web-link (ix) Appendix 9: Bleeding risks other than intracerebral (x) Appendix 10: Risk/benefits statistics and references (xi) Appendix 11: Blood glucose management

KEY POINTS IN PRACTICE The main prerequisites for thrombolysis in acute ischaemic stroke is a history and clinical findings consistent with stroke as defined earlier; a presentation within 3 h of onset of symptoms, measured from when patient was last awake or when last seen well; a NIH Stroke Scale score of .5 and ,25, and a CT head scan that excludes any significant bleed or space occupying lesion. Symptoms must be present for at least 30 min and have not significantly improved prior to thrombolysis; and the answer to every question in the exclusion checklist must also be ‘No’. If the patient is dysphasic and there are no next-of-kin contactable after best efforts, then treatment can still be considered if all the criteria are met under ‘best interest’ of the patient. Please also note that in the NIH Stroke Scale checklist, the untestable parameters are arbitrary given a

score of ‘9’, as per convention in the UK. This ‘9’ is not added to the final total NIH Stroke Scale score of the patient. Finally, strict adherence to the inclusion/exclusion criteria is essential to minimize harm from avoidable intracerebral haemorrhages in high-risk patients.

TRAINING RESOURCES Online training and certification by the American Heart Association (AHA) on the NIH Stroke Scale is available at the AHA website.18 The certificate is valid for two years. More online resources for stroke thrombolysis can also be found at the Third International Stroke Trial website.19

References 1 Department of Health. National Audit Office. Reducing Brain Damage: Faster Access to Better Stroke Care, 2005. See http:// www.nao.org.uk/publications/nao_reports/05-06/0506452.pdf (accessed 20 April 2008) 2 National Stroke Strategy, Department of Health, 2007. See http://www.dh.gov.uk/en/Publicationsandstatistics/ Publications/PublicationsPolicyAndGuidance/DH_081062 (accessed 20 April 2008) 3 Leal J, Luengo-Ferna´ndez R, Gray A, et al. Economic burden of cardiovascular diseases in the enlarged European Union. Eur Heart J 2006;27:1610–9 [Epub 22 February 2006] 4 Department of Health. Commissioning Guidance for Stroke Services, ASSET (2), 2006. See http://www.dh.gov.uk/en/ Publicationsandstatistics/Publications/ PublicationsPolicyAndGuidance/DH_063260 (accessed 20 April 2008) 5 National Institute for Health and Clinical Excellence. Alteplase for the Treatment of Acute Ischaemic Stroke, TA122, 2007. See http://www.nice.org.uk/TA122 (accessed 20 April 2008) 6 Wahlgren N, Ahmed N, Da´valos 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 7 Tissue plasminogen activator for acute ischemic stroke. The national institute of neurological disorders and stroke rt-PA stroke study group. N Engl J Med 1995;333:1581–7 8 Albers GW, Clark WM, Madden KP, et al. ATLANTIS trial: results for patients treated within 3 hours of stroke onset. Alteplase thrombolysis for acute non-interventional therapy in ischemic stroke. Stroke 2002;33:493–5 9 Hacke W, Kaste M, Fieschi C, et al. Randomised doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian acute stroke study investigators. Lancet 1998;352:1245–51

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10 Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768–74 11 Wardlaw JM, Zoppo G, Yamaguchi T, et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003;3:CD000213 12 Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 2000;55:1649–55 13 Bruno A, Levine SR, Frankel MR, et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002;59:669–74 14 Hack W, Kaste M, Bogousslavsky J, et al. European stroke initiative recommendations for stroke management-update 2003. Cerebrovasc Dis 2003;16:311–37 15 Alvarez-Sabin J, Molina CA, Montaner J, et al. Effects of admission hyperglycaemia on stroke outcome in reperfused

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tissue plasminogen activator–treated patients. Stroke 2003;34: 1235–41 The Stroke Association. Suspect a Stroke? Act FAST. See http://www.stroke.org.uk/campaigns/current_campaigns/ stroke_is_a_medical_emergency/act_fast.html (accessed 20 April 2008) Nor AM, McAllister C, Louw SJ, et al. Agreement between ambulance paramedic – and physician-recorded neurological signs with face arm speech test (FAST) in acute stroke patients. Stroke 2004;35:1355–9 [Epub April 29 2004] Professional Education Centre, American Heart Association. On-line NIH Stroke Scale Training and Certification. See http:// professionaleducationcenter.americanheart.org//ihtml/ application/student/interface.heart/ (accessed 20 April 2008) The Third International Stroke Trial On-line Training Materials. See http://www.dcn.ed.ac.uk/ist3/

Appendix 1 Acute thrombolysis service – roles and responsibilities Accident and emergency staff: On receipt of stroke patient A&E SpR to:

responsibility for the patient and undertake the following:

† Check indications/contraindications † Insert venflon and send clotting,

† Check NIHSS † Estimate weight † Review the scan † Complete checklist for contraindications † Discuss with duty consultant and

FBC, lipids,

glucose and biochemical profile † Start insulin sliding scale if BM . 10 mmol/L † Alert CT and initiate CT scan † Activate thrombolysis team via switchboard † Stay with patient until thrombolysis team take over. Switchboard: Switchboard staff will:

† Alert casualty if ambulance service ring in to advise

confirm diagnosis † If thrombolysis agreed then notify A&E resuscitation nurse so alteplase can be drawn up ready for administration † Return to A&E resuscitation bay with patient and give alteplase † Transfer patient to MAU monitored bed and ensure action plan and monitoring in hand.

of stroke patient in transit to A&E

† When requested by A&E they will group page the thrombolysis team which will include: W Thrombolysis SpR W Porter W CT radiographer W Thrombolysis consultant W MAU nurse manager.

Thrombolysis consultant: On receipt of thrombolysis alert call consultant will:

† Confirm with A&E that call received and SpR in attendance

Thrombolysis SpR: On receipt of Thrombolysis alert SpR will go directly to A&E to join patient and then will assume

† Will proceed to CT scan † Will supervise SpR role as necessary † Will check patient post alteplase to ensure all safety checks in place.

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INTEGRATED CARE PATHWAYS Appendix 2 NIH stroke scale checklist

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Appendix 3 Checklist for thrombolysis for acute ischaemic stroke Thrombolysis for acute stroke with alteplase has been shown to improve outcome and is licensed in the UK for this purpose; if used in carefully selected patients up to 180 min after stroke onset. All of the conditions below must be satisfied.

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INTEGRATED CARE PATHWAYS Appendix 4 Alteplase weight–dose table

Total dose required is 0.9 mg/kg, up to a maximum of 90 mg. Alteplase comes in 50 mg and 100 mg vials. Use sterile water for injection to make a 1 mg/mL solution. Draw up the required total dose according to patient weight. Give 10% of the total dose as an intravenous bolus, and infuse the remaining 90% over 60 min via a syringe driver.

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INTEGRATED CARE PATHWAYS Appendix 4 Cont’d

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Appendix 5 Nursing protocol for patients receiving r-TPA (1) Cardiac monitoring for 24 h. (2) BP and neurological observations: 15 min 2 h, 30 min 6 h, 60 min 16 h. (3) Notify medical staff if systolic BP . 180 or ,120 mmHg, or diastolic .105 or ,70 mmHg for two or more readings 5–10 min apart. (4) Notify medical staff if change in neurological status (fall of 2 or more on Glasgow Coma Scale or worsening by .4 points on NIHSS score) or bleeding. (5) Bed rest for 24 h. (6) No arterial puncture or central lines unless intra-arterial blood pressure monitoring required. (7) No nasogastric (Ng) tube for 24 h. (8) No bladder catheter for 30 min. (9) No heparin, antiplatelet agents (aspirin/dipyridamole/clopidogrel), warfarin or non-steroidal antiinflammatory drugs for 24 h. (10) Hourly BM if on insulin sliding scale for hyperglycaemia (BM . 10 mmol/L).

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Appendix 6 Stroke thrombolysis pathway algorithm

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INTEGRATED CARE PATHWAYS Appendix 7 NIH stroke scale

The National Institute of Neurological Disorders and Stroke (NINDS) NIH Stroke Scale, has detailed information on the testing of each parameter and includes the standardised graphic and word tools for the best language and dysarthria test. This should be used in conjunction with the NIH Stroke Scale checklist in Appendix 2. The full documentation is available at the following link: http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf

Appendix 8 Alteplase summary of product characteristics For the latest ‘Summary of Product Characteristics’ for alteplase, please visit http://emc.medicines.org.uk/emc/ assets/c/html/DisplayDoc.asp?Document ID=38. This page is maintained by Datapharm Communications Limited and publishes the latest SPC provided by the licensed company Boehringer Ingelheim Limited UK. It is updated on a regular basis and will contain all important information on the licensed use of alteplase.

Appendix 9 Bleeding risks other than intracerebral In The NINDS t-PA Stroke Trial (Parts 1 and 2), the frequency of bleeding requiring red blood cell transfusions was 6.4% for alteplase treated patients compared with 3.8% for placebo, P ¼ 0.19. This would be in keeping with the overall increased bleeding risk of using alteplase for any thrombolytic purposes of between .1 and 5% (Alterplase full summary of product characteristics 2005). For consent For every 10 patients given alteplase, we aim to have full recovery in one (Number Needed to Treat: 10 for full recovery). Treated patients are at least 30% more likely to have no disability at three months. There is about 7% risk of intracerebral haemorrhage in treated patients (Number Needed to Harm: 14 for intracerebral bleed) at seven days. However, there is no increased in mortality at three months observed in the studies above.

Appendix 10 Risks/benefits statistics and references SITS-MOST study 2007, Lancet;369:275–82 Full recovery in treatment arm was 39%. Intracerebral haemorrhage at seven days was 7.3%. Mortality at three months was 11.3% in the treatment group. Pooled meta-analysis of alteplase RCTs 2004, Lancet 2004;363:768–74 Full recovery in treatment arm was 42%. Intracerebral haemorrhage at seven days was 8.6%. Mortality at three months was 17.3% in the treatment group. NINDS study 1995, NEJM 1995;333 34% have full recovery at three months compared with 20% using the NIHSS score. There is also a 55% increase in the number of patients with NIHSS score of 0–1 in the treated arm (overlapping with previous figures). There was 17% mortality in the treatment arm and 21% in the placebo group. However, this difference was not statistically significant (P ¼ 0.30).

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Appendix 11 Guidelines for blood glucose management of patients receiving thrombolytic therapy for ischaemic stroke These guidelines apply to both inpatients with or without a known diagnosis of diabetes receiving thrombolysis for stroke. Laboratory plasma glucose must be checked on admission. If plasma glucose .10.0 mmol/L, intravenous insulin infusion and Sodium Chloride 0.9% are to be used as a combined treatment for blood glucose control.

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Blood glucose control chart for patients with stroke and thrombolysis