1 Emergency Physician, Sangre Grande Hospital, Trinidad.
2 Emergency Physician, Scarborough General Hospital, Tobago.
3 Assistant Professor Emergency Medicine & Critical Care, Dalhousie University, Canada.
4 Neurologist, Eric Williams Medical Sciences Complex, Trinidad.
Corresponding Author: firstname.lastname@example.org
Objectives: Thrombolysis has become the gold standard in the treatment of ischemic stroke that meet specific criteria. While effective, the criteria of suitability are substantial and create an access block for patients. This review seeks to identify the hindrances to the process flow to successful stroke thrombolysis.
Methods: A review of literature was done regarding the challenges facing thrombolysis in stroke patients. All English language papers in the subject matter were reviewed and compared with the local situation in the Caribbean especially Trinidad & Tobago.
Results: The article presents a review of the American Heart Association’s chain of survival for patients presenting with neurological symptoms suggestive of stroke. The achievable outcomes from this paper will be to describe the potential innovations that can be implemented in the Caribbean to overcome these hindrances.
Conclusions: Public health initiatives are an essential part of improving detection. There are many systemic improvements and hospital clinical flow improvements required. It is therefore imperative for health systems managers to appreciate and be aware of all steps in the process given that any impediment abruptly ends the likelihood of successful stroke thrombolysis.
A stroke or Cerebrovascular Accident (CVA) is generally defined as the rapid onset of a neurologic deficit involving a certain vascular territory that lasts longer than 24 hours as opposed to a Transient Ischaemic Attack (TIA) which is similarly characterized but lasts less than 24 hours . The 2013 guideline update by the American Heart Association emphasizes that stroke still remains a significant problem . The World Health Organization has estimated mortality rates as 5.1% in males and 7.8% in females . Statistics from the same source demonstrate an even higher mortality rate of 8.7% for males and 11.2% for females in Trinidad and Tobago .
The standard of care described in the American Heart/Stroke Association in their guidelines for the early management of patients with acute ischemic stroke defines a “chain of survival,” the majority of which is dependent on efficient and adequate function of the pre-hospital and emergency room services . Similar views are held in Europe by the National Institute for Health and Clinical Excellence 2008 reference guide on the diagnosis and initial management of acute stroke and transient ischaemic attack which emphasized the role of immediate imaging, thrombolysis if indicated and admission to a stroke unit .
With this background, this narrative review aimed to determine the evidence in published literature regarding the value and utility of thrombolysis and the various challenges faced by emergency clinicians in the implementation of thrombolysis for stroke.
A Medline literature search was done with keywords – cerebrovascular accident, thromboembolism and thrombolysis. All the studies which determined the advantages and disadvantages of thrombolysis in acute cerebrovascular events and those which tested the utility of thrombolysis and validated in different types of cerebrovascular thrombosis were identified. Literature search included the various drugs used for thrombolysis and their utility. Additionally, it also comprised information regarding the implementation of early thrombolysis in an Emergency setting and the challenges faced by different settings with respect to the implementation.
Searches for cerebrovascular accident and stroke yielded over 300 000 hits, when combined with thrombolysis yielded nearly 10 000 hits. The advantages and disadvantages yielded 10 hits and challenges yielded almost 100 hits.
Results and Discussion
Successful stroke management aims to improve neuronal recovery; during the acute phase of the brain insult the tissue is particularly vulnerable to complications and irreversible changes which may reduce the potential for a positive outcome . One measure of re-establishing blood flow to the affected area of the brain is thrombolysis. Major publications and reviews, including the Safe Implementation and of Thrombolysis Register in United Kingdom indicate that Recombinant Tissue Plasminogen Activator (rt-PA) for ischaemic stroke is safe and effective when administered within the first three hours after symptom onset . Other reviews such as the European Cooperative Acute Stroke Study (ECASS) extended this and showed clinical efficacy at three to four and a half hours but still emphasized that timely administration remains paramount to the achievement of optimal therapeutic outcomes . In order to create efficient process flow, the American Stroke Association has outlined a phase sequence termed the “7 Ds”. This includes the following steps: 1) Detection of symptoms early 2) Dispatch of ambulance services 3) Delivery of patient a stroke unit 4) Door to patient time in the ER to be minimal 5) Data acquisition to be obtained promptly 6) Decision regarding specific therapy and 7)Drug administration if thrombolysis is indicated (2).
The “chain of survival” aims to prioritize interventions to improve rates of thrombolysis for ischemic strokes . Reorganization and reducing delays in the ER aims to improve door to thrombolysis time and rate . Challenges related to the time-frame for intervention have limited the number of patients receiving thrombolysis . These difficulties in implementing the stroke chain of survival and thrombolysis are also present in the local setting.
In terms of detection, it is thought that the capacity of the general population to identify stroke signs is a major determinant for success of stroke management. This continues to be an international challenge. Chandratheva et al. in a 2010 study of 1000 consecutive patients demonstrated that approximately 70% of patients did not correctly recognize their stroke symptoms and that 30% delayed seeking medical attention for more than 24 hours regardless of age, sex, social class, or educational level . The role of family education is important, Tediem et al. in a 2012 randomized trial found that patient’s relatives who were educated via posters were better able to identify stroke and were able to do so earlier (64.5% vs 8% and 74.2% vs 20%, p<0.001 in both) . It has however been noted in the literature that cultural beliefs and practices often hinder control of chronic diseases and seeking medical care, especially in Caribbean populations . Implementing any type of thrombolysis for stroke in the local setting therefore requires mass campaigns to educate the population to identify signs of stroke and seek help early.
With respect to dispatch, Caceres et al. in a 2013 publication found that recognition of symptoms and diagnosis of a potential stroke by paramedics decreases the time to hospital (41.8 vs 49.8 minutes p<0.001) and increases the likelihood of intervention (84% vs 72.8% p<0.001) . Improving this efficiency requires implementing systems to improve the pre-hospital care delivered to suspected stroke patients. Gladstone et al. in a 2009 publication demonstrated that the implementation of a pre-hospital acute stroke activation protocol resulted in a fourfold increase in the number of patients arriving at hospital, who were eligible for and treated with intravenous thrombolysis . The authors concluded that sustainability of such an initiative would be dependent on interdisciplinary teamwork, ongoing paramedic training, adequate hospital staffing, bed availability and repatriation agreements with community hospitals .
Effective pre-hospital triage of stroke patients depends on easy to use screening tools that have been validated. One such is the Los Angeles Motor Scale (LAMS) designed as a 3 item stroke severity assessment measure. Validation of this tool involved the assessment of 119 patients; patients harbouring vascular occlusions had higher scores, with sensitivity of 0.81, specificity of 0.89 and overall accuracy of 0.85, the positive likelihood ratio associated with a LAMS score equal to or greater than 4 being 7.36 . Subsequent to this, a pilot feasibility study published in Stroke 2012 aimed to develop a tele-stroke ambulance prototype, test the reliability of stroke severity assessment and evaluate its feasibility in the pre-hospital emergency setting . However, that study concluded the use of tele-stroke examination was not at an acceptable level for clinical use .
In the local setting, the pre-hospital phase must first be strengthened to improve delivery of care in the stroke chain of survival. The first obstacle to be addressed is the disproportion between the number of calls to the emergency services and the service available. Compounding this is that in the local setting, the process of triage is a hospital based one, meaning that an acutely ill patient with a stroke may wait for long periods at home awaiting transfer to the hospital before being evaluated. Once an ambulance arrives, Emergency Medical Technicians (EMT), Advanced EMTs or paramedics, may manage patients. However, while paramedics and even a small number of critical care trained paramedics exist in the local pre-hospital setting, these are not effectively utilised to provide safe, high quality care. Further compounding this is the lack of communication between the ambulance service and the ER to facilitate continuity of care. In the local setting there is a great opportunity to enhance delivery of service in the pre-hospital setting through training and the formation of interdisciplinary teams.
With regards to delivery, treatment of stroke patients in a dedicated unit has been shown to decrease mortality and residual disability . Jogensen et al. in a 1995 publication of 1241 patients showed that treatment on a stroke unit significantly reduced in hospital mortality (p<0.001), case fatality rate (p<0.001), 6 month mortality (p=0.002), 1 year mortality (p=0.003) and discharge rate to patient’s own home (p<0.001), all while reducing the length of hospitalization by 30% . A subsequent 2012 systematic literature review of cost analyses reviewed six studies that all concurred with the view that care in a stroke unit produced better outcomes but stated that costs were higher relative to conventional care . The Royal College of Physicians have recommended that staffing levels in a stroke unit should include daily consultant coverage by a thrombolysis trained physician, 1.35 stroke trained nurses to 1 patient as well as therapists (22).
In 2010, there were less than five consultant neurologists for a population of 1 341 465, in Trinidad and Tobago (23). This gives a ratio at best of 1 to 268 293 ratio which exceeds the 1 to 200 000 ratio recommended by the Association of British Neurologists (24). The creation of an inter-disciplinary team involving the ER, neurology and early rehabilitation will require an evaluation of staffing availability. In the interim local setting, such teams are informally made up of ER physicians and general medicine consultants who manage stroke patients and can be trained to manage post-stoke thrombolysis patients.
The American Heart Association Stroke Campaign Manual outlines that it is essential to initiate a CT scan within 25 minutes of arrival and complete interpretation of the CT scan within 45 minutes of arrival to exclude intracranial haemorrhage prior to thrombolysis . Like many other timeline targets for intervention, this has been rigidly followed with positive results. Ruff et al. in a 2014 publication in Stroke compared stroke patients pre intervention (2003-2006) and post intervention (2008-2011) and found that the door to CT time in less than 25 minutes improved from 26.7% to 52.3% (p<0.001) and the door to needle time in less than 60 minutes doubled from 32.4% to 70.3% (p<0.001) (26). This is the biggest challenge in the local setting as door to imaging time is influenced by equipment, transportation, and personnel that are beyond the control of the ER. Consequently, this increases the difficulty in modifying the delivery of service practices.
The process flow of hospitals will need to be modified to integrate pre-hospital calls who initiate stroke protocols. The infrastructure of the ER would require change to have CT scan machines physically closer. A more reasonable alternative is improving the process flow and fast tracking patients to imaging who are potential candidates for thrombolysis. The implementation of fast tracking CT for this group of patients was studied by Ratanakorn et al. in in 2012 and showed significantly shorter door to imaging times compared with no fast tracking in patients presenting less than three hours after symptoms (25 minutes vs
2.5 hours, p< 0.001) (27).
Image reporting will require collaboration with the radiology department to achieve prompt responses in this select group of patients. A 2009 publication by Todd et al. described meeting the challenges of CT scanning in stroke patients in remote districts . The authors suggested that additional CT scan machines, weekend scanning and radiologists reporting from home as potental measures to improve thrombolysis rates in stroke . It could also be argued that the attending emergency physician should be able to competently read the scans and initiate treatment, even in the absence of a formal radiologist’s report. Dolatabadi et al. in a 2013 prospective cross sectional study including 544 patients compared CT scan interpretations of emergency physicians and emergency residents compared to a radiologist as gold standards. For emergency physicians there were 35 false negatives and 53 false positives with sensitivity 86.5% and specificity 81.4%, while for emergency residents there were 74 false negatives and 12 false positives with sensitivity 71.4% and specificity 95.8% . The number of false reports in both groups compared to the radiologist was statistically significant (p<0.001). The study included neurologic symptoms and trauma but did not evaluate the impact on door to imaging report time. There was a better performance in the trained staff but this did not compare well with radiology. In the local setting, this implies that there should be a focus on exposure of emergency residents to radiology interpretations and with the integration of radiology reporting into the ER.
Conditions like migraine and seizures may mimic stroke and small artery disease but do not benefit from rt-PA and unnecessarily increase the risk for intracerebral haemorrhage if thrombolysed. These lesions are identified primarily on Magnetic Resonance Imaging (MRI); this has prompted a suggestion that this modality be considered before thrombolysis [30. In the local setting, MRI prior to thrombolysis is not a viable option in terms of time, finance or human resource.
The final step is drug administration. Thrombolysis for an acute ischemic stroke has traditionally necessitated the use of Alteplase, which has had its efficacy validated in large trails such as ECASS and ATLANTIS . The public formulary in Trinidad and Tobago stocks Tenecteplase (third generation tissue plasminogen activator) but not Alteplase (second generation tissue plasminogen activator) at this time (32). In a 2013 review of stroke thrombolytics, Bivard et al. stated that Tenecteplase had a longer half-life (17 minutes versus 5 minutes), greater binding affinity for fibrin, and better resistance to inactivation which may result in better reperfusion than Alteplase . The New England Journal of Medicine published a randomized trial of Tenecteplase versus Alteplase for acute ischemic stroke that enrolled patients with first ever hemispheric ischaemic stroke with a score over 4 on the National Institutes of Health Stroke Scale. Of the over 2500 patients enrolled with symptoms, only 75 met the criteria for inclusion to randomization; other patients were excluded based on haemorrhagic stroke, resolving symptoms, recent surgery or coagulopathy. Three groups were randomized into Alteplase at 0.9mg/kg, Tenecteplase 0.1mg/kg or Tenecteplase 0.25mg/kg all within 6 hours after onset of symptoms. At the end of the study, the Tenecteplase groups showed better outcomes for reperfusion (p= 0.004) and clinical improvement at 24 hours (p<0.001). Overall, the higher dose of Tenecteplase was associated with improvements on all imaging efficacy outcomes while not carry greater risk or death or morbidity (p= 0.02) (34). These outcomes are applicable to the local setting since Tenecteplase is available at most institutions. The complications of thrombolysis are similar to those for other conditions with age being highlighted as an important consideration since older patients have shown a higher rate of bleeding .
Specific guidelines on thrombolytic therapy with intravenous Alteplase (rt-PA) have led to the introduction of time guided management of the patient with stroke. In the United Kingdom, a 614 patient observational study was conducted from 2002 to 2006 to assess the safety and efficacy of thrombolytic therapy of stroke. Under the acronym Safe Implementation of Thrombolysis- Monitoring Study (SIT-MOST), Lee et al. in 2008 analysed the data from the UK national stroke registry and found that implementation of thrombolysis was most successful at Stroke Centres, with “patchy” provision throughout the country and that deficient infrastructure and a lack of support delivery severely affected implementation .
The setting in the Caribbean provides even greater challenges for the provision of thrombolysis. The Lancet Neurology in 2007 published a review article of stroke in Latin America and the Caribbean . This study found that Trinidad and Tobago had a “very high” mortality rate compared to other areas investigated, accounting for 11% of all deaths in 2002. The study also noted that for all territories, intravenous thrombolysis had only been used on a small scale, citing the reported delays in hospital admission, delays in imaging and cost of drug as the major inhibiting factors . These are the challenges that are identified if the chain of survival is applied at this time.
In summary, the challenges faced by developing countries are noted to affect each part of the process flow outlined as the “chain of survival.” Public health initiatives are an essential part of improving detection. Systemic improvements are required to improve the dispatch, delivery and door to patient times. Hospital clinical flow improvements are required to improve data acquisition, decision and drug therapy. It is therefore imperative for health systems managers to appreciate and undestand all steps in the process given that any impediment abruptly ends the likelihood of successful stroke thrombolysis.
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