Q J Med 2003; 96: 179-181
© 2003 Association of Physicians
Editorial |
Stroke: beyond thrombolysis and back to basics
Department of Geriatric Medicine, University of Newcastle upon Tyne e-mail: chris.gray{at}chs.northy.nhs.uk
Thrombolysis with recombinant tissue plasminogen activator (rTPA) is a new but controversial treatment for acute ischaemic stroke.1,2 Despite continuing debate about the safety and efficacy of rTPA, it is likely that its use in acute stroke patients will increase, albeit for highly selected patients. And therein lies the problem, because unlike myocardial infarction, where simple guidelines identify those for whom maximum treatment benefit may be achieved, with stroke the risk/benefit ratio is much less clear. Indeed, even with advanced neuroradiological imaging, it is still not clear which patients may obtain maximal benefit.3 In CT-proven ischaemic stroke, thrombolysis should ideally be administered within the first 3 h and probably no later than 6 h after symptom onset.2 While recent UK evidence suggests that 37% of acute stroke patients already present to hospital within 3 h of symptom onset, only 8% have CT imaging within this potential treatment window.4 Current estimates from countries with several years experience of thrombolysis suggest that at best this treatment will only be administered to 1–5% of all patients with ischaemic stroke.5
Clearly, some stroke patients benefit greatly from thrombolysis and achieve the clinical trial end-point of recovery with no significant disability, thus furthering the argument for its wider application. Enthusiasm for such benefits should however be tempered with the knowledge that thrombolytic therapy may be associated with up to a 10-fold increased risk of early death.6 Against this backdrop of risk/benefit uncertainty, it is unlikely that thrombolysis will change the natural history of acute stroke, nor will the majority of those affected benefit from this treatment advance.
Alternative strategies for the treatment of acute stroke are therefore required. It is generally accepted that clinical trials of neuroprotective agents have been uniformly disappointing, and we are left with the fact that there is still no safe, simple and effective medical therapy that can be administered to the majority of patients with either cerebral infarction or cerebral haemorrhage.
There have however been major advances in the delivery of stroke care. The provision of specialist stroke services and stroke units is associated with reductions in mortality, dependency and subsequent need for institutional care. Although it is not clear precisely which aspects of care are associated with these improvements, there is accumulating evidence that the process of care delivered by specialist stroke teams is significantly different from that of conventional care. Specialist stroke care, while based upon very simple principles, appears to be highly effective; comprehensive multidisciplinary assessment including the early assessment and management of swallowing disorders, early maintenance of hydration and nutrition and early mobilization underpin the principles of acute care. The evidence supporting the effectiveness of specialist stroke care has lead to the widespread introduction of stroke units throughout the UK, a service development further empowered through the recent National Service Framework (NSF) for Older People.7
Nevertheless, the evidence base is still lacking for many of the clinical interventions delivered on stroke units. Within the NSF and the Royal College of Physicians National Clinical Guidelines for Stroke are the recommendations that in the acute phase of stroke, specific interventions to limit or reverse the underlying pathological process(es) should be considered.7,8 Co-morbid conditions should of course be treated in their own right, as should acquired complications of stroke such as infection. But what about variations in physiological variables that are increasingly measured as part of acute stroke monitoring and care? The RCP guidelines acknowledge the uncertainty that exists regarding variations in blood pressure, temperature, blood glucose and oxygen saturation, and conclude that local policies should be agreed for precisely how these variables may be managed. For blood pressure read caution (no change): this should not be routinely lowered in the first week unless accelerated or associated with dissection. Hydration should be maintained within normal plasma osmolality, and pyrexia controlled using simple measures such as paracetamol and fanning. Glucose should be controlled within normal limits, but the normal limits for acute stroke are unclear and the preferred method of treatment is uncertain. In the absence of evidence supporting the clinical effectiveness and safety of routine modulation of physiological variables, the widespread development and introduction of local protocols and guidelines may actually incur risk rather than benefit.
The importance of physiological monitoring following stroke may be reflected in the fact that up to 40% of acute stroke patients suffer neurological deterioration shortly after admission to hospital. This neurological deterioration may be consequent upon natural progression of the initial stroke, but in part may also be due to changes in physiological variables such as glucose, oxygen saturation, temperature and blood pressure.
Abnormalities in physiological variables are a frequent finding immediately following stroke. For example, in one series up to 68% of patients had mild to moderate post-stroke hyperglycaemia (PSH).9 Similarly hypoxia, hypertension and pyrexia are also frequent findings. Clinical and animal studies suggest an association between such abnormal physiological variables and poor stroke outcome.
As acute stroke units develop throughout the UK, it is important that the opportunity to formally evaluate the safety, practicability and indeed effectiveness of strategies to routinely manage physiological variables is not lost. For example, there is very good evidence that hyperglycaemia before, during or immediately after stroke can increase ischaemic cerebral damage and adversely influence outcome. Furthermore, there is some evidence that hyperglycaemia at the time of stroke actually increases the risk of intracerebral haemorrhage in patients treated with thrombolysis.10 While there is accumulating clinical and experimental evidence for a link between hyperglycaemia and enhanced cerebral ischaemic injury, such an association has never been confirmed by any clinical trial. In addition, although the concept of routinely giving insulin to correct hyperglycaemia following stroke has been proposed, it has never been formally investigated. In contrast, the routine management of hyperglycaemia post myocardial infarction is underpinned by clinical trial evidence demonstrating that treatment with a glucose/potassium/insulin infusion for 
24 h followed by subcutaneous insulin four times daily for 3months is associated with significant mortality reductions up to 12 months after the acute event.11 Such a prolonged insulin treatment regimen in acute stroke patients is not feasible in routine practice, where the complexity of clinical care, combined with the practical difficulties in maintaining hydration and nutrition, potentially make routine treatment with insulin beyond 24 h both illogical and unsafe. Furthermore, whilst the majority of acute stroke patients may present with hyperglycaemia, in most this is usually mild and <11 mmol/l.
Accepting that hyperglycaemia is extremely prevalent in acute stroke it is only recently that the safety and practicability of early treatment with a glucose/potassium/insulin infusion regimen has been demonstrated.9 If hyperglycaemia is to exert a direct harmful effect upon the ischaemic brain, then the maximal effect is likely to occur within the first 24 h when peak hyperglycaemia occurs, although plasma glucose levels remain elevated to a lesser degree beyond 48 h. Beyond the first 24 h, changes in plasma glucose are likely to be influenced by non-cerebral stress responses and the effects of early feeding and nutritional strategies.
Although the NSF for Older People Standard Five (Stroke) states that immediate management to improve chances of survival and minimize complications should include management of hyperglycaemia, many questions remain unanswered. There is a need to know not only whether the routine treatment of PSH is effective but also with what regimen PSH can be safely managed? Furthermore, at what threshold should treatment be started, how low should plasma glucose levels be reduced and for how long?
For the immediate future, the important clinical question for the majority of stroke patients will not be whether to deliver thrombolytic therapy, rather whether (and how) mild to moderate fluctuations in blood glucose (or temperature, blood pressure, oxygen saturation) should be routinely managed. These and other questions may be answered by ongoing clinical trials of physiological interventions such as the Glucose Insulin in Stroke Trial (GIST UK).12 Stroke remains a disease primarily of older people for whom we should seek treatments and interventions that can be widely delivered. The majority of stroke patients should not be forgotten in our enthusiasm to introduce new therapies for the minority.
Competing interests
Professor Gray is principal investigator to the Glucose Insulin in Stroke Trial and Dr O'Connell is a co-investigator and member of the steering committee.
References
1. Lenzer J. Alteplase for stroke: money and optimistic claims buttress the brain attack campaign. Br Med J 2002; 324:723–9.
2. Wardlaw J, Yamaguchi T, Del Zoppo G. Thrombolysis for acute ischaemic stroke. The Cochrane Library, Issue 2. Oxford, Update Software, 2002.
3. Keir SM, Wardlaw JM. Systematic review of diffusion and perfusion imaging in acute ischaemic stroke. Stroke 2000; 31:2723–31.
4. Harraf F, Sharma AK, Brown MM, Lees KR, Vass RI, Kalra L, for the Acute Stroke Intervention Study Group. A multicentre observational study of presentation and early assessment of acute stroke. Br Med J 2002; 325:17–20.
5. Morgenstern LB, Staub L, Chan W, et al. Improving delivery of acute stroke therapy. Stroke 2002; 33:160–6.
6. von Kummer R. Brain haemorrhage after thrombolysis: good or bad? Stroke 2002; 33:1446–7.
7. NSF for Older People Implementation Team. The National Service Framework for Older People. Department of Health, 2001. [http://www.doh.gov.uk/nsf/olderpeople.htm.]
8. The Intercollegiate working party for stroke, Royal College of Physicians of London. National clinical guidelines for stroke. Suffolk UK, Tavenham Press, 2000.
9. Gray CS, O'Connell JE, Lloyd H. Diabetes hyperglycaemia and recovery from stroke. Geriat Gerontol Int 2001; 1:2–7.[CrossRef]
10. Els T, Klisch J, Orszagh M, et al. Hyperglycaemia in patients with focal cerebral ischaemia after intravenous thrombolysis: influence on clinical outcome and infarct size. Cerebrovasc Dis 2002; 13:89–94.[CrossRef][ISI][Medline]
11. Malmberg K, Ryden L, Efendic S, et al. Randomised trial of insulin glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at one year. J Am Coll Cardiol 1995; 26:57–65.[Abstract]
12. Gray CS, Alberti KGMM, Scott J, et al. The United Kingdom Glucose Insulin in Stroke Trial (GIST UK). Stroke 2000; 31(Suppl.)46: 382. [AUTHOR: please check reference]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Bhalla, D. Hargroves, A. Rudd, C. S. Gray, and J. E. O'Connell Poststroke Hyperglycemia Management: More Answers Required * Response Stroke, July 1, 2004; 35(7): e341 - e342. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||