Management of blood pressure, blood glucose and body temperature in acute stroke

Hanne Christensen

Department of Neurology, Bispebjerg Hospital, 2400 Copenhagen NV, Denmark

Abstract

On admission a high blood pressure is common in patients with a mild stroke and returns to normal within hours. A U-shaped relation between blood pressure and outcome with an overall tendency to high blood pressure being unfavourable has been has been suggested with an optimal systolic blood pressure of 150 mmHg. There is some evidence that pharmacologically induced decreases of at least 15 – 20 mmHg may be deleterious in the acute phase of stroke. Candesartan seemed to improve outcome without reducing blood pressure after acute stroke.

Blood glucose increases in the first hours after stroke onset reaching higher levels in patients with severe stroke. The glycaemic response is most likely a part of the physiological stress-response and may aggravate the patient’s condition by systemic effect or local effects in the brain. Glucose, insulin and potassium (GIK) infusions safely induce euglycaemia, but there is not yet data to its effect on outcome.

Body temperature increases in the first hours after severe stroke and may aggravate the ischaemic damage. Animal models support the hypothesis that cooling therapy improves outcome. The effect of paracetamol is so small that it is hardly clinically relevant. Mild hypothermia is being investigated in a randomised trial.

Conclusion: Blood pressure, blood glucose, and body temperature are factors, which are subjected to changes in the acute phase of stroke. They are rather easy to modify, and a theoretically plausible treatment benefit exists; however, at the moment there is no support from randomised controlled trials or statistical reviews to modify any of these parameters. Acute stroke unit observation is supported by one randomised controlled trial.

Introduction

Is there any need to monitor blood pressure, blood glucose, and body temperature in the acute phase of stroke? One small study showed effect of monitoring in acute stroke1. However, the effect of each of these interventions has yet to be demonstrated.

Blood pressure

It is well documented that hypertension is a major risk factor of stroke and hypertension has become a primordial treatment target in the secondary prevention of stroke. There is, however, no consensus regarding management of blood pressure in the first hours or days after stroke onset.

Blood pressure is usually high after acute stroke and decreases spontaneously after a short time2 and blood pressure in hypertensive patients is usually higher than in other patients.

Results from observational trials are contradictory as some showed high blood pressure to be deleterious3 while others found it beneficial4. Later observational trials have suggested that a U-shaped relation exists between blood pressure and outcome, as both low and high blood pressure are associated with poor outcome5-8 . The U-shaped relationship is partly mediated by increased rates of early recurrence and death resulting from presumed cerebral oedema in patients with high blood pressure, and increased coronary heart disease in those with low blood pressure5.

The overall result from a meta-analysis of observational studies on blood pressure in acute stroke was that high blood pressure predicted a poor outcome; it was not possible to assess if this was independent of age and stroke severity6.

However, it remains a problem, that the timing of the blood pressure measurement were not included in any of these analyses: the results are based on admission blood pressures (within 24 hours to 7 days after stroke onset) or in the largest study5 blood pressure measured on inclusion in the TOAST-study in which patients were included until 48 hours after stroke onset. Blood pressure in patients with acute stroke no more than 6 hours before admission, changes in the first hours after hospital admission: in patients with mild to moderate stroke higher blood pressure is recorded on admission in comparison to patients with severe stroke after which a significant decrease is recorded in patients with mild to moderate stroke9. This decrease occurs in the first few hours after admission, thus corroborating the earlier finding that admission blood pressure did not correlate with delay from stroke onset to admission10. Seen in this perspective, a high blood pressure reading in a patient with acute stroke is likely to occur both in a patient with mild stroke on admission, who has an excellent prognosis as well as in a patient 2 or 3 days after a large infarction who is at risk of cerebral herniation and obviously holds a poor prognosis. In this perspective it is also likely that the admission blood pressure reflects psychological factors to a higher degree than later blood pressures that are obtained, when the awake patient has accustomed himself to the hospital surroundings and the blood pressure measurements. It may rather be the course of the blood pressure measurements than any single reading that has an association to stroke severity and outcome11.

A recent publication described that a fall in systolic blood pressure of more than 20 mmHg within the first 72 hours after stroke onset was associated with neurological deterioration and poor outcome8; however, this decrease was highly related to antihypertensive treatment, often in the emergency room. Earlier reports support the interpretation that induced blood pressure decreases of this size is deleterious12, according to some diuretic treatment almost doubles the mortality11. A post hoc analysis on the effect of nimodipine within 24 hours of onset of acute ischaemic stroke, reported that a systolic blood pressure reduction was associated with poor outcome whereas spontaneous fall in the placebo group was associated with good outcome13.

Only few clinical trials on blood pressure intervention in acute stroke exist. A Cochrane Review14 on deliberately altering blood pressure within 2 weeks of stroke onset found 5 small trials including 218 patients, who were randomised to antihypertensive treatment or placebo. Due to lack of power it was not possible to assess the treatment effect. The ACCESS study was designed to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of ischaemic stroke15. The ACCESS Study was stopped prematurely after an interim analysis after including 342 patients because of an imbalance in endpoints, which turned out to be in favour of treatment. Patients with blood pressure ³ 200 mmHg or diastolic blood pressure ³ 110 mmHg and a motor deficit were randomised on admission to antihypertensive treatment or placebo in the first 7 days after stroke onset. Outcome was mortality, vascular endpoints, and disability (Barthel Index) 3 months and 12 months after stroke onset.  The target was a blood pressure reduction of 10 – 15 % within the first 24 hours; however no differences in blood pressure were observed between treatment and placebo group. It is therefore likely that the observed treatment benefit - OR 0.475 (95 % CI 0.252 – 0.895) for the combined endpoint in comparison to a balanced placebo group – is caused by other effects of the angiotensin type 1 (AT1) receptor blockade.

A new trial of candesartan in acute stroke, the Scandinavian Candesartan Acute Stroke Trial (SCAST) is planned. The Efficacy of Nitric Oxide in stroke (ENOS) Trial16 is an ongoing international, multicenter, randomised trial that tests safety and efficacy of transdermal glyceryl trinitrate in patients with acute stroke within 48 hours of inclusion. The trial is academically driven and aims at including 5000 patients. The endpoint is death or dependency (modified Rankin Scale 3 – 6) at 3 months, which is assessed in a blinded manner.

Conclusions

There is no conclusive evidence regarding this subject at the moment and it is unclear if and how blood pressure should be manipulated in the acute phase of stroke. One exclusion to this is treatment with labetalol prior to rtPA-treatment. The emerging evidence that pharmacologically induced blood pressure reductions in the range of 15 – 20 mmHg are associated with poor outcome calls for caution in quick pharmacological lowering of blood pressure in acute stroke. As the blood pressure in most cases spontaneously falls within 8 to 12 hours, observation will be sufficient in most cases. Candesartan treatment according to the ACCESS trial is well justified. The results from the ENOS Trial and the SCAST Trial will no doubt help solving this dilemma.

Blood glucose

Hyperglycaemia during the first days after stroke has been related to increased morbidity and mortality and has been reported an independent predictor of outcome. Hyperglycaemia may reflect a stress response to stroke or it may independently contribute to stroke outcome by inducing secondary brain damage; these two hypotheses are not mutually exclusive.

A number of observational studies have reported that blood glucose on admission independently predicts functional outcome and/or mortality after stroke17-23 . A meta-analysis concerning the effect on outcome of hyperglycaemia in non-diabetic and diabetic patients24 found that hyperglycaemia (according to the definitions of the included studies) increased the risk of 30-days mortality in non-diabetic patients OR 3.0 (CI 95% 2.5 – 3.8), but not in diabetic patients. Risk of poor functional outcome was also increased in non-diabetic patients OR 1.4 (CI 95 % 1.2 – 1.7), but not in diabetic patients. This difference may reflect that blood glucose control was more likely to be instituted in patients with diabetes, but another possible explanation is that high blood glucose in non-diabetic patients predominantly occurred after severe stroke: the observational studies in hyperglycaemia in acute stroke are predominately based on single blood glucose measurements and performed in patients admitted to hospital 12 – 24 hours or more after symptom onset. In most studies, the time from symptom onset to blood glucose measurement is not well defined. As blood glucose is reported to increase to higher levels after stroke onset in severe stroke25, late blood glucose measurements would show higher blood glucose in patents with severe stroke, who are no matter what most likely to have an unfavourable outcome. Post-stroke hyperglycaemia is known to decline spontaneously in the absence of diabetic disease26. There are, however, plausible ways through which hyperglycaemia may add to ischaemic damage in acute stroke. Hyperglycemia has been suggested to directly cause higher levels of lactate in the infracted area as measured by Magnetic Resonance Spectroscopi (MRS) and infarction expansion27,28 . Post hoc analyses of data from the NINDS rt-PA Stroke Trial have shown that the risk of haemorrhage increases with increasing admission blood glucose levels29. In non-diabetic patients the sympatico-adrenal stress response is likely to be a major determinant of the glycaemic response to stroke30,31 . In surgery as well as acute ischaemic heart disease the stress-response in acute illness has become a new treatment target. If this could be the case in acute stroke, has not yet been determined.

Glucose-Insulin-Potassium (GIK) –infusions are safe and efficient in inducing euglycaemia (capillary blood glucose 4 – 7 mmol/L) in patients with acute stroke (symptom onset < 24 hours) and blood glucose in the range from 6 – 17 mmol/L26.

The United Kingdom Glucose Insulin in Stroke Trial (GIST) 32 is a randomised controlled multicentre trial that investigates the efficacy of GIK-infusions (target 4 – 7 mmol/L) vs. placebo in patients with acute stroke within 24 hours and blood glucose in the range of 6 – 17 mmol/L. The primary endpoint is all cause mortality at 12 weeks, and the secondary endpoint is modified Rankin Scale 4 – 6 at 12 weeks. Inclusion is planned for 2355 patients and study end is expected in December 2004.

Conclusion

There is evidence supporting an association between non-diabetic hyperglycaemia in acute stroke and poor outcome independent of stroke severity. The results form the GIST trial are expected next year and are likely to tell if euglycaemic treatment in acute stroke improves prognosis. If treatment in selected patients is chosen, GIK-infusion should be selected due to the favourable safety profile.

Body temperature

Several observational studies have described the prevalence and clinical course of patients with high admission body temperature who were admitted within varying time intervals after stroke33-35  and found that post-stroke pyrexia predicted poor outcome even after long-term follow-up36. A meta-analysis based on nine studies and 3790 patients concluded that high body temperature on admission had negative prognostic impact in acute stroke37. The latency form stroke onset to admission and body temperature measurement was, however, not included in the analysis. The results from a study based on serial body temperature measurements in patients admitted within 6 hours of stroke onset, mean 2 hours, showed that body temperature follows a distinctly different time course in the first hours after stroke onset in patients with mild to moderate stroke in comparison to patients with severe stroke38. Body temperature increases 4 – 6 hours after stroke onset in patients with severe stroke, but not in mild to moderate stroke. In patients with severe ischaemic stroke the mean increase was app. 0.5°C, and in severe intracerebral haemorrhage the mean increase was app. 1 °C.  These findings indicate that it is the severity of the stroke that determines the body temperature and not vice versa. Low body temperature on admission was common in patients with severe stroke.

Animal models have repeatedly shown a detrimental effect of post-stroke hyperthermia supporting the hypothesis of post-stroke hyperthermia not only being an epiphenomenon to stroke severity but also in itself contributing to poor outcome.

Temperature monitoring may be performed by tympanic thermometry, which is in acceptable concordance with rectal mercury thermometry39.

Paracetamol is in use for post-stroke hyperthermia but the temperature lowering effects of paracetamol in the temperature span relevant for acute stroke are however not convincing. Two smaller randomised trials have reported temperature decreases of 0.22 °C40 and 0.3 °C41, and intracerebral temperature has been found unaffected by paracetamol42.

There are at the moment ongoing cooling studies as well as some sites that have already implemented cooling therapy. Mild hypothermia (33 – 36 °C) and moderate hypothermia (28 – 32 °C) are in use and cooling is obtained by endovascular cooling or surface cooling, by cooling blankets or pads or cooling helmets.  There is one ongoing international, multicentre, randomised, controlled trial at the moment, the Nordic Cooling Stroke Study (NOCSS), which is designed to assess efficacy of surface cooling in awake acute stroke patients; the target temperature is 35 °C, which is maintained for 9 hours43.

Two large randomised controlled trials investigating mild hyperthermia in head trauma44 and aneurysm surgery45 have been completed with negative results. One small trial of 36 patients with severe acute cerebral infarction compared the results from hemicraniectomi, which was performed in patients with lesions in the non-dominant hemisphere, to the results from moderate hypothermia, which was chosen in patients with lesions to the dominant hemisphere. Mortality was 47 % in the cooling group in comparison to 12 % in the hemicraniectomi group46.

Conclusions

Post-stroke hyperthermia develops in the first hours after severe stroke and may add to the ischaemic lesion. Animal models suggest a neuroprotective effect of hyperthermia. In patients it is unlikely that paracetamol treatment can affect outcome by lowering body temperature by 0.2 – 0.3 °C, however, this has not been tested in a randomised controlled trial. Regarding mild hypothermia, the results from the NOCSS trial are awaited, but out of protocol treatment is at the moment only supported by animal models. Moderate hypothermia is associated with substantially inferior results in comparison to hemicraniectomi.

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