High blood pressure and brain oedema in acute stroke

Stroke is the third most-frequent cause of death after cancer and heart disease in developed countries, and is a more common reason for cardiovascular morbidity and mortality than myocardial infarction among subjects with hypertension [1]. The relationship between blood pressure and the occurrence of stroke, and the effect of blood pressure-lowering treatment in preventing stroke is well established [2–7]. Higher blood pressure levels after stroke increase the risk of recurrent stroke [8], and recent trials indicate that reduction of blood pressure with combined antihypertensive therapy is beneficial in reducing stroke recurrence [9]. By contrast, there is no reliable evidence from randomized controlled trials to guide the management of blood pressure during the acute phase of stroke. Approximately 75% of patients with ischaemic stroke, and more than 80% of those with haemorrhagic stroke, have blood pressure values over 140/90 mmHg when measured within 24 h of onset [10]. The natural history is for blood pressure to start falling within hours of stroke onset and to settle over the first weeks after stroke. There is no single explanation for this phenomenon, although many contributing factors have been suggested, such as pre-existing high blood pressure, activation of neuroendocrine systems, increased cardiac output, the stress of hospitalization and the Cushing reflex (reactive increase in systemic blood pressure in response to intracranial pressure) [10]. Most studies, although not all, have found that high blood pressure in the acute phase of stroke is associated with a poor outcome. The discrepancies between these studies are difficult to interpret and may be attributable to various factors. Many did not distinguish between ischaemic and haemorrhagic stroke, and a large number included only a small sample of subjects. Others used highly selected patient groups and some studies did not examine all patients within the first 24 h after stroke onset. Furthermore, most evaluated office blood pressure in the emergency room (or even retrospectively from clinical records), with ambulatory blood pressure monitoring (ABPM) only being obtained in a minority of studies. Moreover, in some studies, the reported results grouped together untreated patients with patients in whom antihypertensive treatment or manitol was initiated [10]. Nevertheless, high blood pressure was usually associated with an increased risk of death or with an increased risk of either death or dependency [10], as confirmed by a meta-analysis of these and other studies [11]. This relationship between blood pressure and poor stroke outcome has been found to be independent of other prognostic factors such as age, severe clinical outcome, level of consciousness or atrial fibrillation [12]. A convincing explanation for the relationship between high blood pressure in acute stroke and poor outcome has not been given, but it has been speculated that high blood pressure, particularly systolic blood pressure, may induce the haemorrhagic transformation of an ischaemic stroke, promote early recurrence, or induce cerebral oedema [12]. In patients with haemorrhagic stroke, poor outcome with high systolic blood pressure has been associated with haematoma growth, but this may simply reflect the fact that large bleeds are more likely to grow per se and induce an increase in blood pressure secondary to the Cushing reflex [12]. In any case, haematoma growth is always associated with clinical deterioration and poor outcome. One of the more lethal complications among patients admitted to stroke units during the acute phase of either ischaemic or haemorrhagic stroke is brain oedema [13]. Although oedema may begin within the first few hours, it usually does not become clinically apparent until 24–72 h post-stroke, and is characterized by intracellular water accumulation followed by water movement across the blood–brain barrier into the interstitial space, leading to compartmental shift and cerebral herniation [14]. Cerebral oedema has been found to be related to high blood pressure in acute stroke in both experimental and clinical studies. In this issue of the journal, Vemmos et al. [15] present the results of a very elegant clinical study investigating the relationship between blood pressure and heart rate during the first hours of stroke onset and cerebral oedema formation, assessed by 24-h ABPM, among untreated patients with either ischaemic or haemorraghic stroke. Two hundred and forty consecutive first-ever stroke patients were included within 3 h from stroke onset. Twenty-four hour ABPM immediately after admission to the stroke unit and computed tomography scans within 24 h from stroke were performed. Brain oedema was present in 78 patients (32.5%) and, as expected, was more frequent among patients with intracerebral haemorrhage (85%) than in those with ischaemic stroke (19%). Twenty-four-hour (daytime and night-time) systolic, diastolic and pulse pressures, and 24-h heart rate, but not office blood pressure, were significantly higher in patients who developed oedema. In the logistic regression analysis, 24-h systolic blood pressure (SBP) remained significantly associated with oedema formation. Although there were no differences in baseline blood pressure values, a spontaneous and continuous blood pressure decline during the first 27 h after stroke onset was only observed in patients who did not develop brain oedema. The difference between groups regarding blood pressure values was evident after 6 h from onset and continued to increase over the entire period of blood pressure monitoring. In addition to 24-h ABPM systolic blood pressure values, a history of atrial fibrillation, vomiting, intracerebral haemorrhage and decreased levels of consciousness were also significant predictors for oedema formation. The study addresses a relevant issue concerning the pathophysiology, evolution and prognosis of acute stroke related to blood pressure values in the first hours after stroke onset, and the results concur with Robinson et al. [16] who showed that 24-h systolic blood pressure values in the acute stroke period predict early (1 month) and long-term mortality. Vemmos et al. [15] underline the superiority of 24-h ABPM over office blood pressure in predicting target organ damage, reinforcing the findings of many other studies. Their results should encourage the routine use of 24-h ABPM in stroke units for monitoring blood pressure and heart rate and emphasize the need for therapeutic decisions to be taken on the basis of ambulatory and not office blood pressure values during the acute phase of ischaemic stroke. The second relevant aspect of the study is the possible therapeutic implications of their findings with respect to the correct moment for starting therapy after acute stroke. Treatment with antihypertensive agents in this acute phase is still controversial due to the conflicting and inconclusive results obtained in previous clinical trials with small samples of patients. The recent guidelines from the JNC-VII [17] include only a very brief suggestion for stabilizing blood pressure at intermediate levels of 160/100 mmHg in patients with high blood pressure and acute stroke, whereas the European guidelines [18] state that ‘there are more questions than answers concerning treatment of acute phase of stroke’ and recommend following the International Society of Hypertension Statement on the management of blood pressure in acute stroke [10]. This statement recommends lowering blood pressure by approximately 20% from baseline values in patients with cerebral haemorrhage and elevated blood pressure (> 200/120 mmHg) to reduce the perceived risk of haematoma growth and rebleeding. No recommendation is available regarding ischaemic stroke and high blood pressure. The data reported in the present study clearly demonstrate the prognostic significance of 24-h ABPM during the acute phase stroke. Baseline blood pressure values were not different between patients who did or did not develop brain oedema. However, the average 24-h SBP difference between patients with and without further cerebral oedema was approximately 15 mmHg, and the differences were already significant after 6–12 h of monitoring. This suggests that, in those patients admitted to a stroke unit with acute ischaemic stroke and high blood pressure values (> 140/90 mmHg) whose blood pressure is not spontaneously lowered after 6 h should be treated with antihypertensive drugs in order to reduce BP approximately 20% from baseline values. Therapy improves the chances of preventing cerebral oedema formation. The optimal management of blood pressure during the acute phase of both ischaemic or haemorrhagic stroke is not established, reflecting both the need to investigate the effects of active reduction of blood pressure on the pathophysiology of oedema formation or rebleeding, and a lack of large trials assessing the effects of blood pressure reduction on stroke outcomes and survival. Randomized trials of sufficient size and statistical power are urgently required to address several questions. Should blood pressure be lowered in patients with acute ischaemic stroke and high blood pressure? Should previous antihypertensive therapy be continued or stopped temporarily in patients with acute ischaemic stroke and high blood pressure? When should treatment be started? How much should blood pressure be reduced? Which drug classes and formulations should be used? The answer to these questions, together with current evidence for the beneficial effect of antihypertensive treatment on first-stroke prevention in patients with high blood pressure, and the demonstrated efficacy of blood pressure lowering, even in patients with normal or high-normal blood pressure values, in the prevention of recurrent strokes, will allow the establishment of a more effective global strategy for primary or secondary stroke prevention.