Hypertension Management in Acute Ischemic Stroke

An International Exclusive Article for SAGAS

Bruno B. Pedreira, Geoffrey A. Donnan

National Stroke Research Institute, Austin & Repatriation Medical Centre,

Heidelberg Heights, Victoria AUSTRALIA 3081

Dr. Donnan is a professor of neurology from Australia. He kindly accepted to be an international correspondence to SAGAS. This article is written exclusively for the Periodical. Visit this site to get his profile:

http://neurosciencesvic.com.au

Introduction 

The importance of long-term blood pressure control for stroke prevention is well recognised. There is also enough data suggesting that antihypertensives should be prescribed regardless of baseline blood pressure level(1-3). Elevated blood pressure is one of the most potent risk factors for first ever and recurrent stroke. However the management of hypertension in the setting of acute ischaemic stroke remains a source of confusion and controversy. 

Over the last 50 years or so, there has been reduction in the incidence and mortality of stroke by means of risk factors modification as primary and secondary prevention. However current active treatment of acute ischaemic stroke is still unsatisfactory, with only stroke unit admission, aspirin and thrombolysis showing proven benefits(4-8). The most appropriate treatment for hypertension in the immediate period following an acute stroke remains controversial. Intervention in blood pressure is very much based on expert opinion in individual centres and scientific evidence is lacking on how the treating neurologist should manage blood pressure in the acute phase. One could support the view as to whether blood pressure should be lowered, left untreated or elevated in the acute stroke setting. In each of these clinical situations, it is important to understand the underlying pathophysiological changes that occur within the infarct and the surrounding ischaemic but potentially viable (penumbral) tissue. 

Loss of Autoregulation 

Around three quarters of the patients presenting with ischaemic stroke are hypertensive on admission (values ≥ 160/90 mmHg)(9-11). Of these, approximately 50% have previous history of hypertension. And studies have shown that these levels usually gradually decline spontaneously, sometimes to premorbid levels up to 10 days or so post-ictus(9,11-15). There is no definite data from controlled trials to guide how to manage this transient elevation in blood pressure during the acute phase of stroke, and there are conflicting recommendations, mainly from observational studies. 

The cerebral blood flow (CBF) can be defined as a relationship between the cerebral perfusion pressure (CPP) and the cerebrovascular resistance (CVR)(16-17).

Cerebral perfusion pressure is the difference between mean arterial pressure and venous back-pressure. Under normal conditions (without increased intracranial pressure) the venous pressure is negligible and CPP is equal to arterial blood pressure. Normally, a wide range of changes in CPP has little effect on CBF, through autoregulation mediated changes in CVR. In non-hypertensive adults the range for this autoregulation is approximately 60 to 160 mmHg mean arterial pressure. Chronic hypertension shifts this autoregulatory range upward. This autoregulation is also affected by the levels of respiratory gases (oxygen and carbon dioxide), which are altered locally in the setting of ischaemia(16-17) (figure). As a result, autoregulation is impaired in both normotensive and chronically hypertensive stroke patients, which leaves cerebral blood flow dependent solely on mean arterial pressure, and even small decreases in blood pressure might compromise further the blood flow of an area already marginally perfused but still viable.

 

Figure. The relationship between CBF and arterial pressure in human brain. Under conditions of ischaemia the autoregulatory curve is lost.

Because of the more direct relationship between blood pressure and CBF, there is a theoretical likelihood that extreme blood pressure levels could be harmful (causing infarction or haemorrhage). Hence early blood pressure levels may have the potential to influence outcome. 

Influence of BP on outcome (U-shaped curve) 

Most studies have suggested that patients with elevated blood pressure in acute stroke have a worse outcome however without giving clear explanation for this(12,18-19). Conversely, other studies have shown the opposite, indicating that high blood pressure might be protective in the setting of acute stroke(20-21). Yet other studies have suggested a U-shaped relationship of the course of blood pressure in the first 24 h and clinical outcome where both high and low blood pressures are associated with adverse Outcome(10). Still others have tried pharmacologically increasing BP in carefully selected patients(22). 

The rationale to lower blood pressure and possibly the explanation for the findings in the studies that suggested stroke outcome being worse with higher BP levels at presentation is that untreated hypertension in this population could raise the risks of increased brain oedema, also lead to a higher risk of secondary haemorrhage or even early stroke recurrence (see above). As mentioned before some studies have shown an independent association between BP and poor outcome, however there has been no trial analysing whether intervention with BP lowering therapy would modify these results. Even in these situations when intervention is possibly appropriate, there is the question about which antihypertensive should be used and for how long. 

Some clinicians strongly advise leaving BP untreated at least in the first 24 h after stroke on the basis of avoiding decreases in the cerebral blood flow in the penumbra area and therefore increasing infarct volume. The frequency of stroke progression after admission is high and has been independently associated with BP lowering in some studies(20,23). Another reason would be that the risk of early stroke recurrence is considered to be low (1-2% in the first two weeks)(6). 

Results from a recent analysis of the International Stroke Trial showed that this U-shaped curve phenomenon suggests that the level of SBP of 150 mmHg would be “safer”, whereas, above and below this level the outcome would be worse(10).

We have to bear in mind the limitations of these studies; different methods of measuring BP, timing after stroke onset when the data were collected, and also pre-morbid history of hypertension in the studied population not being analysed makes comparison difficult.

 What evidence exists for an effect of altering BP after acute stroke? 

Rordorf et al. in an analysis of patients in whom hypertension was induced with phenylephrine observed that, in some patients, neurological deficits improved above a specific BP and worsened below it, this threshold persisting for a variable number of days following stroke onset(22). And parallel clinical observations have been reported in patients with vasospasm after SAH (24-25) . 

A sub-analysis of the hypertensive patients in the NINDS trial suggested that gentle management with modest reductions in BP is safe(26). This analysis showed that within the placebo treated group of patients (patients were randomized to either rt-PA or placebo), antihypertensive therapy did not adversely affect clinical outcome. The effects of  the antihypertensive therapy in the tPA treated arm is more complex and hard to interpret(26). 

Preliminary results from the ACCESS trial, which was terminated by ethics committee after 342 patients had been enrolled, indicated that acute lowering of blood pressure may be safe and possibly beneficial(27). Of interest, patients were randomised to either placebo or candesartan for the first 7 days, and then all patients were treated with candesartan. In another ongoing trial (Efficacy of Nitric Oxide in Stroke, ENOS), the investigators aim to test the efficacy and safety of lowering blood pressure in acute ischaemic stroke with transdermal glyceryl trinitrate and stopping or continuing previous antihypertensive therapy(28). 

In a small trial using SPECT, Lisk et al randomized 16 patients with acute middle cerebral artery infarction to placebo or active antihypertensive treatment (nicardipine, captopril or clonidine)(29). They analyzed the decline in blood pressure and changes in cerebral blood flow. They observed a negative correlation between the change in CBF and maximum fall in the mean arterial blood pressure. This was more evident in the nicardipine treated arm among which 3/5 patients had a blood pressure drop of more than 16%(29). However overall small numbers make the data difficult to interpret.

There are situations in which rapid lowering of blood pressure is mandatory such us patients receiving thrombolytic therapy and some specific concomitant medical conditions including: acute coronary syndromes, aortic dissection, pulmonary oedema, hypertensive encephalopathy, etc. However, there is frequently some diagnostic confusion between ischaemic stroke with high blood pressure and hypertensive emergencies, mainly hypertensive encephalopathy. 

Where to now? 

It is clear that there are no concrete guidelines for management of acute poststroke hypertension and evidence from controlled trials is needed. There is an ongoing trial with glyceryl-trinitrate (ENOS), also analyzing stopping or continuing prior antihypertensive medication.

In the absence of adequate evidence, a commonsense approach to the management of blood pressure in acute stroke should be to prevent further brain injury due to excessive hypertension without compromising cerebral blood flow. Hence, management could be individualized according to stroke subtype, presence of vascular stenosis and premorbid blood pressure levels. There may be potential benefits in actively (pharmacologically, by withholding antihypertensive therapy, or IV fluids) increasing blood pressure in carefully selected patients, especially those with multiple intracranial or extracranial arterial stenosis. Again, proof that this is efficacious is currently lacking. 

Regardless, when deciding on a given treatment course, it must be done cautiously with the patients being closely monitored. Other theoretical issues to be considered include effects of antihypertensive agents on intracranial pressure. For example, drugs which might cause cerebral vasodilatation.

 

Recommendations: 

Although we recognize that there is no conclusive evidence as yet, some reasonable recommendations for management of blood pressure in acute stroke patients within the first 48 h are as follows: 

Low BP (< 120/80 mmHg):

withhold antihypertensive treatment

review for other drugs with possible effects on BP

IV fluids 

Normal BP – mild elevation (120-160 / 80-95 mmHg):

optimize environment, bed rest, pain control if appropriate

no pharmacological intervention needed

Normal BP – mild elevation (120-160 / 80-95 mmHg):

optimize environment, bed rest, pain control if appropriate

no pharmacological intervention needed

Moderate to severe elevations (160-200 / 95-120 mmHg):

optimize environment, bed rest, pain control if appropriate

consider additional oral antihypertensives

review for other drugs with possible effects on BP

Extreme hypertension (>200/120 mmHg):

optimize environment, bed rest, pain control if appropriate

more rapid, but cautious lowering of BP, consider:

IV labetalol, atenolol

IV enalapril

IV verapamil

IV hydralazine

transdermal GTN

continuos infusion (GTN, sodium nitroprusside, fenoldopam)

review for other drugs with possible effects on BP

References 

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