In acute ischaemic stroke, cerebral blood flow autoregulatory mechanisms may be disrupted so that cerebral perfusion becomes reliant on systemic blood pressure. Too low blood pressure may lead to progression of the infarction and too high blood pressure may cause cerebral oedema or haemorrhagic transformation of the infarct. In patients with BP = 220/120 mm Hg who do not receive intravenous thrombolysis, it is reasonable to lower BP by 15% during the first 24 hours after stroke onset. Patients who have elevated blood pressure and are otherwise eligible for treatment with intravenous rt-PA should have their blood pressure lowered so that systolic blood pressure is < 185 mm Hg and their diastolic blood pressure is < 110 mm Hg before thrombolytic treatment is administered. Acute stroke patients should be assessed for dehydration and a fluid balance chart should be kept. Underlying causes of hypotension should be treated rapidly. There is no beneficial effect of hemodilution treatment for acute ischaemic stroke. Fibrinogen-depleting agents that reduce viscosity may marginally reduce risk of recurrent ischaemic stroke, but more greatly increases symptomatic intracranial haemorrhage. Methylxanthine derivatives such as pentoxyphylline and propenofylline that reduce viscosity and produce vasodilation have insufficient evidence to support their use.
Professor Eivind Berge passed away before the publication of this book. His contributions to stroke science through large clinical trials, major international collaboration and broad experience with systematic reviews have improved the treatment and prognosis of stroke patients. In addition, his unique combination of wisdom, kindness, and determination made him a wonderful colleague and mentor.
Cerebral autoregulation ensures near constant brain perfusion, despite large variations in systemic blood pressure. In acute ischaemic stroke, the autoregulatory mechanisms may be disrupted in the affected hemisphere and, in certain situations, also in the opposite hemisphere, so that the cerebral perfusion becomes reliant on the systemic blood pressure (Strandgaard and Paulson, 1984; Immink et al., 2005). Blood pressure that is too low may lead to progression of the infarction and blood pressure that is too high may cause cerebral oedema or haemorrhagic transformation of the infarct.
Up to 75% of acute ischaemic stroke patients have blood pressure over 140 mm Hg within the first 24 hours of symptoms, and a spontaneous decline usually occurs within 7–10 days (Wallace and Levy, 1981; Qureshi et al., 2007). There are many contributing factors to high blood pressure in the acute phase, such as pre-existing, underdiagnosed, or undertreated hypertension; stress; urinary retention; and activation of sympathetic, adrenocorticotropic hormone (ACTH)–cortisol and renin–angiotensin systems (Qureshi, 2008). In patients with high intracranial pressure secondary to cerebral oedema, the Cushing reflex may also be a factor.
Low-to-normal blood pressure is uncommon in acute stroke. It is most commonly caused by hypovolaemia due to dehydration, or by coexisting disease, for example acute myocardial infarction, arrhythmias, heart failure, or sepsis (Vemmos et al., 2004).
High blood pressure in the acute phase is associated with higher risks of early death and stroke recurrence, and worse functional outcome (Willmot et al., 2006). A U-shaped relationship between blood pressure in the acute phase and long-term outcome has been identified in several populations, with poorer outcomes in patients with the highest and lowest blood pressures in the acute phase (Leonardi-Bee et al., 2002; Vemmos et al., 2004). In the International Stroke Trial, systolic blood pressure in the range of 140 to 179 mm Hg was associated with the best outcome (Leonardi-Bee, 2002).
A systematic review of 16 trials involving 15,489 patients with either ischaemic, haemorrhagic, or mixed stroke found no beneficial effect of blood pressure lowering in the acute phase on death or dependency at the end of follow-up (odds ratio [OR] 0.98, 95% confidence interval [CI]: 0.92–1.05). Blood pressure lowering treatment was given within 7 days of symptom onset, and at the end of trial treatment the overall achieved systolic blood pressure reduction was 6.7 mm Hg (95% CI: 4.1–9.4 mm Hg reduction) (Bath and Krishnan, 2014).
In the same review, a subgroup analysis of 11,015 ischaemic stroke patients from 8 trials found no effect of blood pressure lowering treatment on the risk of death or dependency (OR 1.00, 95% CI: 0.92–1.08) (Bath and Krishnan, 2014) (Figure 8.1).
Figure 8.1 Forest plot showing the effects of any blood pressure lowering treatment pre-stroke antihypertensives on the risk of death or dependency in patients with acute ischaemic stroke. Modified from Bath and Krishnan (2014).
Similar results were found in a subgroup analysis of patients with different stroke locations, from 4 trials. Among 6180 patients with cortical stroke, the OR was 0.94 (95% CI: 0.81–1.09), and the OR was 0.98 among 2383 patients with subcortical stroke (95% CI: 0.76–1.27) (Bath and Krishnan, 2014).
Blood pressure lowering treatment in patients with intracerebral haemorrhage is discussed in Chapter 13.
Data from 16 trials involving 15,489 patients with ischaemic, haemorrhagic, or mixed stroke found a significant reduction in death or dependency if treatment was administered within 6 hours of symptom onset (OR 0.87, 95% CI: 0.76–0.99). No beneficial effects of blood pressure lowering treatment with glyceryl trinitrate were seen in the prehospital Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial-2, where patients were randomized a median 71 minutes after symptom onset (RIGHT-2 Investigators, 2019). Treatment administered later than 6 hours showed no effect on death or dependency (Bath and Krishnan, 2014).
Data from 16 trials involving 15,489 patients with ischaemic, haemorrhagic, or mixed stroke found no significant differences in the risk of death or dependency when comparing drug classes or blood pressure lowering strategies (Bath and Krishnan, 2014).
Data from two trials involving 2860 patients with ischaemic, haemorrhagic, or mixed stroke found that continuing pre-stroke antihypertensives in the acute phase had no effect on death or dependency. Instead, there was an increased risk of disability (measured by the Barthel Index) and of poor quality of life (measured by EuroQoL) (Bath and Krishnan, 2014; Woodhouse et al., 2017; Anderson et al., 2019) (Figure 8.2).
Figure 8.2 Forest plot showing the effects of continuing versus stopping pre-stroke antihypertensives on the risk of death or dependency. Modified from Bath and Krishnan (2014).
In the setting of reperfusion therapy for acute ischaemic stroke, high blood pressure is associated with an increased risk of intracerebral haemorrhage. Similar findings have been found with spikes in blood pressure during or following the administration of thrombolytic drugs.
There are limited data on the effect of blood pressure lowering in the setting of thrombolytic treatment. In a secondary analysis of observational data from the third International Stroke Trial (IST-3) of intravenous recombinant tissue plasminogen activator (rt-PA) vs control, active blood pressure lowering within the first 24 hours was associated with a significantly reduced risk of poor functional outcome at 6 months, both in the rt-PA and control groups (Berge et al., 2015). The randomized controlled Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) assessed whether intensive blood pressure lowering (systolic target 130–140 mm Hg) is beneficial in patients eligible for thrombolysis, compared with guideline treatment (target < 180 mm Hg), and the overall results were neutral, but there was less intracranial haemorrhage in the intensive group (Anderson et al., 2019).
In patients with blood pressure at or above 220/120 mm Hg who do not receive intravenous thrombolysis, the benefit of initiating or reinitiating treatment of hypertension within the first 48–72 hours is uncertain. It might be reasonable to lower blood pressure by 15% during the first 24 hours after stroke onset (American Heart Association [AHA]/American Stroke Association [ASA] guidelines 2018: Class II; Level of Evidence B) (Powers et al., 2018).
Patients who have elevated blood pressure and are otherwise eligible for treatment with intravenous rt-PA should have their blood pressure lowered so that systolic blood pressure is below 185 mm Hg and their diastolic blood pressure is below 110 mm Hg before thrombolytic treatment is administered (AHA/ASA guidelines 2018 Class I; Level of Evidence B) (Powers et al., 2018).
No recommendations can be made regarding drug classes; however, intravenous calcium channel antagonists can cause abrupt and large reductions in blood pressure and should only be used cautiously. Intravenous labetalol or urapidil is commonly used. Sodium nitroprusside can be recommended in cases of resistant hypertension. There is no evidence to support continuation of prestroke antihypertensive drugs. Treatment may be restarted once the patient is medically and neurologically stable and once safe feeding and enteral access is available.
Therapeutic haemodilution reduces blood cell volume and viscosity, and may thereby increase blood flow to hypoperfused brain tissue.
A systematic review identified 21 randomized controlled trials of haemodilution for acute ischaemic stroke. Twelve trials used plasma volume expanders alone (hypervolaemic haemodilution), in 8 trials the use of plasma volume expanders was combined with venesection (isovolaemic haemodilution), and in 1 trial venesection was only performed if there were signs of volume overload. The plasma volume expander was plasma alone in 1 trial, dextran in 12 trials, hydroxyethyl starch (HES) in 5 trials and albumin in 3 trials. Two trials tested haemodilution in combination with another therapy (Chang and Jensen, 2014).
There was no effect of haemodilution on death within 4 weeks or within 3–6 months, or on death or dependency or institutionalization at the end of follow-up (risk ratio [RR] 0.96, 95% CI: 0.85–1.07). The results were similar in trials of isovolaemic and hypervolaemic haemodilution. In subgroup analysis of different haemodilution strategies on functional outcome, trials of hydroxyethyl starch, including 306 patients, showed non-significantly better outcomes in patients treated with hydroxyethyl starch (RR 0.87, 95% CI: 0.71–1.07). No effects were seen for the other haemodilution strategies (Chang and Jensen, 2014) (Figure 8.3).