Keywords

12.1 Introduction

Intracerebral haemorrhage (ICH) is a devastating disease with the highest rate of mortality among the major pathological stroke subtypes. ICH is also the major contributor to disability-adjusted life years lost among all neurologic disorders [1]. Hypertension is the most important modifiable risk factor for both primary and recurrent ICH [2].

Early blood pressure (BP) elevation is observed in the majority of patients with ICH [3]. High BP appears to play a critical role in the pathogenesis of ICH, since it has been shown to be strongly related to haematoma growth [4–6] and subsequent poor clinical outcomes [7–11]. Therefore, acute BP alteration might be of clinical relevance in this cerebrovascular disorder.

In fact, recent clinical trial evidence suggests that BP lowering immediately after ICH may be an important treatment target to prevent haematoma expansion and may be associated with better outcomes [12].

12.2 Epidemiology

ICH is a less common subtype of stroke than cerebral ischaemia, accounting for 9–33 % of all acute cerebrovascular events/strokes worldwide, but is associated with higher mortality rates and poorer functional outcomes. Haemorrhagic stroke is especially common in Asia, particularly in Japan and China, and in African populations, where it constitutes up to 20–33 % of all strokes [13]. In Caucasians, ICH accounts for approximately 9–15 % of all strokes [14]. The incidence of ICH rises with age and therefore the number of ICH is expected to increase substantially in the near future. ICH is associated with high early and late mortality and morbidity. The case fatality rate is 40 % at 1 month, rising to 54 % at 12 months [15, 16]. About 50 % of survivors will be permanently disabled, with only a minority of ICH patients being independent of long-term care at 12 months [17–19].

Most patients receive no warning signs before ICH. Occasionally, some patients with vascular malformations may present with recurrent, usually localized, headaches or seizures.

Among vascular risk factors, elevated BP is well established as the major contributor to ICH, with a much stronger association with ICH than with ischaemic stroke [20, 21]. BP values are linearly associated with the risk of ICH. The higher the BP, the greater the increased risk of haemorrhagic stroke and recurrent stroke, both haemorrhagic [22] and ischaemic [20, 21].

In general, hypertensives have a 2–3 times higher relative risk of ICH than non-hypertensive subjects [23]. High BP is a much stronger predictor of ICH in younger adults than in older subjects [24]. Discontinuation of antihypertensive therapy is also associated with a significantly greater risk of ICH [25].

12.3 Pathophysiology

Pathogenetically, arterial small vessel disease (so-called arteriolosclerosis), cerebral amyloid angiopathy and haemostatic and coagulation disorders – either due to intrinsic systemic or other diseases or to medications – are the leading causes of ICH in the elderly, while vascular malformations, venous disease, acute hypertensive crises or aneurysms are more likely to explain bleeding in younger patients [26, 27]. Cerebral arteriolosclerosis affects the small perforating arteries arising from the large vasculature of the brain and is related mainly, but not exclusively, to chronic uncontrolled hypertension [28]. Hypertension-related ICH tends to be located in the deep structures of the brain (e.g. basal ganglia, thalamus, white matter, pons, cerebellum), although, in rare cases, it may affect the subcortical areas [29].

The percentage of hypertension-related ICH varies between 50 and 70 % in older studies and between 35 and 54 % in more recent studies due to the availability of modern neuroimaging tools allowing other causes of ICH to be diagnosed. However, in about 20 % of ICH cases, no underlying cause is identified with currently available diagnostic tools, and thus they may still be considered cryptogenic [26].

With the advent of modern neuroimaging tools, continued bleeding and haematoma expansion have been demonstrated in one-third of patients with ICH in the first few hours [30] and in a further 10 % in the 3–24 h after stroke onset [31–33]. In ICH associated with anticoagulants, haematoma expansion persists even longer [34]. Haematoma expansion and final lesion volume, determined mainly within the first 24 h after stroke, are the key prognosticators of clinical outcomes in patients with ICH. However, the adverse effects of peri-haematoma edema [35, 36] and inflammation [37, 38] in the first few days post-stroke may also contribute to overall morbidity and mortality.

12.4 BP and Outcomes in ICH

Acutely elevated BP in the first 24 h – the so-called acute hypertensive response (AHR) – occurs in up to 90 % of ICH cases [39–42], whereas pre-existing hypertension (self-reported) with systolic BP (SBP) ≥ 140 mmHg or >160 mmHg is found in 73 % and 60 % of ICH patients, respectively [3]. Stress, pain, increased intracranial pressure and premorbid elevations in BP are associated with AHR in ICH patients [10, 42].

In a recent study by Fisher et al., the first recorded acute-phase SBP was much higher in patients with ICH than in those with ischaemic stroke. Moreover, the first mean SBP after ICH was much higher than premorbid levels, in contrast with findings in patients with ischaemic stroke [43]. Mean SBP also increased steeply in the days and weeks before ICH, but not before ischaemic stroke. SBP appeared to rise substantially after ICH compared with usual premorbid values, and the reported difference between the highest SBP within 3 h of onset was 50 mmHg higher, on average, than the maximum premorbid SBP. Larger acute BP increases during ICH have been reported in Black populations than in Caucasian groups [44].

Rapid BP changes, with a substantial acute BP rise, seem to be specific for the ICH subtype of stroke, while in ischaemic stroke, acute post-event SBP tends to be much closer to premorbid values [43]. A possible explanation may be that ICH causes acute elevations in intracranial pressure more often than ischaemic stroke [45], followed by a reflex increase in systemic BP (the so-called Cushing triad: hypertension, bradycardia and breathing pattern abnormalities) [46]. Raised BP tends to decline spontaneously, primarily in the first few hours after intracerebral bleeding. Consistent with the data mentioned above, in the first 24 h after stroke, BP usually falls much more after ICH than after major ischaemic stroke [43]. However, in a substantial proportion of ICH patients, BP remains increased.

High BP in the acute phase after ICH has been associated with haematoma expansion [5], neurological deterioration and death and dependency [6, 47]. Furthermore, ICH patients with pathologically raised BP have more severe oedema and a higher risk of early stroke recurrence [22, 35, 36]. Therefore, BP-lowering therapy may potentially reduce the ICH-related burden. Not only mean BP values are of clinical importance in ICH patients. In a recent large, prospective randomized trial, BP variations in the first 24 h, and for several days after ICH, have been shown to be independent predictors of a poor outcome [48]. This may reflect the transient character of many individual factors associated with the initial pressor response, with episodic hypertension most likely to be related to the pathomechanisms of ICH triggering and progression. Moreover, raised BP may be both a risk factor and a risk marker for intracerebral bleeding and subsequent intracranial hypertension [8].

Factors associated with a poor outcome after ICH (other than BP) include older age [49, 50], large haemorrhage volume [17, 51–53], reduced level of consciousness [6, 54], extravasation with continued bleeding [49], haematoma expansion [31, 55], hydrocephalus and intraventricular involvement [17, 51, 54]. Patients with ICH are at high risk of other cardiovascular events, including recurrent ICH [56]. Hypertension and older age are important risk factors for ICH recurrence [57, 58]. A deep location of the initial and recurrent haemorrhage is more common in Asians, while in Caucasians, most ICHs (both initial and recurrent) tend to be located more superficially (in the lobes of the brain) [57, 59].

12.5 BP Management After ICH

Population-based studies show that most patients present with small ICH that are readily survivable with good medical care [60]. This suggests that excellent medical care probably has a potent, direct impact on ICH morbidity and mortality. The goal of ICH treatment is to prevent and reverse acute brain injury and prevent neurological impairment and disability. The evidence shows that management in an acute stroke unit improves outcomes compared with care on a general ward, reducing mortality and dependency in patients with ICH [61]. This may partially be explained by continuous monitoring of vital functions, including BP, and early treatment of complications by stroke units.

The treatment of acute BP elevation in ICH has been controversial for decades. The theoretical concept justifying early BP lowering in ICH patients is that it attempts to limit cerebral haemorrhage growth, which occurs mainly in the first few hours after stroke onset [12, 62], and to reduce cerebral oedema and minimize the risk of early hypertensive emergencies, including stroke recurrence, in the acute phase of ICH. However, the treatment plan should consider the potential risk of ischaemic injury to peri-haematoma areas or other vascular beds and the potentially higher disability and mortality, especially when the fall in BP in the acute phase is large and rapid [63]. In fact, acute BP-lowering therapy may be associated with ischaemic strokes remote from the primary haematoma in patients with ICH, as evidenced by recent MRI studies [64]. However, there is some evidence showing that reduced metabolism [65] and preserved autoregulation, the two typical features of the peri-haematoma region [66], might prevent any injury associated with SBP lowering. As indicated in recent prospective studies of acute ICH, BP reduction decreases haematoma expansion but has no adverse effect on peri-haematoma blood flow [4, 67–70].

There is also long-standing clinical debate on the optimal BP values in ICH, which should probably depend on coexisting individual factors including age, pre-existing hypertension, intracranial pressure, presumed cause of bleeding and time from stroke onset. The initial data on the effects of BP lowering in ICH were conflicting, with positive [68, 71, 72], neutral [73] and negative [63, 74, 75] effects attributed to SBP reduction. These clinical uncertainties were reflected in the heterogeneous expert-based recommendations for optimal BP lowering in acute ICH (Table 12.1).

Table 12.1 Suggested previous guidelines recommendations for BP-lowering treatment in patients with acute ICH
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There is now growing evidence supporting the safety of early intensive BP lowering after ICH. Observational studies suggest that more aggressive BP lowering may have a greater effect on reductions in haematoma growth (Table 12.2).

Table 12.2 Results of studies of blood pressure reduction after intracerebral haemorrhage
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The Antihypertensive Treatment of Acute Cerebral Haemorrhage (ATACH) trial was a small multicentre open-label pilot trial to determine the safety of intravenous nicardipine-based BP lowering in 60 patients with chronic hypertension and SBP > 170 mmHg presenting within 12 h after supratentorial ICH. Patients were enrolled into one of three tiers of increasing BP-lowering intensity (170–200, 140–170, 110–140 mmHg). Aggressive SBP lowering (110–140 mmHg) was well tolerated and safe [79].

The Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTRERACT) included over 400 predominantly Chinese patients with acute ICH diagnosed by computed tomography within 6 h of stroke onset, and with SBP in the range of 150–220 mmHg, and no definitive indication or contraindication to BP treatment. Patients were assigned to intensive therapy (target SBP of 140 mmHg) or standard AHA guideline therapy (target SBP of 180 mmHg). After 24 h, SBP decreased to 146 mmHg in the intensive therapy group and to 157 mmHg in the standard therapy group. Mean proportional haematoma growth was lower in the intensive treatment group (13.5 % vs. 36.3 %; p = 0.04), although there was no clinical benefit at 90 days but also no higher risk of adverse events or poorer outcomes. An optimum attenuation of haematoma growth was demonstrated at SBP of 130–140 mmHg [4]. This was particularly true for very early intensive blood pressure lowering [67].

Thus, while the ATACH study was the first to prove the feasibility and tolerability of early intensive SBP lowering, the INTERACT found an additional positive effect of this type of therapy, namely, a reduction in haematoma expansion.

The recently completed INTERACT2 study of approximately 2,800 patients with an acute ICH showed improved functional recovery without any harm after an intensive strategy of BP lowering in patients with ICH. Exclusion criteria included (1) a clear indication for, or a contraindication to, intensive BP lowering; (2) severe neurological symptoms, concurrent medical conditions, a high likelihood of death within 24 h or massive ICH; and (3) early planned surgical intervention. The aggressive BP control (target SBP <140 mmHg) in very early (<6, mean time to start therapy about 3.7) hours after ICH onset was associated with a reduction in haematoma growth, as demonstrated in the INTERACT study and, more importantly, with safety and better functional outcome, as shown in the ordinal analysis of the dichotomous modified Rankin scale (mRS), although not in the primary outcome, which was the dichotomous mRS (i.e. there was a nonsignificant 4 % absolute treatment effect (p = 0.06) on the primary outcome of death or major disability) [12].

The BP-lowering protocols were based on locally available intravenous agents, as the antihypertensive drugs were not prespecified in the trial. Only one-third of patients achieved the target SBP value within 1 h (half achieved the target by 6 h), and most (75 %) presented with mild-to-moderate (<20 mL) haematomas [82].

Nonetheless, the INTERACT2 study has generally been interpreted as a positive trial, demonstrating both radiological and clinical benefit. Moreover, the more aggressive BP lowering was associated with a better outcome, with an optimal BP target around 130–139 mmHg achieved within the first 6 h [83]. Optimal recovery from ICH was observed in hypertensive patients who achieved the greatest SBP reductions (≥20 mmHg) in the first hour and which were maintained for 7 days [84].

The Stroke Acute Management with Urgent Risk Factor Assessment and Improvement – Intracerebral Haemorrhage (SAMURAI-ICH) evaluated the effects of BP lowering in 211 Japanese patients with ICH and SBP > 180 mmHg [85]. Patients were treated with intravenous nicardipine within 3 h of stroke onset. The aim of the study was to achieve SBP between 120 and 160 mmHg and to maintain it in this range for the first 24 h. BP reduction was related to the reduction in the risk of haematoma expansion in the acute period and neurological deterioration and functional status at 3 months.

In the SCAST trial, over 200 (14 %) patients had ICH. Unfortunately, the treatment of elevated BP with candesartan (mean time to start therapy about 18 h) did not reduce, but increased, the risk of a poor outcome. It might be speculated that, if BP lowering is time dependent in ICH, the BP-altering intervention may have been too late in this trial. Alternatively, candesartan, as an angiotensin receptor blocker, might be not the best option for lowering BP in ICH.

The Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS) enrolled patients with a recent stroke (time window 48 h) taking antihypertensive drugs. The majority of participants had ischaemic stroke, although 15 % of patients recruited had an ICH. At the study end point of 2 weeks, the continued treatment group had systolic/diastolic BP that was 13/8 mmHg less than the stop treatment group. However, there were no differences in rates of death and dependency, the primary end point, or in the rates of serious adverse events, 6-month mortality or cardiovascular events. The continuation of BP-lowering agents did not have any significant efficacy on adverse events. Nevertheless, it should be stressed that the absolute number of ICH subjects enrolled in the trial was relatively small.

Thus, although the available evidence is insufficient to provide accurate guidance on the management of BP in the acute phase of ICH, there is recent evidence supporting very early aggressive BP control during this phase. Consequently, it seems reasonable that urgent initiation of the time-sensitive procedure of BP lowering should be made in the emergency department. Specific protocols for the management of ICH should be developed for more efficient, standardized management of patients with ICH.

12.6 Current Guideline Recommendations

The current American Stroke Association [82] and European Stroke Organization [86] guidelines recommend reduction of SBP to <140 mmHg in ICH patients presenting with SBP between 150 and 220 mmHg and with no contraindication to acute BP treatment. Acute lowering of SBP to 140 mmHg is regarded safe and may be effective in improving functional outcomes and may be superior to an SBP target of <180 mmHg. For ICH patients presenting with systolic BP > 220 mmHg, it may be reasonable to consider aggressive BP reduction and frequent BP monitoring. A lower limit for safe reduction is undefined. Short-acting and easily titratable antihypertensive infusions are preferred (Table 12.3).

Table 12.3 Short and rapidly acting intravenous antihypertensive agents that may be considered for control of elevated BP in patients with ICH
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12.7 Future Directions and Ongoing Studies

Further trials are needed to identify the optimal timing and the best drug classes for lowering high BP in ICH. There are no data on drugs specific for ICH patients. In some pivotal trials, the feasibility of calcium channel blockers has been shown. However, the optimal choice of drug and intensity of treatment remain elusive. The benefits (and potential risks) of aggressive BP management may vary according to age and comorbidities.

The ATACH II study – ongoing trial for intensive lowering of elevated BP within 3.5 h with nicardipine IV – will provide information about any differential effect between populations.

Other vascular factors, such as BP variability, the presence of obstructive sleep apnoea [88], obesity, frequent alcohol use [89] and illicit drug use [90], which have been linked to elevated BP and ICH, should also be considered in both the acute and chronic care of ICH patients.