Introduction

Elevated blood pressure (BP)

Associated with hematoma expansion

Neurological deterioration

Unfavorable outcomesAssociations B/W early blood pressure (BP) variability and clinical outcomes with ICH after antihypertensive therapy clarified by a post hoc analysis of Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2)

Confirmed in Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI)-intracerebral hemorrhage study cohort

AIM

To confirm associations between early BP variability, clinical and functional outcome at 3 months

The SAMURAI-ICH study was a prospective, multicenter,observational studyCriteria for inclusion are as follows: ≥20 years of age Glasgow Coma Scale score ≥5Initial SBP >180 mm HgComputed tomography <2.5 hours of onset demonstrating asupratentorial intraparenchymal hematoma with manualvolume measurement <60 mL

Absence of extensive intraventricular hemorrhage.

Methods

Kothari et al

The ABC/2 volume estimation is based on simplificationof the ellipsoid volume equationA=maximum length (in cm), B=width perpendicular to Aon the same head CT slice, and C=the number of slicesmultiplied by the slice thickness

abc/2 Rule for ICH Volume

The predefined standardized protocol of AHT was used to lower and maintain the SBP level below 160 mm Hg and above 120 mm Hg.

Titrating of intravenous nicardipine was initiated at a rate of 5 mg/h within 3 hours of symptom onset and continued for 24 hours.

Levels of BP and pulse rate were measured every 15 minutes during the first 2 hours after initiation of AHT and every 60 minutes during the next 22 hours, as well as at 48 and 72 hours.

Oral antihypertensive agents were started after the first 24 hours

Clinical outcomes include hematoma expansion (>33% in volume from baseline to 24 hours)

Neurological deterioration (a decrease of ≥2 in Glasgow Coma Scale or an increase of ≥4 in the National Institutes of Health Stroke Scale score from baseline to 72 hours)

Unfavorable outcome (modified Rankin Scale score, 4–6 at 3 months)

Hematoma expansion evaluated by an absolute volume difference and a relative volume change

Of the 211 patients in the registry, 205 (81 women,median age 65 [interquartile range, 59–75] years medianinitial National Institutes of Health Stroke Scale score

13[8–17]) whose BP data were available throughout the 24hour observation period were studied

Results

Correlations between rates of clinical outcomes and systolic blood pressure variability quartiles

Neither SD nor SV of diastolic BP demonstrated associations with any clinical outcome

Correlations between rates of clinical outcomes and diastolic blood pressure variability quartiles

Correlations between rates of clinical outcomes and systolic blood pressure variability quartiles.

Tanaka E et al. Stroke. 2014;45:2275-2279

Correlations between rates of clinical outcomes and diastolic blood pressure variability quartiles.

Tanaka E et al. Stroke. 2014;45:2275-2279

The major findings that variability of SBP assessedusing both SD and SV during the initial 24 hours of

ICHwas independently associated with both earlyneurological deterioration and unfavorable outcomeat 3 months

Positive association between SBP variability andabsolute and relative changes in hematoma volume

Discussion

A difference between the INTERACT2 and the present study was the timing of points of BP measurement within the initial 24 hours (6 versus 24 points).

SV which reflects the serial BP variation in a time sequence, was used as indicator of variability, as well as SD

Increased BP variability is associated with female sex, advanced age, and hypertension

Mechanisms to connect BP variability and clinical outcomes

Autonomic dysfunction, including sympathetic overactivity and diminished baroreflex sensitivity

The impaired baroreflex sensitivity increased BP variability and accordingly altered cerebral perfusion, leading to secondary brain injury

Sympathetic overactivity affects the factors that boost the secondary brain injury and enhance brain edema, such as leukocytosis, proinflammatory cytokine production, hyperglycemia, hyperthermia, and increased blood–brain barrier permeability

Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trialBackgroundHigh blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. MethodsINTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150—220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2—7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models

ResultWe studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05—1·90; ptrend=0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14—2·17; ptrend=0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14—1·80; ptrend=0·0014; for the acute phase OR 1·46, 95% CI 1·13—1·88; ptrend=0·0044).

InterpretationSystolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure.

Conclusion

SBP variability during the initial 24 hours of hyperacute ICH was independently associated with neurological deterioration and 3-month unfavorable outcome. Stability with appropriate AHT may ameliorate clinical outcomes in patients with hyperacute ICH. BP variability seems to be an important therapeutic target in acute ICH

Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemorrhageEuropean Journal of Neurology

Background and purposeAn association between high blood pressure (BP) in acute intracerebral hemorrhage (ICH) and hematoma growth (HG) has not been clearly demonstrated.

MethodsIn total, 117 consecutive patients with acute (<6 h) supratentorial ICH underwent baseline and 24-h CT scans, CT angiography for the detection of the spot sign and non-invasive BP monitoring at 15-min intervals over the first 24 h. Maximum and minimum BP, maximum BP increase and drop from baseline, and BP variability values from systolic BP (SBP), diastolic BP and mean arterial pressure (MAP) were calculated. SBP and MAP loads were defined as the proportion of readings >180 and >130 mmHg, respectively. HG (>33% or >6 ml)Early neurological deterioration (END) and 3-month mortality were recorded.

ResultsBaseline BP variables were unrelated to either HG or clinical outcome. Conversely, SBP 180-load independently predicted HG (odds ratio 1.05, 95% CI 1.010–1.097, P = 0.016), whilst both SBP 180-load (odds ratio 1.04, 95% CI 1.001–1.076, P = 0.042) and SBP variability (odds ratio 1.2, 95% CI 1.047–1.380, P = 0.009) independently predicted END. Although none of the BP monitoring variables was associated with HG in the spot-sign-positive group, higher maximum BP increases from baseline and higher SBP and MAP loads were significantly related to HG in the spot-sign-negative group.ConclusionsIn patients with acute supratentorial ICH, SBP 180-load independently predicts HG, whilst both SBP 180-load and SBP variability predict Early neurological deterioration

Hypertension. 2010 Nov;56(5):852-8

Lower treatment blood pressure is associated with greatest reduction in hematoma growth after acute intracerebral hemorrhage.Abstract

The pilot phase of the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT) showed that rapid blood pressure (BP) lowering can attenuate hematoma growth in acute intracerebral hemorrhage. INTERACT included 404 patients with computed tomographic-confirmed intracerebral hemorrhage, elevated systolic BP (150 to 220 mm Hg), and capacity to commence BP lowering treatment within 6 hours of onset. CT was done at baseline and at 24 hours using There was no significant association between baseline systolic BP levels and either the absolute or proportional growth in hematoma volume (P trend=0.26 and 0.12, respectively). By contrast, achieved on-treatment systolic BP levels in the first 24 hours were clearly associated with both absolute and proportional hematoma growth (both P trend=0.03). Maximum reduction in hematoma growth occurred in the one third of participants with the lowest on-treatment systolic BP levels (median: 135 mm Hg). Intensive BP reduction to systolic levels between 130 and 140 mm Hg is likely to provide the maximum protection against hematoma growth after intracerebral hemorrhage.

J Korean Med Sci. 2012 Sep;27(9):1085-90. doi: 10.3346/jkms

Antihypertensive treatment of acute intracerebral hemorrhage by intravenous nicardipine hydrochloride: prospective multi-center studyAbstractThis study included 88 patients (mean age: 58.3 yr, range 26-87 yr) with ICH and acute hypertension in 5 medical centers between August 2008 and November 2010, who were treated using intravenous nicardipine. Administration of nicardipine resulted in a decrease from mean systolic blood pressure (BP) (175.4 ± 33.7 mmHg) and diastolic BP (100.8 ± 22 mmHg) at admission to mean systolic BP (127.4 ± 16.7 mmHg) and diastolic BP (67.2 ± 12.9 mmHg) in 6 hr after infusion (P < 0.001, mixed-effect linear models). Among patients who underwent follow-up by computed tomography, hematoma expansion at 24 hr (more than 33% increase in hematoma size at 24 hr) was observed in 3 (3.4%) of 88 patients. Neurological deterioration (defined as a decrease in initial Glasgow coma scale ≥ 2) was observed in 2 (2.2%) of 88 patients during the treatment. Aggressive nicardipine treatment of acute hypertension in patients with ICH can be safe and effective with a low rate of neurological deterioration and hematoma expansion.

Stroke. 2013 Mar;44(3):620-6. doi: 10.1161/STROKEAHA.111.000188

The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial.Abstract

BACKGROUND AND PURPOSE:Acute blood pressure (BP) reduction aimed at attenuation of intracerebral hemorrhage (ICH) expansion might also compromise cerebral blood flow (CBF). We tested the hypothesis that CBF in acute ICH patients is unaffected by BP reduction

METHODS:Patients with spontaneous ICH <24 hours after onset and systolic BP > 150 mm Hg were randomly assigned to an intravenous antihypertensive treatment protocol targeting a systolic BP of <150 mm Hg (n=39) or <180 mm Hg (n=36). Patients underwent computed tomography perfusion imaging 2 hours postrandomization. The primary end point was perihematoma relative (relative CBF).

RESULTS:Treatment groups were balanced with respect to baseline systolic BP: 182±20 mm Hg (<150 mm Hg target group) versus 184±25 mm Hg (<180 mm Hg target group; P=0.60), and for hematoma volume: 25.6±30.8 versus 26.9±25.2 mL (P=0.66). Mean systolic BP 2 hours after randomization was significantly lower in the <150 mm Hg target group (140±19 vs 162±12 mm Hg; P<0.001). Perihematoma CBF (38.7±11.9 mL/100 g per minute) was lower than in contralateral homologous regions (44.1±11.1 mL/100 g per minute; P<0.001) in all patients. The primary end point of perihematoma relative CBF in the <150 mm Hg target group (0.86±0.12) was not significantly lower than that in the <180 mm Hg group (0.89±0.09; P=0.19; absolute difference, 0.03; 95% confidence interval -0.018 to 0.078). There was no relationship between the magnitude of BP change and perihematoma relative CBF in the <150 mm Hg (R=0.00005; 95% confidence interval, -0.001 to 0.001) or <180 mm Hg target groups (R=0.000; 95% confidence interval, -0.001 to 0.001).CONCLUSIONS:Rapid BP lowering after a moderate volume of ICH does not reduce perihematoma CBF. These physiological data indicate that acute BP reduction does not precipitate cerebral ischemia in ICH patients

Stroke. 2013 Mar;44(3):816-8. doi: 10.1161/STROKEAHA.112.681007Impact of early blood pressure variability on stroke outcomes after thrombolysis: the SAMURAI rt-PA Registry.METHODS:In 527 stroke patients receiving intravenous alteplase (0.6 mg/kg), BP was measured 8 times within the first 25 hours. BP variability was determined as ΔBP (maximum-minimum), standard deviation (SD), coefficient of variation, and successive variation.RESULTS:The systolic BP course was lower among patients with modified Rankin Scale (mRS) 0 to 1 than those without (P<0.001). Most of systolic BP variability profiles were significantly associated with outcomes. Adjusted odds ratios (95% confidence interval) per 10 mm Hg (or 10% for coefficient of variation) on symptomatic intracerebral hemorrhage were as follows: ΔBP, 1.33 (1.08-1.66); SD, 2.52 (1.26-5.12); coefficient of variation, 3.15 (1.12-8.84); and successive variation, 1.82 (1.04-3.10). The respective values were 0.88 (0.77-0.99), 0.73 (0.48-1.09), 0.77 (0.43-1.34), and 0.76 (0.56-1.03) for 3-month mRS 0 to 1; and 1.40 (1.14-1.75), 2.85 (1.47-5.65), 4.67 (1.78-12.6), and 1.99 (1.20-3.25) for death.Initial BP values before thrombolysis were not associated with any outcomes.CONCLUSIONS:Early systolic BP variability was positively associated with symptomatic intracerebral hemorrhage and death after intravenous thrombolysis.

Stroke. 2009 Jul;40(7):2442-9. doi: 10.1161/STROKEAHA

Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR)

BACKGROUND AND PURPOSE:The optimal management of blood pressure (BP) in acute stroke remains unclear. For ischemic stroke treated with intravenous thrombolysis, current guidelines suggest pharmacological intervention if systolic BP exceeds 180 mm Hg. We determined retrospectively the association of BP and antihypertensive therapy with clinical outcomes after stroke thrombolysis.

METHODS:

The SITS thrombolysis register prospectively recorded 11 080 treatments from 2002 to 2006. BP values were recorded at baseline, 2 hours, and 24 hours after thrombolysis. Outcomes were symptomatic (National Institutes of Health Stroke Scale score deterioration >or=4) intracerebral hemorrhage Type 2, mortality, and independence at (modified Rankin Score 0 to 2) 3 months. Patients were categorized by history of hypertension and antihypertensive therapy within 7 days after thrombolysis: Group 1, hypertensive treated with antihypertensives (n=5612); Group 2, hypertensive withholding antihypertensives (n=1573); Group 3, without history of hypertension treated with antihypertensives (n=995); and Group 4, without history of hypertension not treated with antihypertensives (n=2632). For 268 (2.4%) patients, these data were missing. Average systolic BP 2 to 24 hours after thrombolysis was categorized by 10-mm Hg intervals with 100 to 140 used as a reference.

RESULTS:In multivariable analysis, high systolic BP 2 to 24 hours after thrombolysis as a continuous variable was associated with worse outcome (P<0.001) and as a categorical variable had a linear association with symptomatic hemorrhage and a U-shaped association with mortality and independence with systolic BP 141 to 150 mm Hg associated with most favorable outcomes. OR (95% CI) from multivariable analysis showed no difference in symptomatic hemorrhage (1.09 [0.83 to 1.51]; P=0.58) and independence (1.03 [0.93 to 1.10]; P=0.80) but lower mortality (0.82 [0.73 to 0.92]; P=0.0007) for Group 1 compared with Group 4. Group 2 had a higher symptomatic hemorrhage (1.86 [1.34 to 2.68]; P=0.0004) and mortality (1.62 [1.41 to 1.85]; P<0.0001) and lower independence (0.89 [0.80 to 0.99]; P=0.04) compared with Group 4. Group 3 had similar results as Group 1CONCLUSIONS:There is a strong association of high systolic BP after thrombolysis with poor outcome. Withholding antihypertensive therapy up to 7 days in patients with a history of hypertension was associated with worse outcome, whereas initiation of antihypertensive therapy in newly recognized moderate hypertension was associated with a favorable outcome

What Blood Pressure Level Is Considered to Be Too High and Requiring Immediate Reduction?Answer: Despite absence of definitive supportive evidence, some experts believe that a SBP of >180 mm Hg or a mean arterial pressure (MAP) of >130 mm Hg would warrant immediate lowering. In the presence of conditions such as acute heart failure, hypertensive encephalopathy, active cardiac ischemia, and so on, lower BP targets may be appropriate.

What Is the Appropriate Target Blood Pressure in Patients With ICH?Answer: Immediately after an ICH, it is perhaps more appropriate to tailor the target BP to each patient rather than using a “one size fits all” approach. The possibility of increased ICP and a history of chronic untreated hypertension should be considered while choosing the target. Recognizing the absence of definitive data, the American Heart Association/American Stroke Association (AHA/ASA) guidelines suggest maintaining a cerebral perfusion pressure of 60 to 80 mm Hg in patients with possible increased ICP and a BP of 160/90 or a MAP of 110 mm Hg in other patients

What Blood Pressure Level Is Considered to Be Too High and Requiring Immediate Reduction?Answer: Despite absence of definitive supportive evidence, some experts believe that a SBP of >180 mm Hg or a mean arterial pressure (MAP) of >130 mm Hg would warrant immediate lowering. In the presence of conditions such as acute heart failure, hypertensive encephalopathy, active cardiac ischemia, and so on, lower BP targets may be appropriate.

What Is the Appropriate Target Blood Pressure in Patients With ICH?Answer: Immediately after an ICH, it is perhaps more appropriate to tailor the target BP to each patient rather than using a “one size fits all” approach. The possibility of increased ICP and a history of chronic untreated hypertension should be considered while choosing the target. Recognizing the absence of definitive data, the American Heart Association/American Stroke Association (AHA/ASA) guidelines suggest maintaining a cerebral perfusion pressure of 60 to 80 mm Hg in patients with possible increased ICP and a BP of 160/90 or a MAP of 110 mm Hg in other patients

How Fast Should Blood Pressure Be Lowered?

Answer: results of small studies suggest that rapidly lowering MAP by approximately 15% does not lower cerebral blood flow, whereas reductions of >20% can do so. Therefore, if BP-lowering is considered, current guidelines suggest cautious lowering of BP by no more that 20% in the first 24 hours.

What Antihypertensive Agents Are Appropriate for Use in the Acute Setting?

Answer: Short and rapidly acting intravenous antihypertensive agents are preferred. In the United States, labetalol, hydralazine, esmolol, nicardipine, enalapril, nitroglycerin, and nitroprusside have been recommended.Intravenous urapidil is also used in. Sodium nitroprusside and nitroglycerin should be used with caution because these agents can potentially increase ICP.

Should Blood Pressure Be Lowered in Patients With Elevated BP After an Ischemic Stroke?

Answer: As per the AHA/ASA guidelines, it is recommended that before intravenous thrombolytic treatment, BP should be lowered if >185 mm Hg systolic or >110 mm Hg diastolic. After thrombolytic treatment, SBP should be kept <180 mm Hg and DBP <105 mm Hg. Intravenous labetalol, nitropaste, nicardipine infusion, and, if BP remains elevated, sodium nitroprusside are the recommended agents. Despite the absence of supporting evidence, these recommendations are often applied to patients receiving other forms of reperfusion therapy (eg, intra-arterial thrombolysis, clot retrieval, and so on).Patients with other indications for BP-lowering such as acute heart failure, aortic dissection, and so on should have the BP lowered.

Should Blood Pressure Be Elevated to Improve Cerebral Perfusion in Patients With Ischemic Stroke?

Answer: A few small case series have shown neurological improvement with induced hypertensive therapy. Studies are underway to assess the usefulness of this form of therapy in patients with a diffusion–perfusion mismatch on MRI. In the meantime, it is reasonable to try volume expansion and/or vasopressors in patients with hypotensive stroke or in patients who have had a worsening of the neurological deficit in association with a drop in BP.

Should Patients on Antihypertensive Agents Have Their Medications Held or Continued?

Answer: There are no substantial clinical data available to answer this question and a clinical trial is underway to address this issue (Continue or stop poststroke antihypertensives study).The AHA/ASA guidelines recommend restarting antihypertensives at 24 hours in previously hypertensive neurologically stable patients unless contraindicated

When Is It Safe to Lower BP After an Acute Ischemic Stroke for the Purpose of Recurrent Stroke Prevention?

Answer: While awaiting the arrival of more definitive data, the available evidence suggests that it might be reasonable to start oral antihypertensives as soon as 24 to 72 hours after onset of symptoms provided there are no contraindications such as a presumed hemodynamic mechanism of strokeWhat Is the Target BP Goal?Answer: The precise target goal is not definitively known. In the PROGRESS trial, BP was lowered by approximately 10/5 mm Hg, and this BP target has been suggested as a reasonable one for patients according to the AHA/ASA guideline. However, there is variability of absolute BP level and response to BP-lowering by the patient, especially when age is taken into account, and this must be considered before attempting to lower BP. A reasonable goal, if it can be safely achieved after ischemic stroke, is the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) target of <140/90 mm Hg for uncomplicated hypertensive patients and <130/80 mm Hg for those with diabetes mellitus or chronic kidney disease5

Which BP-Lowering Agent Is Most Effective?Answer: Some studies have suggested that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be more effective in recurrent stroke prevention than other antihypertensive agents. The choice of the antihypertensive agent should probably depend more on the associated medical conditions rather than any specific cerebrovascular protective effects of a specific class of antihypertensive agents. β-blockers may have a reduced ability to protect against stroke (particularly atenelol), may favor weight gain, and dyslipidemia and impaired glycemic control Therefore, persons at risk for or with multiple metabolic factors may not be good candidates for β-blocker administration unless they are vasodilator β-blockers, which may not be associated with these latter side effects. Thiazide diuretics also may have dyslipidemic and diabetogenic effects when used at high doses, although this has been questioned by the findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial that failed to support the preference for calcium channel blockers, α-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with metabolic syndrome.The AHA/ASA guideline recommends consideration of a diuretic in combination with an angiotensin-converting enzyme inhibitor

Intracranial pressure treatment algorithm

Morgenstern L B et al. Stroke. 2010;41:2108-2129Copyright © American Heart Association, Inc. All rights reserved.

NameYear of

publication

Initial median blood

pressure (mmHg)

Time to treatment

(hours)Substance Administr

ationStroke

subgroup

BEST 1988 302 n.p. 22–25.3 Atenolol, Propanolol p.o.

Ischemic +

hemorrhagic

INWEST 1994 295 SBP 159–161 10.5–11.5 Nimodipin

e i.v. Ischemic

Rashid et al. 2003 90 SPB 151 51 Glyceryl

Trinitratetransderm

al

Ischemic +

hemorrhagic

IMAGES 2004 2589 MAP 108 7 Magnesium i.v.

Ischemic +

hemorrhagic

CHHIPS 2009 179 SBP 181 17.4–20.5 Labetalol, Lisinopril

p.o., i.v., sublingual

Ischemic +

hemorrhagic

COSSACS 2010 763 SBP 150 23.5 Previously taken AH any

Ischemic +

hemorrhagic

SCAST 2011 2029 SBP 171 17.8 Candesartan p.o.

Ischemic +

hemorrhagic

Important randomised controlled trials of intervention versus control. SBP: systolic blood pressure, MAP: mean arterial pressure, AH: antihypertensive agents, p.o.: per os, i.v.: intravenous, n.p.: not published. (The phase II trial ACCESS comparing candesartan versus placebo has not been included, as the following phase III trial SCAST has been)