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Hemorrhagic Stroke

The Importance of Acute Hypertensive Response in ICH

Adnan I. Qureshi, MD

cute hypertensive response is the elevation of blood

pressure (BP) above normal and premorbid values
that initially occurs within the first 24 hours of symptom
onset in patients with intracerebral hemorrhage (ICH).1
The acute hypertensive response is characterized by its
high prevalence, self-limiting nature, and prognostic significance. To remain consistent with the 2003 World Health
Organization/International Society of Hypertension statement,2 acute hypertensive response is defined as systolic
BP (SBP)140 mmHg demonstrated on 2 recordings taken
5 minutes apart within 24 hours of symptom onset. A total
of 33992 patients (75.0%) had an initial SBP140 mmHg
among 45330 patients presenting with an ICH analyzed in
the National Hospital Ambulatory Medical Care Survey.3
Acute hypertensive response is usually set on the platform
of inadequately treated or undetected chronic hypertension.
However, elevation and spontaneous reduction in the initial BP during the next few days support the role of other
transient and stroke-specific mechanisms. Presumably, the
primary cause of the acute hypertensive response is damage
or compression of specific regions in the brain that mediate autonomic control with functional adaptation during the
next few days.4,5 Hypertensive responses to other factors
are exaggerated and additive because of impaired parasympathetic activity and baroreceptor sensitivity.6 This article
addresses the state of knowledge about acute therapy for
hypertensive response with ICH.
The treatment of acute hypertensive response in ICH has
been controversial for the past 3 decades. The Figure demonstrates the 4 periods of evolution in our understanding of
pathophysiology and treatment. The current notion of treatment is based on the observation that one third of the subjects presenting with ICH demonstrate hematoma expansion
(with subsequent deterioration and death) in the first few
hours after onset.7 An initial SBP of 200 mmHg is associated with hematoma expansion, perihematoma brain edema
formation,8 and increased mortality9 among patients with an
ICH. Recent studies suggest that reduced metabolism (hibernation)10 and preserved autoregulation in the perihematoma
region11 may prevent any ischemic injury associated with SBP
reduction. The current American Stroke Association12 and
European Stroke Initiative13 guidelines recommend reduction
and maintenance of SBP<180 mmHg in patients with an ICH.
A lower limit for safe reduction is undefined. Both guidelines
acknowledge that there may be a subset of patients who can

tolerate more aggressive SBP reduction, such as those with

good neurological status or without chronic hypertension.
Treatment of acute hypertensive response has been
subsequently incorporated as 1 of the 26 quality indicators
related to 18 facets of care to quantify the appropriateness
of medical care.14 The ICH-specific intensity of care
quality metrics14 includes treatment with intravenous
antihypertensive medication for 24 hours after Emergency
Department arrival for elevated BP (SBP180 mmHg) as
a quality parameter on the basis of its high prevalence and
guidelines from professional organizations. The performance
is scored as 1, if SBP target goal is reached within 2.5
hours of the second of the 2 consecutive measurements or
not applicable, and 0, if SBP target range is not achieved.
Treatment success is defined as target BP range achieved
within 2.5 hours of elevated BP detection (on the basis of
the time interval between 2 consecutive SBP180 mmHg
and first SBP<180 mmHg recordings). Actual lowering of
SBP and not the treatment goal specified was chosen because
actual lowering is associated with lower rates of hematoma
expansion and death and disability at 3 months in a previous
study.15 SBP was used to define treatment target because the
present evidence supports the association between SBP and
hematoma expansion.16 No clear relationship with diastolic
BP has been demonstrated. Interestingly, SBP in patients
with an ICH demonstrates greater variability and large
magnitude changes with less prominent changes in diastolic
BP.17 Thus, both diastolic BP and mean arterial pressure may
underestimate dynamic changes in BP in the first 24 hours of
ICH. The quality metrics recommend adequate SBP control
with an infusion for 24 hours after initiation of treatment
(2427 hours after symptom onset), to provide adequate
SBP control during the time that hematoma expansion will
mostly occur. Although the rate of hematoma expansion is
highest in the first 3 hours after symptom onset,18 expansion
occurs in 12% to 37% of patients between 3 and 24 hours
after symptom onset. Early termination of antihypertensive
treatment may lead to poor control of SBP, with subsequent
increase in delayed bleeding. In a validation study, the score
on intensity of care quality metrics in 50 consecutive patients
with an ICH ranged from 17 to 26 points.19 Survival of
patients with an ICH was different in tertiles on the basis of
the performance score with highest survival among tertile of
highest score on the intensity of care quality metrics (100%,
67%, and 55%; P=0.017). The receiver operator curve

Received January 8, 2013; accepted March 4, 2013.

From the Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis, MN.
Correspondence to Adnan I. Qureshi, MD, University of Minnesota, MMC 295, 420 Delaware St SE, Minneapolis, MN 55455. E-mail
(Stroke. 2013;44[suppl 1]:S67-S69.)
2013 American Heart Association, Inc.
Stroke is available at

DOI: 10.1161/STROKEAHA.111.000758

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S68StrokeJune 2013

Figure. Evolution of understanding on acute hypertensive

response in patients with intracerebral hemorrhage (ICH). BP
indicates blood pressure.

demonstrated a high discriminating ability of intensity of care

quality metrics for in-hospital mortality (receiver operator
curve value, 0.73; 95% confidence interval, 0.60.87). In an
exploratory analysis, we adjusted for age, hematoma volume,
initial Glasgow Coma Scale score, and intraventricular
hemorrhage. After adjusting for markers of disease severity,
higher total score on ICH-specific intensity of care quality
metrics continued to demonstrate a relationship with lower
in-hospital mortality (odd ratio, 0.72; 95% confidence
interval, 0.481.06). However, further studies will be
required to determine whether intensity of care or relative
lack of response to treatment because of severity of disease
accounts for this relationship. The current preliminary data
support SBP treatment as a valuable part of intensity of
care among patients with an ICH independent of markers of
disease severity.
More aggressive SBP lowering was initially considered
because an observational study suggested that more aggressive
SBP reduction may have greater benefit in reducing the rate of
hematoma expansion.20 The rate of hematoma expansion was
9% in patients with SBP<150 mmHg and 30% among patients
treated to maintain SBP<160 mmHg or a higher threshold. The National Institute of Neurological Disorders and
Strokefunded Antihypertensive Treatment of Acute Cerebral
Hemorrhage (ATACH)21 trial was a multicenter open-labeled
pilot trial to determine tolerability and safety of 3 escalating
levels of antihypertensive treatment goals for acute hypertensive response in 60 subjects with supratentorial ICH within 6
hours of symptom onset. The observed proportions of neurological deterioration and serious adverse events were below the
prespecified safety thresholds, and the 3-month mortality rate
was lower than expected in all SBP tiers, including the most
aggressive treatment tier (to reduce and maintain SBP<140
mmHg).22 The Intensive Blood Pressure Reduction in Acute
Cerebral Hemorrhage (INTERACT) study was an investigator initiated, blinded outcome, randomized trial that randomized 404 patients with ICH23 with elevated SBP (150 and
<220 mmHg) to either intensive BP management (SBP<140
mmHg) or American Stroke Association-guidelinebased
BP management (SBP<180 mmHg) using available antihypertensive agents. Relative risk of hematoma growth 33%
or 12.5 mL was 36% lower in the intensive group than in
the American Heart Association-guidelinebased BP management group. In subgroup analyses, patients recruited within 3

hours and patients with an initial SBP181 mmHg seemed to

have the greatest benefit with intensive SBP reduction.
After the ATACH I trial22 proved the feasibility and tolerability of intensive SBP reduction, the INTERACT study23
demonstrated attenuation of hematoma expansion with intensive SBP reduction, 2 phase III trials were initiated. In the last
quarter of 2007, the INTERACT phase III was initiated that
combined the data derived from the vanguard phase and the
main phase to perform the final analysis with adequate power.
The trial recruited 2800 patients with acute ICH from 140
centers. The data are being analyzed and anticipated to be
published in 2013. The primary objective of the ATACH II14,24
initiated in 2010 was to determine the efficacy of intensive
BP reduction for acute hypertensive response in 1280 subjects with supratentorial ICH. The primary hypothesis of the
trial is that intensive SBP reduction (SBP<140 mmHg) using
intravenous nicardipine infusion for 24 hours post randomization reduces the proportion of death and disability at 3 months
by >10% compared with standard BP reduction (SBP<180
mmHg) among patients with ICH treated within 4.5 hours of
symptom onset. The ATACH II will provide critically unique
information to address whether the benefit or lack of benefit
is either augmented or unchanged in patients treated within
4.5 hours, those with SBP180 mmHg, or those treated with
a single agent and achieving target SBP at a high rate. The
ATACH study will also provide information about any differential effect between populations, or because of overall intensity of care or threshold for treatment.
The results of the ongoing studies will have direct
implications for 75% of the patients with ICH. SBP treatment
is a strategy that can be made widely available without
specialized equipment or personnel, and can make a major
impact on outcome in patients with ICH. In a post hoc
analysis of ATACH I, we evaluated the effect of SBP reduction
(relative to initial SBP) on poor 3-month outcome (defined as
a modified Rankin scale score of 46) to derive estimates of
treatment benefit.15 The median SBP reduction was 62 mmHg
at 6 hours from treatment initiation. The frequency of poor
3-month outcome was 48% versus 35% in patients having
less (<62 mmHg) versus equal to or more than the median
SBP reduction (62 mmHg) at 6 hours (absolute reduction
of 13%). The lower rate of poor outcome at 3 months was
probably attributed to the lower rate of hematoma expansion
in patients with SBP reduction of 62 mmHg (median value)

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Qureshi Acute Hypertensive Response in ICH S69

at 6 hours from treatment (21% versus 31%, a 10% absolute
reduction). A prominent reduction in morbidity and mortality
may be possible if estimates of treatment effect from our
current pilot trial are accurate.

Dr Qureshi has received funding from the National Institutes of Health
RO1-NS44976-01A2 (medication provided by ESP Parma), American
Heart Association Established Investigator Award 0840053N, National
Institute of Health U01-NS062091-01A2, and the Minnesota Medical
Foundation, Minneapolis, MN.

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Key Words: acute hypertensive response blood pressure clinical trials
hypertension intracerebral hemorrhage stroke

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The Importance of Acute Hypertensive Response in ICH

Adnan I. Qureshi
Stroke. 2013;44:S67-S69
doi: 10.1161/STROKEAHA.111.000758
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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