Acute Blood Pressure Management in Neurocritically

Ill Patients
Caroline Der-Nigoghossian,1 Kimberly Levasseur-Franklin,2 and Jason Makii3*
1
Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York, New York; 2Tufts
Medical Center, Boston, Massachusetts; 3University Hospitals Cleveland Medical Center, Cleveland, Ohio

Optimal blood pressure (BP) management is controversial in neurocritically ill patients due to conflict-
ing concerns of worsening ischemia with decreased BP versus cerebral edema and increased intracra-
nial pressure with elevated BP. In addition, high-quality evidence is lacking regarding optimal BP goals
in patients with most of these conditions. This review summarizes guideline recommendations and
examines the literature for BP management in patients with ischemic stroke, intracerebral hemorrhage,
aneurysmal subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury.
KEY WORDS neurocritical care, blood pressure, stroke.
(Pharmacotherapy 2019;39(3):335–345) doi: 10.1002/phar.2233

Controversy exists regarding appropriate previous reviews evaluating BP management in

blood pressure (BP) management in patients
with acute stroke, traumatic brain injury, spinal
cord injury, and other neurologic emergencies
despite the fact that ischemic stroke (IS) and
intracerebral hemorrhage (ICH) or subarachnoid
hemorrhage account for 24.5% and 4.5% of all
patients with hypertensive crises presenting to
emergency departments, respectively.1 This con-
troversy is due to opposing views regarding
pathophysiologic and epidemiological evidence.
The pathophysiologic concerns with stringent BP
reduction are decreased cerebral perfusion pres-
sure (CPP) and further worsening of the
ischemic injury, whereas epidemiological data
showed that elevated BP is associated with poor
outcomes.2 These outcomes include recurrence,
dependency, and death in patients with IS, and
hematoma expansion, worse functional out-
comes, and death in patients with ICH.2 This
review summarizes the evidence and expands on
Conflict of interest: The authors have declared no con-
flicts of interest for this article.
*Address for correspondence: Jason Makii, Cleveland
Medical Center, University Hospitals, 11100 Euclid Ave-
nue, Mather B400, Cleveland, OH 44106; e-mail: jason.-
makii@uhhospitals.org.
Ó 2019 Pharmacotherapy Publications, Inc.
acute neurologic emergencies.3–5
Literature Search
We performed a search of the PubMed data-
base for English-language literature published
from 2000 to October 2018 using these search
terms: ischemic stroke, intracerebral hemorrhage,
subarachnoid hemorrhage, spinal cord injury, trau-
matic brain injury, hypertension, and blood pres-
sure. We only reviewed studies that evaluated BP
management in these neurologic emergencies
and examined titles and abstracts for possible
inclusion. Relevant references of guidelines and
peer-reviewed articles were also examined.
Cerebral Autoregulation and Pathophysiology
The uninjured brain has the capacity to
autoregulate and will maintain a constant cere-
bral blood flow (CBF) of 50 ml/100 g/minute of
brain tissue, despite a wide CPP range between
50 and 150 mm Hg. This occurs by adjustment
of the cerebral vascular resistance through neu-
romyogenic changes of the precapillary arteriole
diameter to maintain cerebral homeostasis (Fig-
ure 1).5 In patients with chronic hypertension,
the autoregulation curve is shifted to the right,
and their brains will adjust at higher CPP
336 PHARMACOTHERAPY Volume 39, Number 3, 2019

thresholds. Beyond the limits of autoregulation,

the CBF follows the CPP in a linear fashion. Blood Pressure Control in Neurologic
Therefore, below the lower limit of autoregula- Emergencies
tion, pressure passive vascular collapse and
ischemia will occur, and above the higher limit, Acute Stroke
pressure passive vasodilation will result in an Elevated BP is common in the acute stroke
increased cerebral blood volume and therefore setting, and up to 80% of patients with IS and
intracranial pressure (ICP).6 75% of patients with ICH present with hyperten-
During acute neurologic emergencies, cere- sion, regardless of a previous hypertension
brovascular autoregulation can be impaired, diagnosis.2, 8, 9 This acute hypertension usually
and the CBF becomes pressure passive. There- resolves spontaneously within 10 days after the
fore, small changes in the mean arterial pres- event.10 It is unknown if the hypertension
sure (MAP) can predispose patients to exhibited is a response mechanism to maintain
increased risk of ischemia or cerebral edema, collateral blood flow to the ischemic penumbra
and strict BP control is essential to prevent or perihematoma area or if it is a marker of the
further damage.5 stroke severity.11
Multiple mechanisms have been postulated to The relationship between admission BP and
explain the elevation in systemic vascular resis- mortality was researched in a prospective study
tance and therefore BP during acute neurologic of stroke patients.11 The study demonstrated a
emergencies. These include failure of the arterial U-shaped relationship where either high and low
baroreceptor reflex due to damage in the areas systolic or diastolic blood pressure (SBP and
of the brain that regulate cardiovascular function DBP, respectively) was associated with higher
and activation of the neuroendocrine system mortality at 1 and 12 months. Death from car-
including the renin-angiotensin-aldosterone diovascular disease was more frequent in
system, the sympathetic autonomic nervous sys- patients with low admission SBP, whereas death
tem, and hypothalamic-pituitary-adrenal axis. from neurologic damage including cerebral
Another described mechanism is the Cushing edema, mass effect, and transtentorial herniation
reflex that leads to elevation of BP in the setting was more frequent with high admission SBP. An
of elevated ICP.4–7 SBP range of 121–140 mm Hg in patients with

Passive Vasodilatory Zone of Normal Autoregulation

Collapse Cascade Zone Autoregulation Breakthrough Zone

VASCULAR CALIBER

75 60
ICP (mm Hg)
Cerebral Blood Flow
(ml/100 g/min)

50 40

25 20

25 50 75 100 125 150 175

Cerebral Perfusion Pressure (mm Hg)

Figure 1. Cerebral blood flow (black line) and intracranial pressure (ICP; gray line) changes as cerebral perfusion pressure
(CPP) decreases or increases. The uninjured brain has the capacity to autoregulate and will maintain a constant cerebral
blood flow (CBF) of 50 ml/100 g/minute of brain tissue, despite a wide CPP range of 50–150 mm Hg. Beyond the limits of
autoregulation, the CBF follows the CPP in a linear fashion. Therefore, below the lower limit of autoregulation, passive
vascular collapse and ischemia will occur, and above the higher limit, passive vasodilation will result in an increase cerebral
blood volume and therefore ICP. Cerebral vascular resistance adjusts through neuromyogenic changes of the precapillary
arteriole diameter to maintain cerebral homeostasis. (From reference 5 with permission).
 ACUTE BLOOD PRESSURE IN NEUROCRITICAL CARE Der-Nigoghossian et al.
IS and 141–160 mm Hg in patients with ICH
was associated with the lowest mortality.
Another emerging therapeutic consideration
associated with worse outcomes is blood pres-
sure variability (BPV) that could vary depending
on the degree of impairment in cerebral autoreg-
ulation. A systematic review and meta-analysis
of seven studies evaluating the effect of BPV
after acute stroke showed that greater systolic
BPV measured early from IS or ICH onset was
associated with poor longer term functional out-
comes.12
Key determinants of hypertension manage-
ment in patients with acute stroke include the
timing and type of stroke, use of thrombolysis,
and concurrent medical conditions.
Ischemic Stroke Candidates for Intravenous Throm-
bolysis
Treatment guidelines recommend a BP lower
than 185/110 mm Hg before thrombolysis
administration based on the inclusion criteria of
the intravenous thrombolysis trials; a BP lower
than 180/105 mm Hg is recommended after
thrombolysis administration (Table 1).2, 9, 13 A
retrospective analysis of the Safe Implementation
of Thrombolysis in Stroke-International Stroke
Thrombolysis Registry (SITS-ISTR) analyzed the
relationship between postthrombolysis SBP and
symptomatic ICH, mortality, and functional out-
comes.14 This study demonstrated a linear rela-
tionship between SBP and symptomatic
hemorrhage, and a U-shaped relationship was
found between SBP and both mortality and inde-
pendence at 3 months, with most favorable
functional outcomes seen in the range of 141–
150 mm Hg. The Enhanced Control of Hyper-
tension and Thrombolysis in Stroke Study
(ENCHANTED-BP) is an ongoing study evaluat-
ing the effect of lowering SBP to 130–140 mm
Hg compared with 180 mm Hg in this patient
population.15
Ischemic Stroke Patients Not Candidates for Intra-
venous Thrombolysis
BP lowering is not recommended in patients
who are not candidates for intravenous throm-
bolysis and who present with a BP of 220/
110 mm Hg or lower (Table 1).2, 9, 13 This is
based on multiple studies that have evaluated
the benefit of starting different classes of antihy-
pertensives within the first 24–72 hours of
337
stroke onset.16–20 These studies did not find a
benefit in functional outcomes with antihyper-
tensive initiation, and one study found worse
functional outcomes with DBP reduction of 20%
or more or DBP of 60 mm Hg or lower
(Table 2).20
Guidelines state that it might be reasonable to
lower BP by 10–15% in the first 24 hours in
patients who present with a BP higher than 220/
110 mm Hg (Table 1).2, 9, 13 However, patients
with severe hypertension (most commonly
higher than 220/120 mm Hg) were excluded
from clinical trials evaluating BP lowering after
IS. Therefore, although BP reduction has been
advised for these patients, the benefit in the
absence of comorbid conditions has not been
studied. These thresholds for treatment were
arbitrarily chosen based on the upper limits of
normal cerebral autoregulation.9
Ischemic Stroke Patients Treated with Mechanical
Thrombectomy
Optimal BP control in patients receiving
mechanical thrombectomy has not been formally
evaluated. Although clinicians would be inclined
to maintain prethrombectomy BP elevated to opti-
mize CBF, the American Heart Association/Amer-
ican Stroke Association (AHA/ASA) IS guidelines
recommend a BP of 185/110 mm Hg or lower
before the procedure in these patients even if
intravenous thrombolysis is not administered
(Table 1).9 This is based on the inclusion criteria
of the randomized controlled trials that showed
functional outcome benefits with mechanical
thrombectomy using stent retrievers (REVASCAT,
SWIFT PRIME, EXTEND-IA, THRACE, MR
CLEAN, DEFUSE 3, and DAWN trials).21–28 In
addition, the guidelines do not provide recom-
mendations for BP management after thrombec-
tomy, and BP goals were not protocolized in most
trials. REVASCAT and DAWN were the only trials
describing specific BP goals after thrombectomy
depending on the Thrombolysis in Cerebral
Infarction (TICI) grade. For patients achieving
successful recanalization, defined as a TICI grade
of 2b or 3, BP was maintained at lower than 160/
90 mm Hg in the REVASCAT trial and SBP at
140 mm Hg during the first 24 hours in the
DAWN trial to minimize the risk of reperfusion
hemorrhage.21, 28 For unsuccessful recanaliza-
tion, defined as a TICI grade of 2a or lower, BP
was managed similarly to patients who did not
undergo mechanical thrombectomy in the latter
338
Table 1. Target BP Guideline Recommendations for Patients with Ischemic Stroke and Intracerebral Hemorrhage
Ischemic stroke
Patient characteristics
IV thrombolysis
candidate
No IV thrombolysis
and BP ≤ 220/110 mm Hg
No IV thrombolysis and
BP > 220/110 mm Hg
Intraarterial therapy and
no IV thrombolysis
PHARMACOTHERAPY Volume 39, Number 3, 2019
2003 JNC 7 guideline13
< 185/110 mm Hg
before and < 180/105 mm
Hg after thrombolysis
administration
No recommendation
If SBP > 220 or
DBP ≥ 120 mm Hg:
Lower BP by 10–15%
No recommendation
2017 ACC/AHA guideline2
< 185/110 mm Hg before
and < 180/105 mm Hg
after thrombolysis
administration
No benefit of reinitiating
antihypertensives in
first 48–72 hrs
Might be reasonable to
lower BP by 15% during
first 24 hrs
No recommendation
2018 AHA/ASA guideline9
< 185/110 mm Hg before
and < 180/105 mm Hg after
thrombolysis administration
No benefit of reinitiating
antihypertensives in first 48–72 hrs
Might be reasonable to lower
BP by 15% during first 24 hrs
BP ≤ 185/110 mm Hg before
the procedure

Intracerebral hemorrhage
2003 JNC 7
guideline13 2015 AHA/ASA guideline8 2017 ACC/AHA guideline2
SBP 150–220 mm Hg No recommendation Acute lowering of SBP to 140 mm Lowering SBP to lower than 140 mm
Hg is safe and can be effective Hg within 6 hrs of onset is not
for improving functional outcomes beneficial and can be harmful
SBP > 220 mm Hg No recommendation Reasonable to use continuous IV Reasonable to consider aggressive
infusion to lower SBP with close reduction with continuous IV infusion
monitoring and close BP monitoring
ACC = American College of Cardiology; AHA = American Heart Association; ASA = American Stroke Association; BP = blood pressure;
DBP = diastolic blood pressure; IV = intravenous. JNC 7 = Seventh Report of the Joint National Committee on Prevention, Detection, Evalua-
tion, and Treatment of High Blood Pressure; SBP = systolic blood pressure.

Table 2. Summary of Trial Data for BP Lowering in Patients with Acute Ischemic Stroke without Intravenous Thrombolysis
Year of No. of Inclusion Intervention Time to
publication patients criterion for BP, mm Hg drug class response, hrs Key findings
2015 16
393 SBP 150–185 ARB < 48 No significant difference in mRS
scores ≥ 3 at 90 days
201517 1733 SBP ≥ 140 ARB < 30 No significant difference in mRS scores
201418 2038 SBP 140–220 All kinds < 24 No significant difference in mRS
scores ≥ 3 at 14 days or hospital
discharge
200919 1360 SBP 121–180, DBP ≤ 110 ARB < 72 No significant difference in mRS
scores ≥ 3 at 30 days
200020 265 Mean SBP 160, mean DBP 89 Nimodipine < 24 Worst functional outcomes with DBP
reduction of ≥ 20% or
DBP ≤ 60 mm Hg
ARB = angiotensin II receptor blocker; BP = blood pressure; DBP = diastolic blood pressure; mRS = modified Rankin Scale; SBP = systolic
blood pressure.

study.28 To date, one observational study on BP
levels after mechanical thrombectomy was evalu-
ated in consecutive patients with large-vessel
occlusion.29 A 10 mm Hg increment maximum
SBP in the first 24 hours after mechanical
thrombectomy was associated with a higher odds
of 3-month mortality and functional dependence.
In addition, BP lower than 160/90 mm Hg was
independently associated with a lower 3-month
mortality in comparison with permissive hyper-
tension (lower than 220/110 mm Hg or lower
than 180/105 mm Hg when pretreated with
intravenous thrombolysis). Until prospective ran-
domized trials evaluate optimal BP control in this
patient population, it would be reasonable to fol-
low the goals used in these trials.
Intracerebral Hemorrhage
Elevated BP in patients with ICH was associ-
ated with poor outcomes including hematoma
expansion, perihematoma edema, worse func-
tional outcomes, and death.30–33
 ACUTE BLOOD PRESSURE IN NEUROCRITICAL CARE Der-Nigoghossian et al.
There is also the concern that by reducing BP,
the CPP will also decrease, potentially resulting
in worsening ischemic injury to the perihe-
matoma area. However, studies have suggested
that hypometabolism, also known as hiberna-
tion, and preserved autoregulation in this area
may prevent ischemia in these patients. The
Intracerebral Hemorrhage Acutely Decreasing
Arterial Pressure Trial (ICH ADAPT) showed
that perihematoma CBF was maintained with
SBP reduction to lower than 150 mm Hg.34 The
Intensive Blood Pressure Reduction in Acute
Cerebral Hemorrhage Trial (INTERACT) and
Antihypertensive Treatment of Acute Cerebral
Hemorrhage (ATACH) trials suggested that acute
BP lowering in the acute setting is feasible and
safe.35, 36 INTERACT-1 was a pilot trial that
randomized patients with ICH within 6 hours of
onset to a target SBP of either 140 mm Hg (in-
tensive group) or 180 mm Hg (standard treat-
ment group).35 Proportional change in
hematoma volume at 24 hours was not signifi-
cantly different between both groups after
adjustment for initial hematoma volume and
time from symptom onset to computed tomogra-
phy scan. An absolute risk reduction of hema-
toma growth of 8% was seen in the intensive
group. ATACH-1 was a small dose-escalation
phase I trial that used intravenous nicardipine to
achieve three tiers of SBP goals for 24 hours
after onset.36 Neurologic deterioration, defined
as a decline in Glasgow Coma Scale score by 2
or more or an increase in National Institutes of
Health Stroke Scale score of 4 or higher within
24 hours, was low in all groups. INTERACT-2, a
phase III trial randomized patients to a
SBP lower than 140 versus lower than 180 mm
Hg within 6 hours of symptom onset.37 The
study demonstrated no significant reduction in
the rate of death or severe disability with inten-
sive BP treatment; however, the study found a
shift toward improved functional outcomes in a
prespecified ordinal analysis of the modified
Rankin Scale. It is noteworthy to mention that at
1 hour, only 33% of patients in the intensive
group achieved the target BP goal, and the mean
SBP was 150 and 164 mm Hg in the intensive
and standard treatment groups, respectively. The
more recent ATACH-2 trial failed to demonstrate
improved functional outcomes with intensive BP
lowering within 4.5 hours of symptom onset.38
The mean minimum SBP during the first
2 hours was 129 and 141 mm Hg in the inten-
sive and standard treatment groups, respectively.
In addition, a higher rate of renal adverse events
339
occurred within 7 days in the intensive BP
group (Table 3). The major differences between
the ATACH-2 and INTERACT-2 trials are worth
mentioning. The SBP profile of the intensive
group in the INTERACT-2 trial was similar to
the control group of the ATACH-2 trial. In addi-
tion, the ATACH-2 trial achieved larger BP
reduction because it included patients with an
SBP of 180 mm Hg or higher compared with an
SBP of 150 mm Hg or higher, and achieved a
lower mean SBP than in the INTERACT-2 trial.
This could explain the higher incidence of renal
adverse events found in the study.39 Subsequent
trials shed further light on the safety of acute BP
lowering in patients with ICH.40, 41 One retro-
spective analysis showed that an SBP reduction
of more than 90 mm Hg increases the risk of
acute kidney injury (AKI) irrespective of previ-
ous kidney function.40 Another analysis evalu-
ated the impact of the degree of admission
hypertension on renal outcomes in this patient
population.41 Patients with severe hypertension
(SBP of 220 mm Hg or higher) were found to
have higher rates of AKI compared with patients
with mild or moderate admission hypertension.
Although the 2015 AHA/ASA ICH guidelines
recommended that it is reasonable to lower the
SBP to 140 mm Hg based on the findings of the
INTERACT-2 trial, the more recent 2017 AHA
hypertension guidelines recommend against low-
ering the SBP to lower than 140 mm Hg based
on the results of the ATACH-2 trial (Table 1).8
Due to the known harm associated with hyper-
tension in this patient population and minor
safety concerns associated with BP reduction,
SBP lowering is still recommended. To decrease
the risk of AKI with BP lowering, a stepwise BP
reduction can be recommended in patients with
an admission SBP higher than 220 mm Hg. The
ongoing Intracerebral Hemorrhage Acutely
Decreasing Arterial Pressure Trial II (ICH
ADAPT II) study will further evaluate the effect
of BP lowering on ischemic injury after ICH.42
Further research is needed to evaluate the
effect of intensive BP management in patients
with large intraventricular hemorrhage or large
hematoma volume, and, when administered,
intraventricular fibrinolysis therapy.
Aneurysmal Subarachnoid Hemorrhage
Aneurysmal subarachnoid hemorrhage (aSAH)
occurs less frequently than acute IS, and the BP
goals for optimal outcomes vary depending on at
what point the patient is being treated within
340 PHARMACOTHERAPY Volume 39, Number 3, 2019
Table 3. Summary of Trial Data for BP Lowering in Patients with Intracerebral Hemorrhage
Inclusion Time to
No. of criterion for response,
patients SBP, mm Hg hrs Target SBP, mm Hg Pharmacologic agent Key findings
4045 150–220 ≤6 < 140 (intensive Per protocol based Decreased hematoma
group) on agent availability: IV growth in intensive
vs < 180 urapidil, furosemide (35%), group by 8%
(standard nitroglycerin (13%)
treatment group)
6036 ≥ 170 ≤6 Tier 1:170–200 IV nicardipine Low rates of neurologic
Tier 2: 140–170 deterioration and serious
Tier 3: 110–140 adverse events in
patients in all tiers
279437 150–220 ≤6 < 140 vs < 180 Per protocol based on agent No significant difference
availability: IV urapidil (33%), in mRS scores 3–6
nicardipine (16%), nitroglycerin at 90 days
(15%), labetalol (14%), furosemide Prespecified ordinal
(12%), nitroprusside (12%) analysis showed
significant improvement
100038 ≥ 180 ≤ 4.5 110–139 IV nicardipine No significant difference
(intensive group) in mRS scores 4–6
vs 140–179 (standard at 90 days
treatment group) Higher rate of renal
adverse events in
intensive group
IV = intravenous; mRS = modified Rankin Scale; SBP = systolic blood pressure.

the disease state. For BP management, the 2012
AHA/ASA aSAH guidelines recommend that BP
should be controlled to limit the risk of rebleed-
ing but still allow appropriate CPP to prevent
ischemia from occurring.43 Rebleeding is one of
the most devastating complications to occur fol-
lowing the initial aneurysm rupture. It is associ-
ated with a high mortality rate and a low
likelihood of functional recovery. This complica-
tion is most likely to occur within the first
2–12 hours but may occur at any point until
obliteration of the aneurysm is performed. To
our knowledge, no robust data are available on
what optimal BP limit should be used between
time of presentation and obliteration of the
aneurysm, but there appears to be a higher inci-
dence of rebleeding when SBP is above 160 mm
Hg. A systematic review and meta-analysis
included five studies specific to evaluating BP
trends and risk for rebleeding after aSAH.44
Three of the studies defined high BP as SBP
higher than 140 mm Hg, and two of the three
showed no significant difference in rebleeding
occurrence. The third used a tiered approach to
define high BP including a range of 140–
170 mm Hg and higher than 180 mm Hg. The
reviewers conducted a meta-analysis of this third
study, and the remaining two studies using a
high BP definition of higher than 160 mm Hg,
and patients with SBP higher than 160 mm Hg
had a higher incidence of aneurysm rebleed.
Once aneurysm obliteration occurs, the upper
limit SBP of 160 mm Hg is typically removed to
allow for optimal CPP given the risk of rebleed-
ing is now minimized.
Cerebral vasospasm is a common complica-
tion that occurs starting 3–4 days after aneurysm
rupture, peaks at 7–10 days, and dissipates past
21 days.43 Vasospasm may lead to delayed cere-
bral ischemia that results in worsening func-
tional outcomes and increased risk of death. If
cerebral vasospasm occurs, treatment involves
hemodynamic augmentation, specifically main-
taining euvolemia, and using vasopressor ther-
apy, if needed, to increase cardiac output and
ultimately optimize cerebral perfusion to the
area in spasm with the goal of minimizing
ischemic damage and preventing delayed cere-
bral ischemia.43, 45 To our knowledge, no robust
data are available from published studies that
provide a goal SBP that will accomplish the
intent of induced hypertension. Induced hyper-
tension (MAP elevations) to achieve CPP targets
of 80–120 mm Hg were shown to improve cere-
bral oxygenation in the setting of cerebral vasos-
pasm.46 Studies defined elevations of SBP to
greater than 220 mm Hg for induced hyperten-
sion with no resolution of clinical symptoms as
treatment refractory, and alternative treatments
for vasospasm should be pursued.46, 47 Specific
 ACUTE BLOOD PRESSURE IN NEUROCRITICAL CARE Der-Nigoghossian et al.
goal BP augmentation will be patient specific,
based on cerebral vasospasm severity, symptom
resolution with BP elevation, and minimization
of untoward effects from elevated BP.
Traumatic Brain and Spinal Cord Injury
The concepts of maintaining and optimizing
blood flow to injured areas in patients with trau-
matic brain injury (TBI) or acute spinal cord
injury (ASCI) are of utmost importance. In
patients with ASCI or TBI, the objective is to
minimize secondary injury to damaged tissue by
avoiding systemic hypotension and optimizing
perfusion via MAP or CPP, as necessary.
It is well established that hypotension is an
independent risk factor for worse functional out-
comes and mortality in patients with severe
TBI.48 Avoiding hypotension and subsequent
hypoxia has been a mainstay of severe TBI man-
agement. Historically, hypotension for TBI
patients was defined as SBP lower than 90 mm
Hg; however, the most recent Brain Trauma
Foundation guidelines suggest maintaining an
SBP of 100 mm Hg or higher for patients aged
50–69 years and an SBP of 110 mm Hg or
higher for patients aged 15–49 and 70 years and
older as a level III recommendation.49 This
change in BP definition was based on a study
conducted as a retrospective cohort of 15,733
patients, 26.9% of whom had severe TBI.48
Based on the investigators’ evaluation of BP
ranges and conclusions from each BP range for
each group, the BP thresholds just mentioned
were defined based on at what point a lower
mortality rate was observed. Two additional
studies supported the concept that potentially
using a higher BP threshold may positively affect
functional outcomes and mortality. The first was
conducted in 60 patients with severe TBI at a
single level I trauma center in the United
States.50 The continuous BP data from these
patients were collected. Defined hypotension
thresholds were set at SBP lower than 90 mm
Hg, SBP lower than 100 mm Hg, SBP lower than
110 mm Hg, and SBP lower than 120 mm Hg.
Patients who had SBPs within each of these
groups did not overlap with each other. The
purpose was to assess if patients with different
trends of SBP variation fitting within each group
correlated with mortality and negative functional
outcomes, using the extended Glasgow Outcome
Scale at 12 months after injury. Based on the
results of this study, the authors concluded that
within the first 48 hours of intensive care unit
341
admission, hypotension defined as SBP lower
than 110 mm Hg and SBP lower than 120 mm
Hg were associated with mortality and worse
functional outcome differences. Of note, signifi-
cant mortality differences were not seen within
the SBP lower than 90 mm Hg or lower than
100 mm Hg groups. The authors concluded that
the lack of difference seen from these two lower
SBP groups may have been due to the TBI man-
agement protocols at this single institution in
addition to very small patient numbers within
these two groups (less than 20% of all patients).
The second study was an International Mission
of Prognosis and Analysis of Clinical Trials in
TBI (IMPACT) database review of the individual
patient data from three observational studies and
eight randomized controlled trials that evalu-
ated Glasgow Outcome Scale at 6 months after
injury.51 Based on this review, the authors con-
cluded that SBP ranges from 120–150 mm Hg
and MAP ranges from 85–110 mm Hg may be
the thresholds to consider to improve functional
outcomes. These higher SBP thresholds above
90 mm Hg have not been universally accepted,
however, given the limited evidence to support
such changes without clear functional outcome
and mortality benefit.52
Hypotension is commonly associated with
ASCI due to a variety of pathophysiologic rea-
sons including hypovolemia due to trauma or
level of injury to the spinal cord and subsequent
nerve innervation potentially affected. Abundant
data on a target BP threshold when managing
patients with ASCI are lacking.53 The principle
of avoiding hypotension to minimize secondary
injury via hypoxia for patients with ASCI is lar-
gely based on animal data and studies examining
hypotension effects on patients with severe TBI.
Similarly, evidence that autoregulation of spinal
cord blood flow is compromised after injury has
also been supported based on laboratory data.
Although to our knowledge no prospective stud-
ies have evaluated systemic hypotension and
outcomes after ASCI, the data that do exist are
based on six published case series describing
small numbers of patients at single centers.53
The results of these case series suggest that
hypotension (defined as SBP lower than 90 mm
Hg) should be avoided, and maintenance of
MAP at 85–90 mm Hg for the first 7 days after
ASCI may improve perfusion to the spinal cord.
To our knowledge, no data exist confirming that
maintaining MAP at these suggested thresholds
will lead to improved neurologic functional
outcomes.
342 PHARMACOTHERAPY Volume 39, Number 3, 2019
Table 4. Intravenous Antihypertensives for the Management of Neurocritically Ill Patients
Pharmacologic
Antihypertensive class Dosage Onset, min Duration Special considerations
Labetalol a1-, b1-, and Initial: 10–20 mg IV 5 3–6 hrs • Adverse effects: bradycardia
b2-antagonist bolus dose; may double • Prolonged hypotension can
dose up to 80 mg/dose occur with higher doses
to a total maximum
dose of 300 mg
Continuous infusion:
0.5–2 mg/min
Nicardipine Dihydropyridine Initial: 5 mg/hr 5–10 30 min–4 hrs • Low adverse effect profile
L-type calcium Titrate by 2.5 mg/hr • Adverse effect: reflex tachy-
channel blocker every 5–15 min cardia
Maximum: 15 mg/hr • Can lead to large volume
administration
• Avoid in patients with
advanced aortic stenosis
Clevidipine Dihydropyridine Initial: 1–2 mg/hr 2–4 5–15 min • Invasive BP monitoring rec-
L-type calcium Titrate by doubling ommended
channel blocker dose every 90 sec • Formulated with 20% fat
initially, then every 5– emulsion (2 kcal/ml)
10 min when closer to • Adverse effects: hyper-
goal BP triglyceridemia and reflex
Maximum: 32 mg/hr tachycardia
• Use with caution in patients
with allergy to soy or eggs
Hydralazine Arterial Initial: 10–20 mg IV; 10 1–4 hrs • Recommended in pregnant
vasodilator may repeat in 20– (can be up patients
(minimal venous 40 min to 12 hrs) • Unpredictable dose
effect) response
• Adverse effects: reflex
tachycardia
Nitroprusside Arterial and Initial: 0.25–0.5 mg/kg/ <2 1–2 min • Invasive BP monitoring rec-
venous min ommended
vasodilator Titrate by 0.5 mg/kg/ • Cyanide toxicity in patients
min every 5 min with liver failure and thio-
Maximum: 10 mg/kg/ cyanate toxicity in patients
min (for 10 min) with renal failure
• Can lead to elevated ICP
• Can result in coronary steal
Nitroglycerin Arterial and Initial: 10–20 lg/min 2–5 5–10 min • Not commonly used due to
venous Titrate by 10–20 lg/ tachyphylaxis
vasodilator (more min every 5–15 min • Adverse effects: flushing,
venous effects) Maximum: 400 lg/min headache, erythema
BP = blood pressure; ICP = intracranial pressure; IV = intravenous.

Pharmacologic Agent Selection

Characteristics of the ideal agent for BP man-
agement in the acute setting include a rapid
onset of action, reliable response, low BPV, and
a minimal adverse effect profile. A summary of
the commonly used intravenous antihyperten-
sives is provided in Table 4. The intravenous
dihydropyridine calcium channel blockers
nicardipine and clevidipine are commonly used
for the treatment of hypertension in neurocriti-
cally ill patients due to their favorable adverse
effect profiles. They inhibit the influx of calcium
in vascular smooth muscle, causing vasodilation.
The main difference between agents is that clev-
idipine exhibits a faster onset of action and
shorter half-life due to its metabolism by plasma
esterases. In addition, patients receiving clev-
idipine typically receive less fluid volume com-
pared with nicardipine based on its
concentration and dose required. Lastly, clev-
idipine is formulated in a lipid emulsion; there-
fore, it is recommended to use less than
 ACUTE BLOOD PRESSURE IN NEUROCRITICAL CARE Der-Nigoghossian et al.
1000 ml in 24 hours, monitor triglyceride levels,
and adjust patients’ nutrition to account for the
amount of lipid infused (2 kcal/ml).54 b-Block-
ers are another pharmacologic class used for the
management of hypertensive emergencies. Labe-
talol is a combined a1- and b-antagonist with an
a1:b ratio of 1:7 when administered intra-
venously compared with a 1:3 ratio for oral
administration. Labetalol can be administered as
intravenous bolus doses or a continuous infu-
sion. Even though a labetalol continuous infu-
sion is thought to be safe, overtreatment and
prolonged hypotension, at doses of more than
300 mg/day, were reported due to its prolonged
half-life.55 Other agents that are less commonly
used include sodium nitroprusside, nitroglyc-
erin, and hydralazine. Sodium nitroprusside is
not a preferred agent for BP management in
patients with neurologic emergencies due to its
association with elevated ICP. This is thought to
occur through dilation of cerebral blood vessels,
leading to an increase in cerebral blood volume
and impairment of cerebral autoregulation.56–59
It also has other potential adverse effects includ-
ing cyanide and sodium thiocyanate toxicity
with prolonged infusions, especially in patients
with liver and renal impairment, respectively. A
Premier database retrospective analysis compar-
ing nitroprusside and nicardipine treatment dur-
ing the first 24 hours in patients with ICH
found that nitroprusside use was associated with
higher in-hospital mortality after adjustment for
baseline risk of mortality.57 Hydralazine is a
peripheral arterial vasodilator with an unpre-
dictable response and prolonged duration of
action rendering it another less favorable option.
Finally, nitroglycerin is a primarily venous
vasodilator that is infrequently used in the neur-
ocritically ill due to hemodynamic and antiangi-
nal tolerance that develops within 24–48 hours
of continuous infusion therapy.54
A few studies have evaluated the use of differ-
ent antihypertensives in the management of neu-
rocritically ill patients. A retrospective analysis
of 90 patients with acute stroke (54% ICH, 22%
aSAH, and 23% IS) receiving labetalol or
nicardipine for hypertension management found
that nicardipine was associated with less BPV
and dosage adjustment, and it required adminis-
tration of less additional hypertensive agents in
the first 24 hours of therapy.60 The same
authors conducted a prospective pseudo-rando-
mized study comparing both agents in 54
patients with acute stroke presenting to the
emergency department.61 This study confirmed
343
the results of the retrospective analysis.60 All
patients in the nicardipine group achieved goal
BP within 60 minutes compared with 61% of
patients in the labetalol group.61 In addition,
patients in the nicardipine group spent more
time within the goal BP and had less BPV. Simi-
lar results were found in patients with aSAH,
and nicardipine was associated with longer time
within MAP goal range, faster response, and less
treatment failure than labetalol.62 However, this
study did not find a significant difference in BPV
between both groups. A retrospective analysis of
272 patients diagnosed with ICH and receiving
labetalol, hydralazine, and/or nicardipine within
24 hours of hospital admission evaluated their
effects on BPV.63 This study showed that
nicardipine use was associated with less BPV
and a higher likelihood to achieve an SBP goal
lower than 140 mm Hg. Clevidipine and
nicardipine were compared in a retrospective
analysis of 57 neurocritically ill patients.64 The
investigators found no significant difference in
the time to target SBP or percentage time within
target BP range between both groups, but
nicardipine administration was associated with a
higher volume infused.
Due to the lack of high-quality evidence
comparing the effect of different antihyperten-
sives on patient outcomes, treatment guidelines
do not recommend a specific agent for the
management of BP in the acute setting.2, 9, 13
The AHA IS guidelines list different options for
acute BP reduction including labetalol intermit-
tent dosing or continuous infusion, and
nicardipine or clevidipine continuous infu-
sions.9 Nicardipine and clevidipine offer a more
favorable adverse effect profile, faster onset,
lower BPV, and higher maintenance of BP goal
compared with other antihypertensives. There-
fore, these agents can be used preferentially in
this patient population.
Conclusion
Strict BP control is essential in patients with
neurologic emergencies to maintain adequate
CPP and minimize ischemia in zones of
impaired cerebral autoregulation. Hypertension
is associated with worse outcomes in patients
with acute IS and ICH. Despite minor safety
concerns, acute BP reduction is still recom-
mended in patients with ICH. Similarly, acute
BP control is essential for patients with aSAH to
avoid rebleeding and to minimize delayed cere-
bral ischemia, noting that BP goals will change
344 PHARMACOTHERAPY Volume 39, Number 3, 2019
depending on aneurysm obliteration and the
incidence of cerebral vasospasm. Lastly, for sev-
ere patients with TBI and ASCI, avoiding
hypotension is of utmost importance; however,
the target SBP or MAP threshold in these
patients is still controversial.
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