Pharmacologic Treatment of Hypertensive Urgency

in the Outpatient Setting: A Systematic Review

Claudia L. Campos, MD1, Charles T. Herring, PharmD, BCPS, CPP1,2, Asima N. Ali, PharmD1,2,
Deanna N. Jones, MD1, James L. Wofford, MD, MS1, Augustus L. Caine, MD1,
Robert L. Bloomfield, MD, MS1, Janine Tillett, MSLS AHIP1, and Karen S. Oles, PharmD, MS, BCPS, CPP1
1
Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, NC, USA; 2Campbell University College of Pharmacy & Health Sciences,
Buies Creek, NC, USA.

BACKGROUND: Hypertensive urgency (HU), defined as KEY WORDS: hypertension; hypertensive urgency; cardiovascular disease.
acute severe uncontrolled hypertension without end- J Gen Intern Med 33(4):539–50
organ damage, is a common condition. Despite its associ- DOI: 10.1007/s11606-017-4277-6
ation with long-term morbidity and mortality, guidance © The Author(s) 2018. This article is an open access publication
regarding immediate management is sparse. Our objec-
tive was to summarize the evidence examining the effects
of antihypertensive medications to treat.
INTRODUCTION
METHODS: We searched the PubMed, Cochrane Central
Register of Controlled Trials (CENTRAL), Database of Hypertensive urgency (HU) is defined as systolic blood pres-
Abstracts of Reviews of Effects (DARE), Cochrane Data- sure of at least 180 mmHg and/or diastolic blood pressure of at
base of Systematic Reviews, Web of Science, Google Schol- least 110 mmHg, without associated end-organ damage.1
ar, and Embase through May 2016. Study selection: We
Patients with HU may be completely asymptomatic or may
evaluated prospective controlled clinical trials, case–con-
trol studies, and cohort studies of HU in emergency room
present with symptoms such as headache, epistaxis, faintness,
(ER) or clinic settings. We initially identified 11,223 pub- malaise, psychomotor agitation, nausea, or vomiting.2
lished articles. We reviewed 10,748 titles and abstracts Up to 65 million Americans have hypertension; about 1%
and identified 538 eligible articles. We assessed the full will have an episode of HU during their lives. The prevalence
text for eligibility and included 31 articles written in En- of HU in emergency room (ER) or office settings is estimated
glish that were clinical trials or cohort studies and provid- at 3–5%.3, 4 In a recent cohort study, cardiovascular events
ed blood pressure data within 48 h of treatment. Studies were found to occur in less than 1% of patients within a 6-
were appraised for risk of bias using components recom-
month period.4
mended by the Cochrane Collaboration. The main out-
come measured was blood pressure change with antihy- Guidance for immediate management of HU is unclear,
pertensive medications. Since studies were too diverse since there is no consensus on the optimal target for acute
both clinically and methodologically to combine in a blood pressure reduction or the time frame for achieving a
meta-analysis, tabular data and a narrative synthesis of normal blood pressure range. Most patients receive drug ther-
studies are presented. apy for elevated blood pressure within the first 48 h of pre-
RESULTS: We identified only 20 double-blind random- sentation.2–4 Knowledge of the effectiveness and safety of
ized controlled trials and 12 cohort studies, with 262
different medication choices and associated comorbidities is
participants in prospective controlled trials. However, we
could not pool the results of studies. In addition, comor- crucial for clinicians, especially generalists.
bidities and their potential contribution to long-term The aim of this systematic review is to summarize evidence
treatment of these subjects were not adequately of the benefits and harms associated with antihypertensive
addressed in any of the reviewed studies. medications used to treat HU in adults, either in the clinic or
CONCLUSIONS: Longitudinal studies are still needed to ER. This systematic review is intended for a broad audience,
determine how best to lower blood pressure in patients including clinicians—especially general internists—along
with HU. Longer-term management of individuals who
with policymakers and funding agencies, professional socie-
have experienced HU continues to be an area requiring
further study, especially as applicable to care from the
ties developing clinical practice guidelines, patients and their
generalist. care providers, and researchers.

Electronic supplementary material The online version of this article

(https://doi.org/10.1007/s11606-017-4277-6) contains supplementary
material, which is available to authorized users. METHODS
Received August 9, 2017 Eligibility Criteria
Revised October 24, 2017
Accepted December 13, 2017 We defined HU as severe hypertension without evidence of
Published online January 16, 2018 acute end-organ damage. We included studies with non-
539
540 Campos et al.: Pharmacologic Treatment of Hypertensive Urgency JGIM

pregnant adults with systolic blood pressure (SBP) >

179 mmHg or diastolic blood pressure (DBP) > 109 mmHg,
with no end-organ damage. Because of inconsistent termi-
nology, we selected studies based on the above blood
pressure criteria. We included both clinic and ER settings
in the search, but excluded studies where patients were
hospitalized.

Data Sources and Search. Following the PRISMA

guidelines,5 and in collaboration with a librarian (JT), two
reviewers (CLC, KO) searched the literature using PubMed,
the Cochrane Central Register of Controlled Trials
(CENTRAL), Database of Abstracts of Reviews of Effects
(DARE), Cochrane Database of Systematic Reviews, Web of
Science, Google Scholar, and Embase. The medical librarian
created search strategies with standardized terms and
keywords. We excluded case reports, letters, and editorials.
Searches were limited to English-language publications and to
human studies using the limits provided by the databases. The
Bhuman^ filter recommended in the Cochrane Handbook for
Systematic Reviews of Interventions6 was used in PubMed.
Studies on pulmonary hypertension were excluded. The gray
literature was also searched utilizing Google Scholar. In addi-
tion, one expert (PD) identified key literature for the review.
All search results were exported to EndNote. Using the End-
Note duplicate locator, 4861 duplicate articles were removed.
The librarian updated the search in May 2016, and all searches
were completed in July 2016. The full search strategy is shown
in Appendix A.
Two evaluators (CLC and KO) independently identified
and screened articles for inclusion. Reference lists of studies
were manually scanned, and cited references were screened by Figure 1 Methods algorithm.
each evaluator (Fig. 1).

Study Selection. Studies that 1) reported on adults with HU angina, heart failure, pulmonary edema, arrhythmia, re-
who received pharmacologic therapy in outpatient settings nal impairment, new-onset proteinuria, and hospitaliza-
(clinic or ER) and 2) reported initial and subsequent blood tion. None of the studies reported on cardiovascular or
pressure values within 48 h of medication administration all-cause mortality.
were reviewed. Studies were excluded if they included Data extraction: Using standardized Excel forms, four
animals, pediatric or pregnant patients, or the presence groups of two investigators each (JLW, AJC, KO, DJ, CLC,
of acute end-organ damage. Because the U.S. Food and AA, BB, CH) independently extracted data including the
Drug Administration (FDA) prohibits the use of nifedipine author, country, year, study type, setting, sample size, demo-
for acute management of elevated blood pressure, articles graphics, medications, details of treatment, primary outcome,
that included only this drug were also excluded (532 adverse effects, and initial and subsequent blood pressure
studies).7 values. The team calculated MAP values when not explicitly
Primary outcome(s): Given the lack of consensus regarding calculated by the authors.
the blood pressure reduction goal when treating HU, most Two members of the team independently graded the
studies did not report dichotomous outcomes. The primary strength of clinical data and subsequent recommendations
measures of treatment efficacy were reduction in SBP, DBP, for treatment of patients with HU according to the Oxford
and mean arterial pressure (MAP; in mmHg) within 48 h of Centre for Evidence-Based Medicine levels of evidence. Any
pharmacologic treatment. discrepancies were resolved after a joint review and discussion
Secondary outcomes: We extracted adverse effects with a third reviewer. Levels of evidence were as follows:
including headache, dizziness, dry mouth, hypotension, level 1A, systematic reviews (with homogeneity of random-
stroke, transient ischemic attack, myocardial infarction, ized clinical trials); level 1B, individual randomized clinical
JGIM Campos et al.: Pharmacologic Treatment of Hypertensive Urgency 541

trials (with narrow confidence intervals); level 2A, systematic Amlodipine (5 or 10 mg PO) was evaluated in one
reviews (with homogeneity of cohort studies); and level 2B, small (n = 46) retrospective cohort.14 Both doses signifi-
individual cohort studies (including low-quality randomized cantly reduced the MAP at 1 h (from 140 and 148 to 103
clinical trials). Grades of recommendation are as follows: A = and 131, respectively). No side effects were reported.
consistent level 1 studies; B = consistent level 2 or 3 studies, or Isradipine was investigated in two trials, one a prospective
extrapolations from level 1 studies; C = level 4 studies or cohort10 and the other an RCT,9 which found that PO
extrapolations from level 2 or 3 studies; and D = level 5 doses ranging from 1.25 to 5 mg reduced SBP from
evidence or inconsistent or inconclusive studies of any level. 196–204 to 155–165 at 2 h. Reported side effects with
Studies with a high loss to follow-up were flagged. isradipine were dizziness and nausea. In four trials,8, 15, 16,
19
lacidipine (4 mg, 10 mg, 20 mg), in SLl or PO for-
mulations, significantly reduced SBP, from 238–186 to
Risk of Bias Assessment 178–145, over 2–24 h. Four trials of nicardipine in vari-
ous formulations significantly reduced SBP over 1–2 h,
For controlled trials, we used the Cochrane Risk of Bias
from 186–238 to 161–163. Reported side effects from
Assessment tool. For cohort studies, we used the Newcastle-
nicardipine were mild headache, hypotension, orthostasis,
Ottawa Scale to assess study quality.
chest pain, and tachycardia. In single trials, nitrendipine
5 mg PO (n = 85) reduced SBP from 228 to 156 over 2–
Data Synthesis
8 h,22 and verapamil SL reduced SBP significantly over
We could not combine results statistically because of 1–2 h, with 80 mg more effective than 40 mg. Reported
heterogeneity among interventions and outcome meas- side effects with verapamil were decreased heart rate and
ures. Furthermore, studies often lacked clearly defined headache.13
primary outcomes. Therefore, we qualitatively synthe-
sized results by antihypertensive medication class and ACE Inhibitors
created tables summarizing the evidence across all stud-
ies reviewed. There were nine trials of ace inhibitors (one retrospective
cohort,14 two prospective cohorts,23, 24 five RCTs,16, 25–28
one non-randomized controlled trial29). All used captopril in
doses ranging from 6.25 to 25 mg in both PO and SL for-
RESULTS
mulations. SBP values were reduced from 244–198 to 177–
144 at 0.17–12 h of captopril administration, with greater BP
Our search strategy identified 11,223 published articles. We reduction seen using higher doses (25 mg).
reviewed 10,748 titles and abstracts (after duplicates were Side effects reported with captopril were dizziness, head-
removed) and identified 538 eligible articles. We identified ache, nausea and vomiting,24 dry mouth, vertigo,15 and
20 double-blind randomized controlled trials and 13 cohort flushing26.
studies, with 262 participants in prospective controlled trials
(Fig. 1). After applying our eligibility criteria to the full texts Beta-Blockers
of these articles, we included 31 English-language articles
(Fig. 1). We included studies with nifedipine only if it was There were five trials of beta blockers (three prospective
included as a comparison drug. We excluded the results of the cohorts30–32 and two RCTs18, 33). Labetalol was studied in
nifedipine arm because of its black box warning in the man- doses ranging from 20 to 300 mg in both IV and PO formu-
agement of HU. lations. Blood pressure values were reduced after 0.33–24 h of
The characteristics of included trials are summarized in labetalol administration in all studies. Labetalol PO was in-
Table 1. Studies were generally characterized by small sample vestigated in only one small RCT (n = 10), which found that
size, different timing of the effects of antihypertensive thera- the mean PO dose of 221 mg reduced SBP from 195 to 154 at
pies (0.17–24 h), and short-term follow-up. Most recent stud- 4 h. Side effects reported with labetalol were dizziness,31, 33
ies were conducted outside the United States. drowsiness,33 headache,33 bradycardia,31 and pain at the in-
We compiled the blood pressure effects by antihypertensive jection site.32
class (Table 2) and their reported side effects:
Centrally Acting Antihypertensives
Calcium Channel Blockers Two centrally acting agents, clonidine and ketanserin, were
Seven calcium channel blockers were studied in 14 trials. 8–20 studied in seven trials. Clonidine was investigated in six trials
Nicardipine and nifedipine were the most commonly studied (one prospective cohort,34 one retrospective cohort,35 four
(three trials15, 16, 20 and four trials,8, 11, 19, 21 respectively). RCTs11, 12, 33, 36), which found that PO doses ranging from
Isradipine and lacidipine each had two studies,8–10, 13, 19 and 0.1 to 0.6 mg reduced SBP from 204–196 to 165–155 at 2 h.
amlodipine, nitrendipine, and verapamil each had one study.12–14 Side effects reported with the use of clonidine were
542 Campos et al.: Pharmacologic Treatment of Hypertensive Urgency JGIM

Table 1 Studies

Trial, year, Medication(s) Study design Sample size Age, years Male, % Ethnicity
country (mean)
Al-Waili, 1999, Verapamil RCT Verapamil 40 mg SL: n = 30 42–70 56% Not specified
International Verapamil 80 mg SL: n = 30
(UAE, Iraq, UK)
Atkin, 1992, USA Labetalol RCT n = 36 47 58% AA = 34
vs. Labetalol 200 mg: n = 18 W=2
Clonidine Clonidine 0.2 mg: n = 18
Bottorff, 1988, Urapidil Prospective Urapidil 103 mg IV: n = 9 43 78% Not specified
USA cohort
Castro del Castillo, Captopril Prospective Captopril 12.5 mg SL: n = 41 Not specified Not specified Not specified
1988, USA dose–response
study
Finnerty, 1963, Diazoxide Prospective Diazoxide 300 mg IV: n = 33 Not specified Not specified Not specified
USA cohort
Garrett, 1982, Diazoxide Prospective Diazoxide 15 mg/min IV (300– 43 33% AA = 13
USA cohort 1095 mg): n = 9 W=5
Diazoxide 30 mg/min IV
(300–1200 mg): n = 9
Gemici, 2003, Captopril RCT Captopril 25 mg SL: n = 15 Captopril: 56 ± Not specified Not specified
Turkey vs. Nifedipine 10 mg SL: n = 13 11
Nifedipine Nifedipine:
54 ± 10
Greene, 1990, Clonidine Prospective Clonidine 0.1–0.2 mg oral: n = 50 46% AA = 10
USA cohort 13 W=3
(then 0.1 mg/h as needed
(average 0.24 mg) PO)
Habib, 1995, USA Nicardipine RCT Nicardipine 30 mg oral: n = 26 48 ± 11 68% AA = 43
Placebo Placebo: n = 27 W = 10
Hirschl, 1998, Urapidil RCT Urapidil 60 mg PO: n = 20 59 40% Not specified
Austria vs. Placebo: n = 20
Placebo
Huey, 1988, USA Labetalol Prospective Labetalol 20–300 mg IV: n = 20 55 100% AA = 12
cohort W=8
Jaker, 1989, USA Clonidine RCT Clonidine 0.1 mg hourly up to 48 39% H=5
vs. 0.6 mg PO: n = 28 AA = 46
Nifedipine Nifedipine 20 mg oral: n = 23
Joekes, 1976, Labetalol Prospective Labetalol 0.5–1 mg/kg IV: n = Not specified Not specified Not specified
England cohort 14
Just, 1991, USA Clonidine Retrospective Clonidine 0.1–0.2 mg and 0.1 48 50% AA = 78
vs. cohort hourly as needed PO: n = 32 W = 16
Nifedipine Nifedipine 10–20 mg oral:
vs. n = 35
Variety of drug Grp 3: n = 27
therapies (Grp
3)
Kaya, 2016, Captopril RCT Captopril 25 mg SL: n = 108 Captopril SL: 46% Not specified
Turkey Captopril 25 mg PO: n = 104 63 ± 13
Captopril PO:
64 ± 11
Klocke, 1992, Nitrendipine RCT Nitrendipine 5 mg. If BP did 58 ± 12 52% Not specified
Germany vs. not fall below 180/100 mmHg
Clonidine 60 min after administration,
nitrendipine 5 mg was given:
n = 140
Clonidine 0.15 mg IV. If BP did
not fall below 180/100 mmHg
60 min after administration,
nitrendipine 5 mg was given:
n = 139
Komsuoglu, 1991, Nicardipine RCT Nicardipine 20 mg SL: n = 22 62 51% Not specified
Turkey vs. Captopril 25 mg SL: n = 20
Captopril Nifedipine 20 mg bite &
vs. swallow: n = 23
Nifedipine
Lechi, 1981, Italy Labetalol Prospective Labetalol 1 mg/kg IV bolus: n = 25–60 57% Not specified
cohort 15
Labetalol 1–4 mg/kg IV over
3 h.: n = 6
(continued on next page)

hypotension, orthostasis, impotence, sedation, 37 dry Ketanserin (unavailable in the U.S.) was studied in one
mouth,33,36 mild transient drowsiness, and lower heart rate RCT, also reducing BP after IV and SL administration. Som-
(average 6.2 beats/min).34 nolence was reported.11
JGIM Campos et al.: Pharmacologic Treatment of Hypertensive Urgency 543

Table 1. (continued)

Trial, year, Medication(s) Study design Sample size Age, years Male, % Ethnicity
country (mean)
Maleki, 2011, Iran Grp A - Nifed- RCT Grp A - Nifedipine 5 mg SL: Grp A: 61 45% Not specified
ipine n = 40 Grp B: 58
vs. Grp B - Captopril 25 mg SL: Grp C: 63
Grp B - Capto- n = 40
pril Grp C – Nitroglycerin SL:
vs. n = 40
Grp C - Nitro-
glycerin
McDonald, 1993, Labetalol RCT Labetalol 200 mg oral Labetalol: 46 50% AA = 20
USA vs. 200 mg repeated if DBP was Nifedipine: 48
Nifedipine ≥120 mmHg; 100 mg given if
DBP was >110 mmHg but
<120 mmHg. Mean dose
221 mg: n = 10
Nifedipine 10 mg bite and
swallow every hour up to a total
dose of 20 mg: n = 10
Panacek, 1995, Fenoldopam RCT Fenoldopam - Fenoldopam: Fenoldopam: Fenoldopam:
International vs. IV starting dose 0.1 mcg/kg/min 46 ± 1 52% AA = 57
(mainly USA) Nitroprusside and increased in increments of Nitroprusside: Nitroprusside: W = 33
≤0.2 mcg/kg/min. Max rate 1.6 48 ± 1 53% Nitroprusside:
mcg/kg/min. Mean titrated dose AA = 59
0.41 mcg/kg/min: n = 90 W = 33
Nitroprusside - Other = 4
IV starting dose 0.5 mcg/kg/min
and increased in increments of
≤1 mcg/kg/min. Max rate
8 mcg/kg/min. Mean titrated
dose 1.67 mcg/kg/min: n = 93
Peacock, 2011, Nicardipine RCT Nicardipine Nicardipine: 53 47% AA = 172
USA vs. Dosing per physician discretion. ± 15 W = 52
Labetalol Recommended 5 mg/h IV, Labetalol: (2 patients
increased every 5 min by 52 ± 14 withdrew)
2.5 mg/h, until target SBP
reached or max of 15 mg/h
achieved. IV median titrated
dose 3.1 mg: n = 110
Labetalol
Dosing per physician discretion.
Recommended 20 mg IV over
2 min, then repeated at 20, 40, or
80 mg injections every 10 min,
until target SBP reached or max
of 300 mg given. IV median
titrated dose 40 mg: n = 116
Ram, 1979, USA Diazoxide Non- Grp 1 - Diazoxide 105 mg IV, Grp 1 - Diazo- Not specified Not specified
randomized followed by 150 mg every 5 min xide 105 mg:
controlled until DBP of ≤110 mmHg or 48 ± 2
cumulative dose of 600 mg Grp 2 - Diazo-
achieved: n = 12 xide 150 mg:
Grp 2 - Diazoxide 150 mg IV, 46 ± 3
followed by 150 mg every 5 min
until DBP of ≤110 mmHg or
cumulative dose of 600 mg
achieved: n = 20
Sahasranam, 1988, Captopril Prospective Captopril 12.5 mg SL: n = 16 Not specified Not specified Not specified
India cohort
Salkic, 2015, Captopril Non- Captopril 12.5 mg – 25 mg SL: 58 ± 11 50% Not specified
Bosnia vs. randomized n = 60
Urapidil controlled Urapidil 12.5 mg – 25 mg IV:
n = 60
Sanchez, 1999, Lacidipine RCT Lacidipine 4 mg PO: n = 15 55 ± 11 31% Not specified
USA vs. Nifedipine 20 mg PO: n = 14
Nifedipine
Saragoca, 1992, Isradipine RCT 1.25 mg SL: n = 10 Not specified Not specified Not specified
Brasil 2.5 mg SL: n = 10
5 mg SL: n = 7
Saragoca, 1993, Isradipine Prospective Mean 3.9 mcg/kg/h IV: n = 10 Not specified Not specified Not specified
Brasil cohort
(continued on next page)
544 Campos et al.: Pharmacologic Treatment of Hypertensive Urgency JGIM

Table 1. (continued)

Trial, year, Medication(s) Study design Sample size Age, years Male, % Ethnicity
country (mean)

Sechi, 1989, Italy Nifedipine RCT Nifedipine 20 mg SL: n = 12 53 Not specified Not specified
vs. Ketanserin 20 mg SL: n = 13
Ketanserin Ketanserin 10 mg IV: n = 12
Sruamsiri, 2014, Amlodipine Retrospective Amlodipine 5 mg PO: n = 11 57 43% Not specified
Thailand vs. cohort Amlodipine 10 mg PO: n = 36
Captopril Captopril 6.25 mg PO: n = 2
vs. Captopril 12.5 mg PO: n = 58
Hydralazine Captopril 25 mg PO: n = 20
vs. Hydralazine 25 mg PO: n = 19
Nifedipine Nifedipine 10 mg PO: n = 5
Woisetschlaeger, Captopril RCT Captopril 25 mg PO: n = 29 56 ± 13 50% Not specified
2006, Austria vs. Urapidil 12.5 mg IV: n = 27
Urapidil
Zampaglione, Lacidipine Retrospective Lacidipine 4 mg SL: n = 20 Lacidipine: 69 Lacidipine: Not specified
1994, Italy vs. cohort Nifedipine 10 mg SL: n = 20 Nifedipine: 64 60%
Nifedipine Nifedipine:
60%
Zeller, 1989, USA Clonidine + RCT Grp 1 (n = 21) Not specified Not specified Not specified
Chlorthalidone Initial: clonidine
0.2 mg + chlorthalidone 25 mg,
then clonidine 0.1 mg/h (max 4
doses)
Maintenance: clonidine 0.2 mg
PO QD and chlorthalidone
25 mg PO BID:
Grp 2 : n = 16)
Initial: 0.2 mg clonidine +25 mg
chlorthalidone, then hourly
placebo
Maintenance: clonidine 0.2 mg
PO QD + chlorthalidone 25 mg
PO BID
Grp 3 (n = 27)
Initial: 0.2 mg clonidine and
25 mg chlorthalidone, no further
acute meds
Maintenance: clonidine 0.2 mg
PO QD and chlorthalidone
25 mg PO BID: n = 27
Zellkanter, 1991, Labetalol + Prospective Labetalol + Furosemide 20 mg 44 69% H=1
USA Furosemide cohort IV – 300 mg PO: n = 16 AA = 12
W=3
RCT = randomized controlled trial, H = Hispanic, AA = African American, W = white, SL = sublingual, PO = oral, IV = intravenous, QD = daily, BID =
twice a day
Any class of medication not included did not have studies that met our guidelines for being included

Vasodilators reduced SBP from 212 to 178, hydralazine (n = 19) reduced

MAP from 244 to 126 at 0.5 h, and nitroglycerin (n = 40)
Six vasodilators were studied across nine trials. Urapidil and
reduced SBP from 190 to 150 at 1 h.
diazoxide were the most commonly studied (three25, 38, 39 and
two trials, respectively40, 41). Fenoldopam,17 hydralazine,14
Combinations of Antihypertensives
nitroglycerin,26 and nitroprusside17 were each evaluated once.
In three trials, urapidil in IV or PO formulations significantly Combinations of agents were studied in two trials: labetalol
reduced SBP from 215–165 to 179–132 over 0.5–12 h. Side plus furosemide and clonidine plus chlorthalidone. Labetalol
effects reported with urapidil were nausea, vomiting, drowsi- 300 mg PO plus Lasix 20 mg IV was evaluated in one small
ness,39 headache, and orthostatic hypotension.38 (n = 16) prospective cohort,43 which showed a decrease in
Diazoxide (150–1290 mg IV) was investigated in two pro- SBP from 206 to 154 at 3 h. Clonidine plus chlorthalidone
spective cohort studies,41, 42 which found that 150–1290-mg was investigated in one RTC,37 which found that PO clonidine
IV doses rapidly reduced SBP, from 214–225 to 187–159 in doses of 0.2–0.8 mg plus chlorthalidone 25 mg reduced SBP
less than 1 h. Side effects reported with diazoxide were ure- from 193–182 to 142–137 at 24 h.
mia, acute pulmonary edema,40 palpitations, transient hemi-
paresis,42 pain at the site of IV infusion, a mild increase in Direct Comparisons
heart rate, atrial tachycardia, and chest pain.41 In single trials,
SL and PO nifedipine were the most commonly studied anti-
IV fenoldopam (n = 90) at a mean dose of 0.41 mcg/kg/min
hypertensives (four trials), with two comparisons against
JGIM Campos et al.: Pharmacologic Treatment of Hypertensive Urgency 545

Table 2 Compiled Medication List

Medication Dose Trial Study design Baseline Follow-up

SBP DBP MAP Time (h) SBP DBP MAP

Calcium channel blockers

Amlodipine 5 mg PO Sruamsiri Retrospective * * 140 1 * * 103
10 mg PO cohort * * 148 1 * * 131
Isradipine 1.25 mg SL Saragoca, 1993 Prospective 204 136 159 2 155 105 122
Mean 3.9 mcg/kg/h IV cohort * * 135 3 * * 129
12 * * 116
1.25 mg SL Saragoca, 1992 RCT 204 136 159 2 155 105 122
2.5 mg SL 214 132 159 2 165 97 120
5 mg SL 196 127 150 2 160 95 117
Lacidipine 4 mg SL Zampaglione Retrospective 208 125 153 0.5 178 110 133
cohort 2 155 96 117
4 145 90 109
4 mg PO Sanchez RCT 223 125 158 8 170 104 126
24 165 100 122
20 mg SL Komsuoglu RCT 238 134 169 2 161 98 119
30 mg PO Habib RCT 186 127 147 2 162 105 124
Nitrendipine 5 mg PO. If BP did not fall Klocke Prospective 228 125 159 2 157 89 112
below 180/100 mmHg 60 cohort 6 154 89 111
min after administration, 8 156 90 112
Nitrendipine 5 mg was
given
Verapamil 40 mg SL Al-Waili RCT 200 127 151 1 177 95 122
2 171 91 118
80 mg SL 201 129 153 1 150 91 111
2 147 81 103
Ace inhibitors
Captopril 6.25 mg PO Sruamsiri Retrospective * * 137 0.5 * * 122
cohort
12.5 mg PO * * 146 0.5 * * 126
25 mg PO * * 148 0.5 * * 124
12.5 mg PO Sahasranam Prospective 198 130 153 0.5 162 106 125
cohort
25 mg PO Woisetschlaeger RCT 211 110 144 12 159 88 112
12.5 mg PO Castro del Prospective 212 129 157 2 162 91 115
Castillo cohort
12.5 mg SL Salkic Non- 213 130 158 0.5 177 112 134
25 mg SL randomized 213 130 158 1 152 95 114
controlled
25 mg SL Maleki RCT 198 * * 1 142 * *
25 mg SL Gemici RCT 200 125 150 0.17 165 108 127
25 mg SL Komsuoglu RCT 244 133 170 2 162 100 121
25 mg SL Kaya RCT 189 116 140 1 150 81 104
25 mg PO 191 116 141 1 151 83 107
Beta-blockers
Labetalol 0.5–1 mg/kg IV Joekes Prospective 176 113 140 0.33– 146 92 *
cohort 0.66
1 mg/kg IV bolus Lechi Prospective 226 137 167 3 180 114 136
cohort 6 177 112 134
24 185 118 140
1–4 mg/kg IV over 3 h 216 128 157 3 149 97 114
Labetalol 6 164 103 123
(con’t) 24 191 119 143
20–300 mg IV Huey Prospective 185 120 142 0.5 155 98 117
cohort (median
time)
200 mg PO; 200 mg McDonald RCT 195 127 150 4 154 100 118
repeated if DBP ≥120
mmHg; 100 mg given if
DBP >110 mmHg but <120
mmHg. Mean dose 221 mg
200 mg, followed by Atkin RCT 201 132 155 6 172 111 131
hourly 200 mg, up to 1200
mg
Centrally acting
(continued on next page)

lacidipine (one prospective cohort,8 one RCT19), one against retrospective cohort 14 ), urapidil (one RCT 25 and one
ketanserin (RCT11), and one against captopril and nitroglyc- prospective cohort29), and with nitroglycerin and nifedipine
erin (RCT26). Captopril was evaluated in four comparative (one RCT26). Clonidine was compared with labetalol (one
trials: with amlodipine, hydralazine and nifedipine (one RCT33) and nitrendipine (one RCT12).
546 Campos et al.: Pharmacologic Treatment of Hypertensive Urgency JGIM

Table 2. (continued)

Medication Dose Trial Study design Baseline Follow-up

SBP DBP MAP Time (h) SBP DBP MAP

Clonidine 0.15 mg IV. If BP did not Klocke RCT 229 124 159 2 156 89 111
fall below 180/100 mmHg 6 155 88 110
60 min after administration, 8 156 90 112
Nitrendipine 5 mg was
given
0.2 mg PO followed by Atkin RCT 196 132 153 6 172 108 129
hourly 0.1 mg, up to 0.7
mg.
0.1–0.2 mg, then 0.1 mg Greene Prospective 202 126 151 1.4 149 97 114
hourly as needed (average cohort
0.24 mg) PO
0.1 mg and 0.1 hourly as Just Retrospective 200 124 149 0.33–4.9; 159 99 119
needed PO cohort mean
time 1.3
0.1 mg hourly, up to 0.6 mg Jaker RCT 206 132 157 2 171 113 132
PO
Ketanserin 20 mg SL Sechi RCT 195 120 145 3 178 110 133
10 mg IV 184 119 141 3 183 118 140
Vasodilators
Diazoxide 15 mg/min IV (300–1095 Garrett Prospective 225 141 169 0.63 183 102 129
mg) cohort
30 mg/min IV (300–1290 214 145 168 0.35 159 103 122
mg)
150 mg IV followed by 150 Ram Non- 216 139 165 0.25 186 111 136
mg every 5 min until DBP randomized
of ≤110 mmHg, or controlled
cumulative dose of 600 mg
IV achieved
150 mg followed by 150 214 138 163 0.25 187 117 140
mg every 5 min until DBP
of ≤110 mmHg or
cumulative dose of 600 mg
achieved
300 mg IV Finnerty Prospective 175 113 133 4 129 73 91
cohort
Fenoldopam IV starting dose 0.1 mcg/ Panacek RCT 212 135 161 1 178 106 130
kg/min and increased in 6 173 106 128
increments of ≤0.2 mcg/kg/ End (24) 183 106 132
min. Max rate 1.6 mcg/kg/
min. Mean titrated dose
0.41 mcg/kg/min
Hydralazine 25 mg PO Sruamsiri Retrospective * * 144 0.5 * * 126
cohort
Nitroglycerin SL Maleki RCT 190 * * 1 150 * *
Nitroprusside IV starting dose 0.5 mcg/ Panacek RCT 210 133 159 1 165 101 122
kg/min and increased in 6 166 100 122
increments of ≤1 mcg/kg/ End (24) 168 102 124
min. Max rate 8 mcg/kg/
min. Mean titrated dose
1.67 mcg/kg/min
Urapidil 12.5 mg IV Woisetschlaeger RCT 216 110 145 12 163 85 111
Urapidil (con’t) 12.5 mg IV Salkic Non- 213 130 158 0.5 179 110 133
25 mg IV randomized 213 130 158 1 152 95 114
controlled
60 mg PO Hirschl RCT 165 89 114 12 132 79 96
103 mg IV bolus Bottorff Prospective 190 126 147 0.2 164 105 125
cohort
Combinations
(continued on next page)

One direct comparison study (RCT17) evaluated fenoldo- In two studies comparing captopril and urapidil,25, 29 both
pam and nitroprusside. drugs were found to effectively lower blood pressure within
When captopril was compared to amlodipine, hydralazine, 1 h29 and at 12 h25 (p = 0.38/0.40).
and nifedipine in a retrospective cohort study,14 there were no When fenoldopam and nitroprusside were compared,17 the
significant differences between these medications in their ef- two antihypertensive agents were equivalent in controlling and
fect on BP reduction (p = 0.513). Captopril was superior to maintaining BP. The adverse effect profiles of the drugs were
sublingual nitroglycerin in the first hour following administra- similar: headache, dizziness, flushing, hypotension, nausea,
tion (p = 0.001).26 vomiting, hyperhidrosis, and hypokalemia.
JGIM Campos et al.: Pharmacologic Treatment of Hypertensive Urgency 547

Table 2. (continued)

Medication Dose Trial Study design Baseline Follow-up

SBP DBP MAP Time (h) SBP DBP MAP

Clonidine + Initial PO: clonidine 0.2 mg Zeller RCT 193 126 148 24 142 99 113
Chlorthalidone and chlorthalidone 25 mg,
then clonidine 0.1 mg/
h (max 4 doses)
Maintenance: clonidine
0.2 mg PO QD and
chlorthalidone 25 mg PO
BID
Initial PO: 0.2 mg clonidine 183 124 144 24 137 94 108
and chlorthalidone 25 mg,
then hourly placebo
Maintenance: clonidine
0.2 mg PO
QD + chlorthalidone 25 mg
PO BID
Initial PO: clonidine 0.2 mg 182 123 143 24 136 97 110
and chlorthalidone 25 mg,
no further acute meds
Maintenance: clonidine
0.2 mg PO QD and
chlorthalidone 25 mg PO
BID
Labetalol + 300 mg PO Zell-Kanter Prospective 206 132 157 3 154 110 123
Furosemide 20 cohort
mg IV
SBP = systolic blood pressure, DBP = diastolic blood pressure, MAP = mean arterial pressure, RCT = randomized controlled trial, SL = sublingual,
PO = oral, IV = intravenous, QD = daily, BID = twice a day
*No data
Any class of medication not included did not have studies that met our guidelines for inclusion

Clonidine and labetalol were compared in an RCT,33 with a drugs that lowered blood pressure but are unavailable in the
similar reduction in blood pressure at 6 h and similar side U.S. include lacidipine, ketanserin, and urapidil. Clinical
effect profiles. Sedation, dizziness, orthostatic hypotension, choices in the setting of HU seemed to broaden as we con-
and dry mouth were reported with clonidine; dizziness, drows- ducted our extensive literature search. Side effects ranged from
iness, and headache with labetalol. mild (dizziness, headache, nausea and vomiting, dry mouth,
Nitrendipine and IV clonidine were compared in one mild tachycardia, and sedation) to severe (hypotension, tran-
RCT,12 with similar reductions in BP up to 8 h. Side effects sient ischemic attack, uremia, and acute pulmonary edema).
reported with nitrendipine were flushing and headache, and Most studies limited data collection to the first few hours after
with clonidine were dizziness, somnolence, and bradycardia. initial presentation, which is not sufficient to assess morbidity
Risk of bias is summarized in Table 3. Most studies had and mortality.3 Studies were too clinically and methodologically
unclear quality control standards regarding blood pressure diverse for a meta-analysis, and those that met our criteria for this
measurements and excluded patients with significant comor- systematic review included few patients. Most studies excluded
bidities, such as chronic kidney disease,15, 34–36, 38, 41 which patients with significant comorbidities, such as chronic kidney
are seen frequently in patients with hypertension. impairment; however, HU is a common complication in patients
Among the controlled trials, only those by Komsuoglu,16 with associated comorbidities. In light of these factors, the
Woisetschlaeger,25 and Just35 had a low risk of bias for both generalizability of our findings is limited. Most studies that
the study design (random sequence generation and conceal- met our inclusion criteria provided only surrogate endpoint data,
ment of allocation) and the primary clinical outcome (blinding i.e. blood pressure lowering, and were short-term, lacking long-
of outcome assessor). term morbidity and/or mortality outcomes, and providing statis-
tical power only for differences in blood pressure lowering.
Our comprehensive systematic review regarding treatment
of outpatient HU includes office and ER settings, limiting data
DISCUSSION to short-term observations of blood pressure (less than 24 h).
In this systematic review of HU, the optimal choice of antihy- This review also included studies based on blood pressure cut-
pertensive agent remains unclear (level 2B). Many agents offs, allowing us to distinguish studies that were mislabeled as
demonstrated blood pressure-lowering benefit: captopril, labe- urgencies or emergencies.
talol, clonidine, amlodipine, verapamil, nitrendipine, isradi- A limitation of this review is that it evaluated only English-
pine, nifedipine, nitroglycerin, hydralazine, chlorthalidone, fu- language reports. However, Morrison et al.44 found no evidence
rosemide, diazoxide, nitroprusside, and fenoldopam. Other of a systematic bias from language restrictions in systematic
548 Campos et al.: Pharmacologic Treatment of Hypertensive Urgency JGIM

Table 3 Cochrane Risk of Bias*

Author/Year Random Allocation Blinding of Addressed Free of Free of

sequence concealment participants, incomplete selective other
generation (selection bias) personnel, and data (attrition reporting sources of
(selection bias) outcomes bias) (reporting bias
(performance bias) bias)

Al-Waili NS, Hasan NA/1999 − ? ? ? ? −

Atkin/1992 − − + + + +
Gemici/2003 ? ? ? + + +
Habib/1995 ? ? ? ? + +
Hirschl/1998 ? ? ? + + +
Jaker/1989 ? ? + − + +
Kaya/2016 ? − − + + +
Klocke RK, Kux A, ? ? − ? ? ?
Spah F, et al/1992
Komsuoglu/1991 ? ? + + + +
McDonald AJ, Yealy DM, ? ? − − ? ?
Jacobson S/1993
Panacek E A, et al/1995 ? ? − ? ? ?
Ram CVS, Kaplan NM/1979 ? ? ? − − −
Sahasranam KV, − − − − ? −
Ravindran KN/1988
Sanchez/1999 ? ? ? ? + ?
Saragoca/1992 ? − − − − −
Sechi, et al/1989 ? − − − ? −
Woisetschlaeger C, et al/2006 ? ? ? ? − ?
Zampaglione/1994 ? ? ? ? ? −
Zeller/1989 + ? − + − −
*Risk of bias is indicated as uncertain (?), low (−), or high (+)

review-based meta-analyses in conventional medicine. We

attempted to minimize publication bias by searching the gray hypertension outcomes trials. One such study, conducted by
literature; we may have missed negative or small(er) studies. Grassi et al.,46 evaluated the long-acting dihydropyridine cal-
The most recent systematic review of HU, by Souza45 in cium channel blocker amlodipine and the ACE inhibitor peri-
2008, included studies in outpatient and inpatient settings. ndopril in slowly lowering blood pressure toward goal for
Their Cochrane Review was limited to randomized controlled patients with HU. This study did not meet the inclusion criteria
trials of calcium channel blockers or angiotensin-converting of our review, since it did not report changes in blood pressure
enzyme inhibitors. Although they excluded commonly used within 48 h of treatment.
agents (e.g. clonidine, hydralazine, and labetalol3), many other
reviews have demonstrated a benefit in blood pressure reduc-
tion from these agents. Side effects were problematic mainly CONCLUSION
for nifedipine and clonidine. Additional longitudinal studies are needed to determine how
Intravenous medications, although effective, carry added best to safely decrease blood pressure in patients with HU.
costs, and therefore we do not recommend them; many available Larger and longer-term studies are also needed, including
oral agents are appropriate alternatives. Some studies included in participants with other common comorbidities. Such research
this review evaluated diuretics.37 However, since HU may be would hopefully provide more guidance to improve both
associated with hypovolemia, some recommend avoiding diu- short- and long-term cardiovascular outcome.
retics unless intravascular volume overload is present.37, 46–48
For HU, current data suggest that a 30-min rest may signifi- Acknowledgements: We would like to thank Dr. Pirouz Daeihagh,
cantly decrease blood pressure. However, many studies in this Associate Professor of Nephrology, Wake Forest Baptist Health, for
providing assistance with key literature identification, and Ms. Lisa
review did not have patients rest for 30 min prior to intervention. Porter, Wake Forest Baptist Health, for her administrative support.
Most medications used in reports we review here were short-
Corresponding Author: Claudia L. Campos, MD; Wake Forest
acting. Lowering blood pressure too rapidly in patients with Baptist Health, Medical Center Boulevard, Winston-Salem, NC
HU may be harmful. In their review, Kessler and Joudeh49 27157, USA (e-mail: [email protected]).
noted that there appears to be no benefit in attaining goal blood
Compliance with Ethical Standards:
pressure within hours to days, and that findings from the
VALUE trial50 suggest that lowering blood pressure within a Conflict of Interest: The authors declare that they have no conflict of
interest.
6 month-period may be a better approach. Therefore, avoid-
ance of rapid-acting agents such as clonidine and nifedipine Open Access This article is distributed under the terms of the
should be considered. Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
Other studies have used long-acting antihypertensive agents use, distribution, and reproduction in any medium, provided you give
which have demonstrated morbidity and mortality benefits in appropriate credit to the original author(s) and the source, provide a
JGIM Campos et al.: Pharmacologic Treatment of Hypertensive Urgency 549

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