Journal of General Internal Medicine

, Volume 33, Issue 4, pp 539–550 | Cite as

Pharmacologic Treatment of Hypertensive Urgency in the Outpatient Setting: A Systematic Review

  • Claudia L. Campos
  • Charles T. Herring
  • Asima N. Ali
  • Deanna N. Jones
  • James L. Wofford
  • Augustus L. Caine
  • Robert L. Bloomfield
  • Janine Tillett
  • Karen S. Oles
Open Access
Review Paper

Abstract

Background

Hypertensive urgency (HU), defined as acute severe uncontrolled hypertension without end-organ damage, is a common condition. Despite its association with long-term morbidity and mortality, guidance regarding immediate management is sparse. Our objective was to summarize the evidence examining the effects of antihypertensive medications to treat.

Methods

We searched the PubMed, 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 through May 2016. Study selection: We evaluated prospective controlled clinical trials, case–control studies, and cohort studies of HU in emergency room (ER) or clinic settings. We initially identified 11,223 published articles. We reviewed 10,748 titles and abstracts and identified 538 eligible articles. We assessed the full text for eligibility and included 31 articles written in English that were clinical trials or cohort studies and provided blood pressure data within 48 h of treatment. Studies were appraised for risk of bias using components recommended by the Cochrane Collaboration. The main outcome measured was blood pressure change with antihypertensive medications. Since studies were too diverse both clinically and methodologically to combine in a meta-analysis, tabular data and a narrative synthesis of studies are presented.

Results

We identified only 20 double-blind randomized controlled trials and 12 cohort studies, with 262 participants in prospective controlled trials. However, we could not pool the results of studies. In addition, comorbidities and their potential contribution to long-term treatment of these subjects were not adequately addressed in any of the reviewed studies.

Conclusions

Longitudinal studies are still needed to determine how best to lower blood pressure in patients with HU. Longer-term management of individuals who have experienced HU continues to be an area requiring further study, especially as applicable to care from the generalist.

KEY WORDS

hypertension hypertensive urgency cardiovascular disease 

INTRODUCTION

Hypertensive urgency (HU) is defined as systolic blood pressure of at least 180 mmHg and/or diastolic blood pressure of at least 110 mmHg, without associated end-organ damage.1 Patients with HU may be completely asymptomatic or may present with symptoms such as headache, epistaxis, faintness, malaise, psychomotor agitation, nausea, or vomiting.2

Up to 65 million Americans have hypertension; about 1% will have an episode of HU during their lives. The prevalence of HU in emergency room (ER) or office settings is estimated at 3–5%.3, 4 In a recent cohort study, cardiovascular events were found to occur in less than 1% of patients within a 6-month period.4

Guidance for immediate management of HU is unclear, since there is no consensus on the optimal target for acute blood pressure reduction or the time frame for achieving a normal blood pressure range. Most patients receive drug therapy for elevated blood pressure within the first 48 h of presentation.24 Knowledge of the effectiveness and safety of different medication choices and associated comorbidities is crucial for clinicians, especially generalists.

The aim of this systematic review is to summarize evidence of the benefits and harms associated with antihypertensive medications used to treat HU in adults, either in the clinic or ER. This systematic review is intended for a broad audience, including clinicians—especially general internists—along with policymakers and funding agencies, professional societies developing clinical practice guidelines, patients and their care providers, and researchers.

METHODS

Eligibility Criteria

We defined HU as severe hypertension without evidence of acute end-organ damage. We included studies with non-pregnant adults with systolic blood pressure (SBP) > 179 mmHg or diastolic blood pressure (DBP) > 109 mmHg, with no end-organ damage. Because of inconsistent terminology, 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 “human” 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 addition, one expert (PD) identified key literature for the review. All search results were exported to EndNote. Using the EndNote 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 each evaluator (Fig. 1).
Figure 1

Methods algorithm.

Study Selection

Studies that 1) reported on adults with HU who received pharmacologic therapy in outpatient settings (clinic or ER) and 2) reported initial and subsequent blood pressure values within 48 h of medication administration were reviewed. Studies were excluded if they included animals, pediatric or pregnant patients, or the presence of acute end-organ damage. Because the U.S. Food and Drug Administration (FDA) prohibits the use of nifedipine for acute management of elevated blood pressure, articles that included only this drug were also excluded (532 studies).7

Primary outcome(s): Given the lack of consensus regarding the blood pressure reduction goal when treating HU, most studies did not report dichotomous outcomes. The primary measures of treatment efficacy were reduction in SBP, DBP, and mean arterial pressure (MAP; in mmHg) within 48 h of pharmacologic treatment.

Secondary outcomes: We extracted adverse effects including headache, dizziness, dry mouth, hypotension, stroke, transient ischemic attack, myocardial infarction, angina, heart failure, pulmonary edema, arrhythmia, renal impairment, new-onset proteinuria, and hospitalization. None of the studies reported on cardiovascular or all-cause mortality.

Data extraction: Using standardized Excel forms, four groups of two investigators each (JLW, AJC, KO, DJ, CLC, AA, BB, CH) independently extracted data including the author, country, year, study type, setting, sample size, demographics, medications, details of treatment, primary outcome, adverse effects, and initial and subsequent blood pressure values. The team calculated MAP values when not explicitly calculated by the authors.

Two members of the team independently graded the strength of clinical data and subsequent recommendations for treatment of patients with HU according to the Oxford Centre for Evidence-Based Medicine levels of evidence. Any discrepancies were resolved after a joint review and discussion with a third reviewer. Levels of evidence were as follows: level 1A, systematic reviews (with homogeneity of randomized clinical trials); level 1B, individual randomized clinical trials (with narrow confidence intervals); level 2A, systematic reviews (with homogeneity of cohort studies); and level 2B, individual cohort studies (including low-quality randomized clinical trials). Grades of recommendation are as follows: A = consistent level 1 studies; B = consistent level 2 or 3 studies, or extrapolations from level 1 studies; C = level 4 studies or extrapolations from level 2 or 3 studies; and D = level 5 evidence or inconsistent or inconclusive studies of any level. Studies with a high loss to follow-up were flagged.

Risk of Bias Assessment

For controlled trials, we used the Cochrane Risk of Bias Assessment tool. For cohort studies, we used the Newcastle-Ottawa Scale to assess study quality.

Data Synthesis

We could not combine results statistically because of heterogeneity among interventions and outcome measures. Furthermore, studies often lacked clearly defined primary outcomes. Therefore, we qualitatively synthesized results by antihypertensive medication class and created tables summarizing the evidence across all studies reviewed.

RESULTS

Our search strategy identified 11,223 published articles. We reviewed 10,748 titles and abstracts (after duplicates were removed) and identified 538 eligible articles. We identified 20 double-blind randomized controlled trials and 13 cohort studies, with 262 participants in prospective controlled trials (Fig. 1). After applying our eligibility criteria to the full texts of these articles, we included 31 English-language articles (Fig. 1). We included studies with nifedipine only if it was included as a comparison drug. We excluded the results of the nifedipine arm because of its black box warning in the management of HU.

The characteristics of included trials are summarized in Table 1. Studies were generally characterized by small sample size, different timing of the effects of antihypertensive therapies (0.17–24 h), and short-term follow-up. Most recent studies were conducted outside the United States.
Table 1

Studies

Trial, year, country

Medication(s)

Study design

Sample size

Age, years (mean)

Male, %

Ethnicity

Al-Waili, 1999, International (UAE, Iraq, UK)

Verapamil

RCT

Verapamil 40 mg SL: n = 30

Verapamil 80 mg SL: n = 30

42–70

56%

Not specified

Atkin, 1992, USA

Labetalol

vs.

Clonidine

RCT

n = 36

Labetalol 200 mg: n = 18

Clonidine 0.2 mg: n = 18

47

58%

AA = 34

W = 2

Bottorff, 1988, USA

Urapidil

Prospective cohort

Urapidil 103 mg IV: n = 9

43

78%

Not specified

Castro del Castillo, 1988, USA

Captopril

Prospective dose–response study

Captopril 12.5 mg SL: n = 41

Not specified

Not specified

Not specified

Finnerty, 1963, USA

Diazoxide

Prospective cohort

Diazoxide 300 mg IV: n = 33

Not specified

Not specified

Not specified

Garrett, 1982, USA

Diazoxide

Prospective cohort

Diazoxide 15 mg/min IV (300–1095 mg): n = 9

Diazoxide 30 mg/min IV (300–1200 mg): n = 9

43

33%

AA = 13

W = 5

Gemici, 2003, Turkey

Captopril

vs.

Nifedipine

RCT

Captopril 25 mg SL: n = 15

Nifedipine 10 mg SL: n = 13

Captopril: 56 ± 11

Nifedipine: 54 ± 10

Not specified

Not specified

Greene, 1990, USA

Clonidine

Prospective cohort

Clonidine 0.1–0.2 mg oral: n = 13

(then 0.1 mg/h as needed (average 0.24 mg) PO)

50

46%

AA = 10

W = 3

Habib, 1995, USA

Nicardipine

Placebo

RCT

Nicardipine 30 mg oral: n = 26

Placebo: n = 27

48 ± 11

68%

AA = 43

W = 10

Hirschl, 1998, Austria

Urapidil

vs.

Placebo

RCT

Urapidil 60 mg PO: n = 20

Placebo: n = 20

59

40%

Not specified

Huey, 1988, USA

Labetalol

Prospective cohort

Labetalol 20–300 mg IV: n = 20

55

100%

AA = 12

W = 8

Jaker, 1989, USA

Clonidine

vs.

Nifedipine

RCT

Clonidine 0.1 mg hourly up to 0.6 mg PO: n = 28

Nifedipine 20 mg oral: n = 23

48

39%

H = 5

AA = 46

Joekes, 1976, England

Labetalol

Prospective cohort

Labetalol 0.5–1 mg/kg IV: n = 14

Not specified

Not specified

Not specified

Just, 1991, USA

Clonidine

vs.

Nifedipine

vs.

Variety of drug therapies (Grp 3)

Retrospective cohort

Clonidine 0.1–0.2 mg and 0.1 hourly as needed PO: n = 32

Nifedipine 10–20 mg oral: n = 35

Grp 3: n = 27

48

50%

AA = 78

W = 16

Kaya, 2016, Turkey

Captopril

RCT

Captopril 25 mg SL: n = 108

Captopril 25 mg PO: n = 104

Captopril SL: 63 ± 13

Captopril PO: 64 ± 11

46%

Not specified

Klocke, 1992, Germany

Nitrendipine

vs.

Clonidine

RCT

Nitrendipine 5 mg. If BP did not fall below 180/100 mmHg 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

58 ± 12

52%

Not specified

Komsuoglu, 1991, Turkey

Nicardipine

vs.

Captopril

vs.

Nifedipine

RCT

Nicardipine 20 mg SL: n = 22

Captopril 25 mg SL: n = 20

Nifedipine 20 mg bite & swallow: n = 23

62

51%

Not specified

Lechi, 1981, Italy

Labetalol

Prospective cohort

Labetalol 1 mg/kg IV bolus: n = 15

Labetalol 1–4 mg/kg IV over 3 h.: n = 6

25–60

57%

Not specified

Maleki, 2011, Iran

Grp A - Nifedipine

vs.

Grp B - Captopril

vs.

Grp C - Nitroglycerin

RCT

Grp A - Nifedipine 5 mg SL: n = 40

Grp B - Captopril 25 mg SL: n = 40

Grp C – Nitroglycerin SL: n = 40

Grp A: 61

Grp B: 58

Grp C: 63

45%

Not specified

McDonald, 1993, USA

Labetalol

vs.

Nifedipine

RCT

Labetalol 200 mg oral

200 mg repeated if DBP was ≥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

Labetalol: 46

Nifedipine: 48

50%

AA = 20

Panacek, 1995, International (mainly USA)

Fenoldopam

vs.

Nitroprusside

RCT

Fenoldopam -

IV starting dose 0.1 mcg/kg/min and increased in increments of ≤0.2 mcg/kg/min. Max rate 1.6 mcg/kg/min. Mean titrated dose 0.41 mcg/kg/min: n = 90

Nitroprusside -

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

Fenoldopam: 46 ± 1

Nitroprusside: 48 ± 1

Fenoldopam: 52%

Nitroprusside: 53%

Fenoldopam:

AA = 57

W = 33

Nitroprusside:

AA = 59

W = 33

Other = 4

Peacock, 2011, USA

Nicardipine

vs.

Labetalol

RCT

Nicardipine

Dosing per physician discretion. Recommended 5 mg/h IV, increased every 5 min by 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

Nicardipine: 53 ± 15

Labetalol: 52 ± 14

47%

AA = 172

W = 52

(2 patients withdrew)

Ram, 1979, USA

Diazoxide

Non-randomized controlled

Grp 1 - Diazoxide 105 mg IV, followed by 150 mg every 5 min until DBP of ≤110 mmHg or cumulative dose of 600 mg achieved: n = 12

Grp 2 - Diazoxide 150 mg IV, followed by 150 mg every 5 min until DBP of ≤110 mmHg or cumulative dose of 600 mg achieved: n = 20

Grp 1 - Diazoxide 105 mg: 48 ± 2

Grp 2 - Diazoxide 150 mg: 46 ± 3

Not specified

Not specified

Sahasranam, 1988, India

Captopril

Prospective cohort

Captopril 12.5 mg SL: n = 16

Not specified

Not specified

Not specified

Salkic, 2015, Bosnia

Captopril

vs.

Urapidil

Non-randomized controlled

Captopril 12.5 mg – 25 mg SL: n = 60

Urapidil 12.5 mg – 25 mg IV: n = 60

58 ± 11

50%

Not specified

Sanchez, 1999, USA

Lacidipine

vs.

Nifedipine

RCT

Lacidipine 4 mg PO: n = 15

Nifedipine 20 mg PO: n = 14

55 ± 11

31%

Not specified

Saragoca, 1992, Brasil

Isradipine

RCT

1.25 mg SL: n = 10

2.5 mg SL: n = 10

5 mg SL: n = 7

Not specified

Not specified

Not specified

Saragoca, 1993, Brasil

Isradipine

Prospective cohort

Mean 3.9 mcg/kg/h IV: n = 10

Not specified

Not specified

Not specified

Sechi, 1989, Italy

Nifedipine

vs.

Ketanserin

RCT

Nifedipine 20 mg SL: n = 12

Ketanserin 20 mg SL: n = 13

Ketanserin 10 mg IV: n = 12

53

Not specified

Not specified

Sruamsiri, 2014, Thailand

Amlodipine

vs.

Captopril

vs.

Hydralazine

vs.

Nifedipine

Retrospective cohort

Amlodipine 5 mg PO: n = 11

Amlodipine 10 mg PO: n = 36

Captopril 6.25 mg PO: n = 2

Captopril 12.5 mg PO: n = 58

Captopril 25 mg PO: n = 20

Hydralazine 25 mg PO: n = 19

Nifedipine 10 mg PO: n = 5

57

43%

Not specified

Woisetschlaeger, 2006, Austria

Captopril

vs.

Urapidil

RCT

Captopril 25 mg PO: n = 29

Urapidil 12.5 mg IV: n = 27

56 ± 13

50%

Not specified

Zampaglione, 1994, Italy

Lacidipine

vs.

Nifedipine

Retrospective cohort

Lacidipine 4 mg SL: n = 20

Nifedipine 10 mg SL: n = 20

Lacidipine: 69

Nifedipine: 64

Lacidipine: 60%

Nifedipine: 60%

Not specified

Zeller, 1989, USA

Clonidine + Chlorthalidone

RCT

Grp 1 (n = 21)

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

Not specified

Not specified

Not specified

Zellkanter, 1991, USA

Labetalol + Furosemide

Prospective cohort

Labetalol + Furosemide 20 mg IV – 300 mg PO: n = 16

44

69%

H = 1

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

We compiled the blood pressure effects by antihypertensive class (Table 2) and their reported side effects:
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 cohort

*

*

140

1

*

*

103

10 mg PO

*

*

148

1

*

*

131

Isradipine

1.25 mg SL

Saragoca, 1993

Prospective cohort

204

136

159

2

155

105

122

Mean 3.9 mcg/kg/h IV

*

*

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 cohort

208

125

153

0.5

178

110

133

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 below 180/100 mmHg 60 min after administration, Nitrendipine 5 mg was given

Klocke

Prospective cohort

228

125

159

2

157

89

112

6

154

89

111

8

156

90

112

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 cohort

*

*

137

0.5

*

*

122

12.5 mg PO

  

*

*

146

0.5

*

*

126

25 mg PO

  

*

*

148

0.5

*

*

124

12.5 mg PO

Sahasranam

Prospective cohort

198

130

153

0.5

162

106

125

25 mg PO

Woisetschlaeger

RCT

211

110

144

12

159

88

112

12.5 mg PO

Castro del Castillo

Prospective cohort

212

129

157

2

162

91

115

12.5 mg SL

Salkic

Non-randomized controlled

213

130

158

0.5

177

112

134

25 mg SL

213

130

158

1

152

95

114

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 cohort

176

113

140

0.33–0.66

146

92

*

1 mg/kg IV bolus

Lechi

Prospective cohort

226

137

167

3

180

114

136

6

177

112

134

24

185

118

140

1–4 mg/kg IV over 3 h

216

128

157

3

149

97

114

Labetalol (con’t)

6

164

103

123

24

191

119

143

20–300 mg IV

Huey

Prospective cohort

185

120

142

0.5 (median time)

155

98

117

200 mg PO; 200 mg repeated if DBP ≥120 mmHg; 100 mg given if DBP >110 mmHg but <120 mmHg. Mean dose 221 mg

McDonald

RCT

195

127

150

4

154

100

118

200 mg, followed by hourly 200 mg, up to 1200 mg

Atkin

RCT

201

132

155

6

172

111

131

Centrally acting

Clonidine

0.15 mg IV. If BP did not fall below 180/100 mmHg 60 min after administration, Nitrendipine 5 mg was given

Klocke

RCT

229

124

159

2

156

89

111

6

155

88

110

8

156

90

112

0.2 mg PO followed by hourly 0.1 mg, up to 0.7 mg.

Atkin

RCT

196

132

153

6

172

108

129

0.1–0.2 mg, then 0.1 mg hourly as needed (average 0.24 mg) PO

Greene

Prospective cohort

202

126

151

1.4

149

97

114

0.1 mg and 0.1 hourly as needed PO

Just

Retrospective cohort

200

124

149

0.33–4.9; mean time 1.3

159

99

119

0.1 mg hourly, up to 0.6 mg PO

Jaker

RCT

206

132

157

2

171

113

132

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 mg)

Garrett

Prospective cohort

225

141

169

0.63

183

102

129

30 mg/min IV (300–1290 mg)

214

145

168

0.35

159

103

122

150 mg IV followed by 150 mg every 5 min until DBP of ≤110 mmHg, or cumulative dose of 600 mg IV achieved

Ram

Non-randomized controlled

216

139

165

0.25

186

111

136

150 mg followed by 150 mg every 5 min until DBP of ≤110 mmHg or cumulative dose of 600 mg achieved

214

138

163

0.25

187

117

140

300 mg IV

Finnerty

Prospective cohort

175

113

133

4

129

73

91

Fenoldopam

IV starting dose 0.1 mcg/kg/min and increased in increments of ≤0.2 mcg/kg/min. Max rate 1.6 mcg/kg/min. Mean titrated dose 0.41 mcg/kg/min

Panacek

RCT

212

135

161

1

178

106

130

6

173

106

128

End (24)

183

106

132

Hydralazine

25 mg PO

Sruamsiri

Retrospective cohort

*

*

144

0.5

*

*

126

Nitroglycerin

SL

Maleki

RCT

190

*

*

1

150

*

*

Nitroprusside

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

Panacek

RCT

210

133

159

1

165

101

122

6

166

100

122

End (24)

168

102

124

Urapidil

12.5 mg IV

Woisetschlaeger

RCT

216

110

145

12

163

85

111

Urapidil (con’t)

12.5 mg IV

Salkic

Non-randomized controlled

213

213

130

130

158

158

0.5

179

110

133

25 mg IV

1

152

95

114

60 mg PO

Hirschl

RCT

165

89

114

12

132

79

96

103 mg IV bolus

Bottorff

Prospective cohort

190

126

147

0.2

164

105

125

Combinations

Clonidine + Chlorthalidone

Initial PO: clonidine 0.2 mg 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

Zeller

RCT

193

126

148

24

142

99

113

Initial PO: 0.2 mg clonidine and chlorthalidone 25 mg, then hourly placebo

Maintenance: clonidine 0.2 mg PO QD + chlorthalidone 25 mg PO BID

183

124

144

24

137

94

108

Initial PO: clonidine 0.2 mg and chlorthalidone 25 mg, no further acute meds

Maintenance: clonidine 0.2 mg PO QD and chlorthalidone 25 mg PO BID

182

123

143

24

136

97

110

Labetalol + Furosemide 20 mg IV

300 mg PO

Zell-Kanter

Prospective cohort

206

132

157

3

154

110

123

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

Calcium Channel Blockers

Seven calcium channel blockers were studied in 14 trials.820 Nicardipine and nifedipine were the most commonly studied (three trials15, 16, 20 and four trials,8, 11, 19, 21 respectively). Isradipine and lacidipine each had two studies,810, 13, 19 and amlodipine, nitrendipine, and verapamil each had one study.1214

Amlodipine (5 or 10 mg PO) was evaluated in one small (n = 46) retrospective cohort.14 Both doses significantly reduced the MAP at 1 h (from 140 and 148 to 103 and 131, respectively). No side effects were reported. Isradipine was investigated in two trials, one a prospective cohort10 and the other an RCT,9 which found that PO doses ranging from 1.25 to 5 mg reduced SBP from 196–204 to 155–165 at 2 h. Reported side effects with isradipine were dizziness and nausea. In four trials,8, 15, 16, 19 lacidipine (4 mg, 10 mg, 20 mg), in SLl or PO formulations, significantly reduced SBP, from 238–186 to 178–145, over 2–24 h. Four trials of nicardipine in various formulations significantly reduced SBP over 1–2 h, from 186–238 to 161–163. Reported side effects from nicardipine were mild headache, hypotension, orthostasis, chest pain, and tachycardia. In single trials, nitrendipine 5 mg PO (n = 85) reduced SBP from 228 to 156 over 2–8 h,22 and verapamil SL reduced SBP significantly over 1–2 h, with 80 mg more effective than 40 mg. Reported side effects with verapamil were decreased heart rate and headache.13

ACE Inhibitors

There were nine trials of ace inhibitors (one retrospective cohort,14 two prospective cohorts,23, 24 five RCTs,16, 2528 one non-randomized controlled trial29). All used captopril in doses ranging from 6.25 to 25 mg in both PO and SL formulations. SBP values were reduced from 244–198 to 177–144 at 0.17–12 h of captopril administration, with greater BP reduction seen using higher doses (25 mg).

Side effects reported with captopril were dizziness, headache, nausea and vomiting,24 dry mouth, vertigo,15 and flushing26.

Beta-Blockers

There were five trials of beta blockers (three prospective cohorts3032 and two RCTs18, 33). Labetalol was studied in doses ranging from 20 to 300 mg in both IV and PO formulations. Blood pressure values were reduced after 0.33–24 h of labetalol administration in all studies. Labetalol PO was investigated in only one small RCT (n = 10), which found that the mean PO dose of 221 mg reduced SBP from 195 to 154 at 4 h. Side effects reported with labetalol were dizziness,31, 33 drowsiness,33 headache,33 bradycardia,31 and pain at the injection site.32

Centrally Acting Antihypertensives

Two centrally acting agents, clonidine and ketanserin, were studied in seven trials. Clonidine was investigated in six trials (one prospective cohort,34 one retrospective cohort,35 four RCTs11, 12, 33, 36), which found that PO doses ranging from 0.1 to 0.6 mg reduced SBP from 204–196 to 165–155 at 2 h. Side effects reported with the use of clonidine were hypotension, orthostasis, impotence, sedation,37 dry mouth,33,36 mild transient drowsiness, and lower heart rate (average 6.2 beats/min).34

Ketanserin (unavailable in the U.S.) was studied in one RCT, also reducing BP after IV and SL administration. Somnolence was reported.11

Vasodilators

Six vasodilators were studied across nine trials. Urapidil and diazoxide were the most commonly studied (three25, 38, 39 and two trials, respectively40, 41). Fenoldopam,17 hydralazine,14 nitroglycerin,26 and nitroprusside17 were each evaluated once. In three trials, urapidil in IV or PO formulations significantly reduced SBP from 215–165 to 179–132 over 0.5–12 h. Side effects reported with urapidil were nausea, vomiting, drowsiness,39 headache, and orthostatic hypotension.38

Diazoxide (150–1290 mg IV) was investigated in two prospective cohort studies,41, 42 which found that 150–1290-mg IV doses rapidly reduced SBP, from 214–225 to 187–159 in less than 1 h. Side effects reported with diazoxide were uremia, acute pulmonary edema,40 palpitations, transient hemiparesis,42 pain at the site of IV infusion, a mild increase in heart rate, atrial tachycardia, and chest pain.41 In single trials, IV fenoldopam (n = 90) at a mean dose of 0.41 mcg/kg/min reduced SBP from 212 to 178, hydralazine (n = 19) reduced MAP from 244 to 126 at 0.5 h, and nitroglycerin (n = 40) reduced SBP from 190 to 150 at 1 h.

Combinations of Antihypertensives

Combinations of agents were studied in two trials: labetalol plus furosemide and clonidine plus chlorthalidone. Labetalol 300 mg PO plus Lasix 20 mg IV was evaluated in one small (n = 16) prospective cohort,43 which showed a decrease in SBP from 206 to 154 at 3 h. Clonidine plus chlorthalidone was investigated in one RTC,37 which found that PO clonidine doses of 0.2–0.8 mg plus chlorthalidone 25 mg reduced SBP from 193–182 to 142–137 at 24 h.

Direct Comparisons

SL and PO nifedipine were the most commonly studied antihypertensives (four trials), with two comparisons against lacidipine (one prospective cohort,8 one RCT19), one against ketanserin (RCT11), and one against captopril and nitroglycerin (RCT26). Captopril was evaluated in four comparative trials: with amlodipine, hydralazine and nifedipine (one retrospective cohort14), urapidil (one RCT25 and one prospective cohort29), and with nitroglycerin and nifedipine (one RCT26). Clonidine was compared with labetalol (one RCT33) and nitrendipine (one RCT12).

One direct comparison study (RCT17) evaluated fenoldopam and nitroprusside.

When captopril was compared to amlodipine, hydralazine, and nifedipine in a retrospective cohort study,14 there were no significant differences between these medications in their effect on BP reduction (p = 0.513). Captopril was superior to sublingual nitroglycerin in the first hour following administration (p = 0.001).26

In two studies comparing captopril and urapidil,25, 29 both drugs were found to effectively lower blood pressure within 1 h29 and at 12 h25 (p = 0.38/0.40).

When fenoldopam and nitroprusside were compared,17 the two antihypertensive agents were equivalent in controlling and maintaining BP. The adverse effect profiles of the drugs were similar: headache, dizziness, flushing, hypotension, nausea, vomiting, hyperhidrosis, and hypokalemia.

Clonidine and labetalol were compared in an RCT,33 with a similar reduction in blood pressure at 6 h and similar side effect profiles. Sedation, dizziness, orthostatic hypotension, and dry mouth were reported with clonidine; dizziness, drowsiness, and headache with labetalol.

Nitrendipine and IV clonidine were compared in one RCT,12 with similar reductions in BP up to 8 h. Side effects reported with nitrendipine were flushing and headache, and with clonidine were dizziness, somnolence, and bradycardia.

Risk of bias is summarized in Table 3. Most studies had unclear quality control standards regarding blood pressure measurements and excluded patients with significant comorbidities, such as chronic kidney disease,15, 3436, 38, 41 which are seen frequently in patients with hypertension.
Table 3

Cochrane Risk of Bias*

Author/Year

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants, personnel, and outcomes (performance bias)

Addressed incomplete data (attrition bias)

Free of selective reporting (reporting bias)

Free of other sources of 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 (+)

Among the controlled trials, only those by Komsuoglu,16 Woisetschlaeger,25 and Just35 had a low risk of bias for both the study design (random sequence generation and concealment of allocation) and the primary clinical outcome (blinding of outcome assessor).

DISCUSSION

In this systematic review of HU, the optimal choice of antihypertensive agent remains unclear (level 2B). Many agents demonstrated blood pressure-lowering benefit: captopril, labetalol, clonidine, amlodipine, verapamil, nitrendipine, isradipine, nifedipine, nitroglycerin, hydralazine, chlorthalidone, furosemide, diazoxide, nitroprusside, and fenoldopam. Other drugs that lowered blood pressure but are unavailable in the U.S. include lacidipine, ketanserin, and urapidil. Clinical choices in the setting of HU seemed to broaden as we conducted our extensive literature search. Side effects ranged from mild (dizziness, headache, nausea and vomiting, dry mouth, mild tachycardia, and sedation) to severe (hypotension, transient ischemic attack, uremia, and acute pulmonary edema).

Most studies limited data collection to the first few hours after initial presentation, which is not sufficient to assess morbidity and mortality.3 Studies were too clinically and methodologically diverse for a meta-analysis, and those that met our criteria for this systematic review included few patients. Most studies excluded patients with significant comorbidities, such as chronic kidney impairment; however, HU is a common complication in patients with associated comorbidities. In light of these factors, the generalizability of our findings is limited. Most studies that met our inclusion criteria provided only surrogate endpoint data, i.e. blood pressure lowering, and were short-term, lacking long-term morbidity and/or mortality outcomes, and providing statistical power only for differences in blood pressure lowering.

Our comprehensive systematic review regarding treatment of outpatient HU includes office and ER settings, limiting data to short-term observations of blood pressure (less than 24 h). This review also included studies based on blood pressure cut-offs, allowing us to distinguish studies that were mislabeled as urgencies or emergencies.

A limitation of this review is that it evaluated only English-language reports. However, Morrison et al.44 found no evidence of a systematic bias from language restrictions in systematic review-based meta-analyses in conventional medicine. We attempted to minimize publication bias by searching the gray literature; we may have missed negative or small(er) studies.

The most recent systematic review of HU, by Souza45 in 2008, included studies in outpatient and inpatient settings. Their Cochrane Review was limited to randomized controlled trials of calcium channel blockers or angiotensin-converting enzyme inhibitors. Although they excluded commonly used agents (e.g. clonidine, hydralazine, and labetalol3), many other reviews have demonstrated a benefit in blood pressure reduction from these agents. Side effects were problematic mainly for nifedipine and clonidine.

Intravenous medications, although effective, carry added costs, and therefore we do not recommend them; many available oral agents are appropriate alternatives. Some studies included in this review evaluated diuretics.37 However, since HU may be associated with hypovolemia, some recommend avoiding diuretics unless intravascular volume overload is present.37, 4648

For HU, current data suggest that a 30-min rest may significantly decrease blood pressure. However, many studies in this review did not have patients rest for 30 min prior to intervention.

Most medications used in reports we review here were short-acting. Lowering blood pressure too rapidly in patients with HU may be harmful. In their review, Kessler and Joudeh49 noted that there appears to be no benefit in attaining goal blood pressure within hours to days, and that findings from the VALUE trial50 suggest that lowering blood pressure within a 6 month-period may be a better approach. Therefore, avoidance of rapid-acting agents such as clonidine and nifedipine should be considered.

Other studies have used long-acting antihypertensive agents which have demonstrated morbidity and mortality benefits in hypertension outcomes trials. One such study, conducted by Grassi et al.,46 evaluated the long-acting dihydropyridine calcium channel blocker amlodipine and the ACE inhibitor perindopril in slowly lowering blood pressure toward goal for patients with HU. This study did not meet the inclusion criteria of our review, since it did not report changes in blood pressure within 48 h of treatment.

CONCLUSION

Additional longitudinal studies are needed to determine how best to safely decrease blood pressure in patients with HU. Larger and longer-term studies are also needed, including participants with other common comorbidities. Such research would hopefully provide more guidance to improve both short- and long-term cardiovascular outcome.

Notes

Acknowledgements

We would like to thank Dr. Pirouz Daeihagh, Associate Professor of Nephrology, Wake Forest Baptist Health, for providing assistance with key literature identification, and Ms. Lisa Porter, Wake Forest Baptist Health, for her administrative support.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

11606_2017_4277_MOESM1_ESM.docx (33 kb)
ESM 1 (DOCX 33 kb)

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Copyright information

© The Author(s) 2018

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Claudia L. Campos
    • 1
  • Charles T. Herring
    • 1
    • 2
  • Asima N. Ali
    • 1
    • 2
  • Deanna N. Jones
    • 1
  • James L. Wofford
    • 1
  • Augustus L. Caine
    • 1
  • Robert L. Bloomfield
    • 1
  • Janine Tillett
    • 1
  • Karen S. Oles
    • 1
  1. 1.Wake Forest Baptist Health, Medical Center BoulevardWinston-SalemUSA
  2. 2.Campbell University College of Pharmacy & Health SciencesBuies CreekUSA

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