S YS T E M AT I C R E V I E W P R O T O C O L

Risk factors for hypertensive crisis in adult patients:

a systematic review protocol
Irina Benenson 1,2  Frederick A. Waldron 3  Yuri T. Jadotte 1,2,4,5  Cheryl Holly 1,2,5
1
Rutgers University School of Nursing, Newark, USA, 2The Northeast Institute for Evidence Synthesis and Translation (NEST): a Joanna Briggs
Institute Centre of Excellence, 3Newark Beth Israel Medical Center, Newark, USA, 4Stony Brook School of Medicine, Stony Brook, USA, and 5Rutgers
University School of Public Health, Department of Epidemiology, Newark, USA

ABSTRACT

Objective: The objective of this review is to conduct comprehensive appraisal and synthesis of evidence on risk
factors for hypertensive crisis and, specifically, hypertensive emergencies among adult patients with hypertension.
Introduction: Hypertensive crisis is the most extreme form of poorly controlled hypertension that may lead to
acute target organ damage (hypertensive emergency). Hypertensive crisis is associated with increased mortality,
high utilization of health care and escalated healthcare costs.
Inclusion criteria: This review will include epidemiological studies with participants over 18 years old with
diagnosis of hypertension. The review will exclude pediatric, pregnant and postpartum patients. The review will
consider studies that explore risk factors for hypertensive crisis, defined as an acute elevation of blood pressure equal
or above 180/110 mmHg.
Methods: The search strategy aims to find both published and unpublished studies. The databases to be searched
will include MEDLINE (Ovid), Embase, Cochrane Database of Systematic Reviews and Web of Science. Following the
search, all identified studies will be screened against the inclusion criteria. Selected studies will be critically appraised
for methodological quality. Data on exposures and outcomes will be extracted from papers included in the review.
Quantitative data, where possible, will be pooled in meta-analysis. Effect sizes expressed as odds ratio and their 95%
confidence intervals will be calculated. Heterogeneity of studies will be assessed statistically. Subgroup analysis to
determine the association of risk factors with hypertensive emergencies will be conducted, if possible. Where
statistical pooling is not possible, the findings will be presented in a narrative form.
Systematic review registration number: PROSPERO CRD42019140093
Keywords Hypertensive crisis; hypertensive emergency; hypertensive urgency; malignant hypertension; risk
factors
JBI Database System Rev Implement Rep 2019; 17(11):2343–2349.

Introduction of damage to vital organs, particularly the heart,

ypertension (HTN) is one of the most common
H chronic conditions in the United States (US). If
a threshold of 130/80 mmHg is used, approximately
45% of US adults have HTN.1 The advent of effec-
tive antihypertensive therapies has led to improve-
ments in blood pressure (BP) control and contributed
to a reduction in HTN-related mortality.2 However,
despite these advances, poorly controlled HTN
remains a major health problem with increased risk
Correspondence: Irina Benenson, benensir@sn.rutgers.edu
The authors declare no conflict of interest.
DOI: 10.11124/JBISRIR-2017-003996
brain and kidneys.
Hypertensive crisis (HTNC) is the most extreme
form of poorly controlled HTN that can develop in
patients with known pre-existing HTN and in indi-
viduals who are not aware that they have HTN (i.e.
have not yet been diagnosed with HTN). Hyperten-
sive crisis may be an initial manifestation of HTN in
those patients.3,4 Hypertensive crisis is defined as a
severe and abrupt elevation of BP, which is classified
into two types: hypertensive emergency (HTN-E)
and hypertensive urgency (HTN-U) based on the
presence or absence of acute target organ damage,
respectively.5-8 Acute target organ damage is an
acute and potentially life-threatening dysfunction

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SYSTEMATIC REVIEW PROTOCOL
affecting cardiovascular, cerebrovascular and renal
systems.5,9 A hypertensive emergency is defined as a
severe increase in BP associated with potentially life-
threatening target organ damage such as myocardial
infarction, ischemic stroke, hemorrhagic stroke, pul-
monary edema, acute renal injury or aortic dissec-
tion.5-8 In this condition, hospitalization, preferably
in an intensive care unit, is required for prompt BP
control through administration of intravenous anti-
hypertensive medications. Hypertensive urgency, on
the other hand, is characterized by equally high BP in
the absence of symptoms suggesting acute organ
dysfunction.5-8 Hypertensive urgency is a manifesta-
tion of uncontrolled HTN that carries little short-
term risk,10,11 thus referral to the emergency depart-
ment (ED), hospitalization and immediate reduction
of BP is not necessary.12 These patients can be
effectively treated in outpatient settings by institu-
tion or intensification of antihypertensive drug ther-
apy.11,12 While HTN-E and HTN-U are often
described as two distinct types of HTNC, it still
remains unclear whether HTN-E is a more perni-
cious form of the disease relative to HTN-U or
whether they have disparate etiologies.
Historically, ‘‘malignant hypertension’’ described
an acute rise in BP accompanied by target organ
injuries such as encephalopathy, acute nephropathy
and retinopathy (including papilledema and retinal
hemorrhages).9 This terminology was listed in the
medical lexicon in the 1930s because, at that time,
patients with this condition had a prognosis that was
similar to patients with many cancers. However,
antihypertensive medications that safely lower BP
have improved outcomes of severe HTN,13 and,
therefore, the term is now considered outdated.
Hypertensive crisis is defined as a severe acute
elevation in BP. The levels of BP for the definition of
HTNC are not uniformly established. Some studies
define HTNC as an elevation of BP to at least 180
mmHg systolic and/or 110 mmHg diastolic,3,14
while others cite higher thresholds ( 180 and/or
120 mmHg).15-17 The US guidelines (the 2017
American College of Cardiology/American Heart
Association and the Seventh Report of the Joint
National Committee) define HTNC as systolic BP
180 mmHg and/or diastolic BP 120 mmHg.12,18
However, international guidelines from the 2016
National Heart Foundation of Australia, the 2016
National Institute for Health and Care Excellence,
the 2013 and 2018 European Society of
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I. Benenson et al.
Hypertension, and the European Society of Cardiol-
ogy use  180 mmHg systolic and/or  110 mmHg
diastolic as the definition of the HTNC.19-22 This
discrepancy reflects variability in clinical presenta-
tions and outcomes of HTNC, as the same degree of
blood pressure increase may translate into life-
threatening target organ injuries in one patient
(HTN-E) or may result in minimal or no symptoms
in another patient (HTN-U).5
Hypertensive crisis is relatively common. It is esti-
mated that approximately 1% of patients with hyper-
tension will at some point develop HTNC.13 Acute
severe HTN is present in 25% of all ED visits.13
Compared with the frequency of encounters for
severely elevated BP, true HTN-E is quite rare. A
recent nationwide study demonstrated that the fre-
quency of HTN-E was 0.2% of all adult ED visits in
the US.23 Although uncommon, HTN-E accounts for
most morbidity and mortality associated with HTNC.
Mortality from HTNC, more precisely from
HTN-E, has declined significantly with the wide-
spread use of antihypertensive drugs. The five-year
survival rate in patients diagnosed with ‘‘malignant
HTN’’ has shown improvement from 37% in 1960 s
to 91% in 2000 s.2 Despite this remarkable progress,
HTNC carries a significant risk for cardiovascular
morbidity and mortality. In a large multi-centered
study from the US that included patients with severe
acute HTN treated with intravenous therapy, the
hospital mortality rate was 6.9%, with a subsequent
90-day mortality of 4.6%.13 More than half of these
patients (59%) developed new or worsening end-
organ damage, most commonly renal insufficiency,
acute heart failure, myocardial ischemia or infarc-
tion, and encephalopathy.13 Registry data from
Europe revealed 4% mortality (30-day) in patients
who required parenteral antihypertensive therapy to
control BP, and an overall rate of vital organ injuries
of 19%.24
In addition to poor clinical outcomes, hospital
admission and readmission rates for patients with
HTNC are strikingly high. An analysis of the nation-
wide inpatient database revealed that there was a
63% increase in the number of admissions for HTN-
E from 2002 to 2012 (9511 to 15,479 admissions).25
It was reported that approximately one-third of
patients discharged after hospitalization with severe
HTN were re-hospitalized within 90 days.13 Reho-
spitalizations with recurrent severe HTN accounted
for 29% of rehospitalizations and tended to occur
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early (<1 month) after discharge.13 These data sug-
gest that HTNC is responsible for major use of
healthcare resources and is a significant economic
burden on the system; a large portion of these are
directly attributable to recurrent episodes of HTNC.
Hypertensive crisis is associated with adverse
patient outcomes and high utilization of healthcare
services. In this context, understanding risk factors
for the development of HTNC is a first step in
improving medical care of hypertensive patients
while reducing healthcare burden. Several studies
have addressed the effect of non-modifiable (age,
sex, ethnicity) and modifiable (medication non-
adherence, poor access to medical care, cardiovas-
cular and renal comorbidities) risk factors associated
with severely elevated BP. It was reported that male
sex, African American race, older age and history of
cardiovascular comorbidities increase the likelihood
of HTNC.16,17,26-29 Lack of medical insurance and
poor access to medical care were found to be the
strongest predictors of HNTC in an inner-city
minority population where financial barriers to care
contribute to the poor control of HTN and subse-
quent development of HTNC.27 Non-adherence to
antihypertensive medications was identified as the
most important risk factor for HTNC.3,15,17,30
Patients with comorbid cardiovascular conditions
(e.g. coronary artery disease, congestive heart fail-
ure), chronic renal failure and obesity had a higher
risk for developing HTNC and HTN-E.15,26,31
Despite the growing interest in the risk factors of
HTNC and specifically HTN-E, to date no compre-
hensive appraisal of the evidence has been con-
ducted. A preliminary search of PROSPERO,
MEDLINE, the Cochrane Database of Systematic
Reviews and the JBI Database of Systematic Reviews
and Implementation Reports was conducted and no
current or underway systematic reviews on the topic
were identified. A systematic review of the available
studies will therefore add to the body of knowledge
and inform clinicians, healthcare administrators and
public health workers on high-risk populations, and
assist in creating targeted interventions for these
groups.
Review questions
i) What are the modifiable and non-modifiable
risk factors for HTNC in adult hypertensive
patients?
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I. Benenson et al.
ii) What are the modifiable and non-modifiable
risk factors for HTN-U in adult hypertensive
patients?
iii) What are the modifiable and non-modifiable
risk factors for HTN-E in adult hypertensive
patients?
Inclusion criteria
Population
This review will consider studies that include par-
ticipants of both sexes who are over 18 years old
with the diagnosis of HTN. The review will exclude
pediatric, pregnant or immediate postpartum
patients as the etiology and risk factors for HTNC
are different in these populations.
Exposure of interest
This review will consider studies that explore risk
factors for HTNC and hypertensive emergencies.
The factors will include non-modifiable (age, sex,
ethnicity) and modifiable factors, such as socio-eco-
nomic factors (e.g. lack of medical insurance, lack of
access to medical care), adherence to medical thera-
pies, presence of comorbidities (e.g. diabetes, hyper-
lipidemia, coronary artery disease, history of stroke,
chronic kidney disease, congestive heart failure) and
substance abuse.
Outcomes
The primary outcome of interest is incidence of
HTNC and its subtypes, HTN-E and HTN-U, mea-
sured as odds ratio. The incidence of HTNC, HTN-E
and HTN-U will be treated separately, since they are
not analogous conditions. Hypertensive crisis will be
defined as an acute elevation of BP  180 mmHg
systolic and/or  110 mmHg diastolic. Hypertensive
emergency will be defined as an acute elevation of BP
 180 mmHg systolic and/or  110 mmHg diastolic
accompanied by acute target organ damage (e.g.
myocardial infarction, acute or worsening heart
failure, pulmonary edema, ischemic stroke, hemor-
rhagic stroke, acute kidney injury, aortic dissection,
hypertensive encephalopathy, acute hypertensive
retinopathy). Hypertensive urgency will be defined
as an acute elevation of BP  180 mmHg systolic
and/or  110 mmHg diastolic without evidence of
acute target organ damage. The level of BP  180
mmHg systolic and/or  110 mmHg diastolic will be
used since this is the lowest threshold for the defini-
tion of HTNC across major guidelines. Studies that
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SYSTEMATIC REVIEW PROTOCOL
do not include these specific BP thresholds will
be excluded.
The secondary outcome is the prevalence of non-
modifiable and modifiable risk factors measured as
an event rate (frequency). Studies that do not report
on these specific outcomes of interest will be
excluded.
Types of studies
The review will consider epidemiological study
designs including prospective and retrospective
cohort studies, case control studies and analytical
cross-sectional studies.
Methods
The proposed systematic review will be conducted in
accordance with the Joanna Briggs Institute meth-
odology for systematic reviews of etiology and
risk.32,33
Search strategy
The search strategy aims to find both published and
unpublished studies. A three-step search strategy will
be utilized in this review. An initial limited search of
MEDLINE will be undertaken followed by an anal-
ysis of the text words contained in the title and
abstract, and of the index terms used to describe
each article. A second search using all identified
keywords and index terms will then be undertaken
across all included databases. The MEDLINE (Ovid)
search strategy is shown in Appendix I. Thirdly, the
reference lists of all identified reports and articles
will be searched for additional studies. Only studies
published in English language and available in full
text will be considered for inclusion in this review. A
search range based on the year of publication will
not be set to allow greater sensitivity.
Information sources
The databases to be searched include: MEDLINE
(Ovid), Embase, Cochrane Database of Systematic
Reviews, Web of Science and CINAHL (EBSCO).
The search for unpublished studies will include:
ProQuest Dissertation and Theses, the directory of
gray literature via the New York Academy of Medi-
cine website, ClinicalTrials.gov, WHO International
Clinical Trials Registry Platform (who.int), open-
grey.eu, greynet.org, Institute of Medicine reports
(nationalacademies.org), Google Scholar/MedNar,
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I. Benenson et al.
websites of World Hypertension League, American
Heart Association, American College of Cardiology,
International Society of Hypertension, European
Society of Hypertension, and American Society
of Hypertension.
Study selection
Following the search, all identified citations will be
collated and uploaded into EndNote X9 (Clarivate
Analytics, PA, USA) and duplicates removed. Titles
and abstracts will then be screened by two indepen-
dent reviewers for assessment against the inclusion
criteria for the review. Studies that may meet the
inclusion criteria will be retrieved in full and their
details imported into JBI System for the Unified
Management, Assessment and Review of Informa-
tion (JBI SUMARI; Joanna Briggs Institute, Ade-
laide, Australia). The full text of selected studies
will be retrieved and assessed in detail against the
inclusion criteria. Full-text studies that do not meet
the inclusion criteria will be excluded and reasons
for exclusion will be provided in an appendix in the
final systematic review. The results of the search will
be reported in full in the final report and presented in
a Preferred Reporting Items for Systematic Reviews
and Meta-analyses (PRISMA) flow diagram.34 Any
disagreements that arise between the reviewers (IB,
FAW) will be resolved through discussion or with a
third reviewer (YTJ, CH).
Assessment of methodological quality
Selected studies will be critically appraised by two
independent reviewers (IB, FAW) at the study level
for methodological quality in the review using stan-
dardized critical appraisal instruments from the
JBI.32 Authors of papers will be contacted to request
missing or additional data for clarification, where
required. Any disagreements that arise will be
resolved through discussion or with a third reviewer
(YTJ, CH). The results of critical appraisal will be
reported in narrative form and in a table. The assess-
ment of methodological quality will contribute to an
evaluation of the quality of the evidence and impact
of bias on the findings. No studies will be excluded
based on methodological quality.
Data extraction
Data will be extracted from papers included in the
review using the standardized data extraction tools
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SYSTEMATIC REVIEW PROTOCOL
in JBI SUMARI32 by two independent reviewers (IB,
FAW). The data extracted will include specific
details about the exposure of interest including dif-
ferent exposure categories if applicable, populations,
study methods and outcomes or dependent variables
of significance to the review question and specific
objectives. Any disagreements that arise between the
reviewers will be resolved through discussion or with
a third reviewer (YJT, CH). Authors of papers will
be contacted to request missing or additional data,
where required.
Data synthesis
Quantitative data will, where possible, be pooled in
statistical meta-analysis. All results will be subject to
double data entry. Where effect sizes are expressed
as odd ratios, relative ratios, correlation coefficients
or rates, OpenMeta [Analyst] software will be used
for statistical pooling. For studies that report only
the results of regression analyses, the authors will
aim to extract the maximally adjusted effect sizes for
the predictors of interest to facilitate greater compa-
rability of the effect size data across studies. Effect
sizes expressed as odds ratio (for categorical data)
and their 95% confidence intervals will be calculated
for analysis. Heterogeneity will be assessed statisti-
cally using Q-statistic, which will provide a test of
the null hypothesis that all included studies in the
analysis share a common effect size. The I2 statistics
will be calculated to estimate what proportion of the
observed variance reflects differences in true effect
sizes rather than a sampling error. All studies that
report on HTNC, HTN-E or HTN-U based on the
threshold of  180 mmHg systolic and/or  110
mmHg diastolic pressure will initially be pooled into
one meta-analysis, which will provide evidence of
the impact of the risk factors on the outcome of
HTNC (since both HTN-U and HTN-E meet the
threshold of hypertensive crisis). Data from studies
that provide detailed definitions for distinguishing
between the outcomes of HTN-E versus HTN-U will
then be pooled separately using subgroup analysis to
determine the association of the risk factors with
these two outcomes. The evidence of end-organ
damage will be used to determine how to classify
studies for the subgroup analyses. Where statistical
pooling is not possible, the findings will be presented
in narrative form including tables and figures to aid
in data presentation where appropriate.
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I. Benenson et al.
Assessing certainty in the findings
A Summary of Findings (SoF) will be created using
the Grades of Recommendation, Assessment, Devel-
opment and Evaluation (GRADE) approach to grade
the quality of evidence. The SoF will present the
following information where appropriate: estimates
of relative risk and a ranking of the quality of the
evidence based on study limitations (risk of bias),
indirectness, inconsistency, imprecision and publica-
tion bias. The following outcomes will be included in
the SoF: risk of HTNC, risk of HTN-U and risk of
HTN-E.
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Appendix I: Search strategy for MEDLINE (Ovid)

1. Exp Hypertension, Malignant/

2. Hypertension/co [Complications]
3. malignant hypertension.mp
4. hypertensive emergenc.mp
5. hypertensive urgenc.mp
6. accelerated hypertens.mp
7. severely elevated blood pressure.mp
8. severely elevated hypertens.mp
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. Exp Risk Factors/
11. Risk Assessment/
12. Exp Population Characteristics/
13. Exp Epidemiology/ cl, do, mt, pc, st, sn, td [classification, diagnosis, methods, prevention, standards,
statistics, trends]
14. risk factor.mp
15. predict.mp
16. characteristic.mp
17. epidemiolog.mp
18. profile.mp
19. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20. Exp Adult/
21. Young adult/
22. adult.mp
23. 20 or 21 or 22
24. 9 and 19 and 23

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