European Journal of Cardiovascular Medicine

Systemic arterial hypertension is a chronic medical condition with elevated blood pressure in the arteries. It very often leads to many acute as well as chronic complications. An important complication of uncontrolled arterial hypertension is manifested as hypertensive crisis.

Hypertensive crisis (malignant or accelerated hypertension) refers to the uncontrolled arterial hypertension with elevated blood pressure (systolic ≥180 and / or diastolic ≥120) and conferring a high risk of morbidity and mortality.¹

Hypertensive urgency refers to severe elevation of blood pressure without any target organ dysfunction. Hypertensive emergency is characterized by severe elevation of blood pressure (systolic ≥180 and / or diastolic ≥120) with evidence of impending or progressive target organ damage requiring immediate blood pressure reduction to prevent or limit target organ damage.²

Early intervention with appropriate therapeutic strategies is needed to limit morbidity and mortality in these patients.²

The incidence of hypertensive crises has changed over the previous few decades, even though they still carry significant mortality and morbidity. Different scientific societies have produced repeated and updated guidelines for the management of hypertensive crises, but no clear data is available about the possible influence of drug differences on morbidity and mortality in patients treated for hypertensive crises. The choice for the appropriate medication(s) depends on the clinical picture and the associated co-morbidities.³

Studies from Europe and America have showed that hypertensive crisis constituted 3% of all medical emergencies with 24% of them being hypertensive emergencies and 76% hypertensive urgencies,2 resulting in about 2 out of every 1000 adult emergency visits, and 6 out of 1000 adult emergency visits in previous hypertensive subjects. ⁴ Studies in Indian population have shown that hypertensive crisis constituted 0.59% of total medical admissions and 18.04% of ICU admissions with the prevalence of hypertensive emergencies being 1.22%.^5,6

Subjects of either gender aged ≥18 years with systolic BP ≥180 and / or diastolic BP ≥110 presenting to the Department of Emergency Medicine and / or admitted to the ICU of Kempegowda institute of medical sciences Hospital and Research Centre, Bangalore were included in the study. Clearance and approval were obtained from the Institutional Ethics Committee before the initiation of the study. Written informed consent was obtained from all the study subjects / legal representatives for scrutinizing the records as well as collection of data after fully explaining the study procedure to their satisfaction.

Study Duration

The study duration was 18 months.

Sampling

Purposive sampling including 100 patients who received treatment for hypertensive crisis.

Study procedure

After obtaining written informed consent, demographic data of all subjects including the age, religion, and place of residence were recorded. A detailed history was obtained including the presenting complaints/symptoms of the study subjects. An exhaustive and detailed past medical history along with history of drug use with particular emphasis on antihypertensive medication was obtained from all study subjects. Risk factors including history of alcohol use and tobacco smoking was recorded.

All study subjects underwent thorough physical examination including recording of vital signs, the body mass index (BMI) was estimated in all study subjects. Arterial blood pressure was recorded in the supine position in both arms using standard cuff using calibrated sphygmomanometer. BP was estimated serially and continuously at an interval of one hour for the first 24 hours, every 3 hours for the 24-48 hours interval and every 6 hours thereafter till the BP returned to normal levels. The details of the drug(s) used in the management of hypertensive crisis were recorded in all study subjects including their generic name, dose, route of drug administration. Any change in the dose or in the medication(s) was also recorded. Following tests were done in subjects with hypertensive emergencies as an as-needed basis depending upon the clinical presentation.

1. Ocular Fundoscopy
2. Electrocardiogram
3. CT scan
4. Estimation of Troponin-I
5. 2D echocardiography

Statistical analysis

The data collected was analyzed statistically using descriptive statistics namely mean, standard deviation for quantitative variables. The results were depicted in the form of percentages and graphs. Statistical software namely SPSS v20 was used for the analysis of data and Microsoft Word and Excel to generate graphs and tables.

Inclusion Criteria

1. Subjects of either gender aged ≥18 years with systolic BP ≥180 and / or diastolic BP ≥110.
2. Subjects and/or legal representatives willing to give written informed consent.

Exclusion Criteria

1. Pregnancy related hypertensive crises.

Socio-demographic characteristics:

In our study, we report that the mean (SD) age of participants diagnosed with HTN-U was 53.83 (13.57). This is in accordance to the other published studies where higher age group is more susceptible for hypertensive crisis (Table 1). In the study by Varun et al, 28 out of 50 participants belonged to age group of 50-69 years.⁷ A similar finding was seen in the study published by Salkic et al where the mean (SD) age of the male subjects was 55.83 (11.06) years, while the female subjects' average age was 59.41 (11.97) years and the majority (28.23%) belonged to the age group 60 – 69 years.⁸As per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7), hypertension occurs in two thirds of individuals after age of 65.² The Framingham Heart Study showed that in men and women free of hypertension at 55 years of age, have a remaining lifetime risks for development of hypertension through 80 years which is 93% and 91% respectively.⁹ This means that more than 90% of individuals who are free of hypertension at 55 years of age will develop it during their remaining lifespan.¹⁰ The important reasons that have caused an increase in incidence of hypertension with age is increasing arterial stiffness,¹¹ decline in neurohormonal mechanisms such as the renin-angiotensin-aldosterone system¹² and the progressive development of glomerulosclerosis and interstitial fibrosis, which is associated with a decline in GFR and reduction of other homeostatic mechanisms.¹³

We also report that a majority of our participants followed Hinduism by faith and are from the urban areas. This is greatly due to the population that our hospital serves. The hospital is located in the urban area and is a tertiary care referral centre with an attached medical college which explains why we also receive participants from rural areas as they are being referred for specialized and advanced care. Also our nation being a Hindu predominant nation with 79.8% following Hinduism as per the 2011 census, we have a larger representation of participants who follow Hinduism.¹⁴

Symptoms at presentation:

We report that headache is the most common symptom at presentation which was seen in 33% of our study population. This was followed by giddiness. This is also similar to the other studies published in India (Table 2). In the study by Varun et al, headache was seen in 48% and giddiness in 38% of the study population.¹⁵ These included, chest pain (4 out of 37), dyspnoea (5 out of 37), altered sensorium (8 out of 37) and confusion (5 out of 37). In a study by Dhadke et al, the most common presenting complaint in subjects with HTN-E was dyspnoea seen in 17 subjects (34%), followed by neurological deficit seen in 14 subjects (28%).¹⁵  The clinical pattern of presentation of hypertensive crises as studied by Zampaglione et al also revealed a similar picture where in chest pain (27%), dyspnoea (22%), and neurological deficit (21%) were the most frequent signs in hypertensive emergencies.¹⁶ In the study by Salkic et al, the most common symptoms were headache (74.11%), chest pain and shortness of breath (62.35%), vertigo (49.41%), and nausea and vomiting (41.17%).¹⁸ Another study from Tanzania also reported that altered mental status and headache were the two most common clinical presentations in the hypertensive emergency group.¹⁷ Nausea. Vomiting and weakness were other non-specific symptoms which were noted in our participants similar to the reports from other studies mentioned here.^16,17,18,

Co-morbidities associated with hypertensive crisis:

We report that, major population (73%) in the HTN-U group were not aware that they had been suffering from hypertension even before this episode of crisis, whereas in the HTN-E group, 16.2% did not know that they were hypertensive. The study by Martin et al, also show similar findings though the number of unknown hypertensives in the HTN-U subjects were very less (15.4%) when compared to our study. The number of unknown hypertensions in the HTN-E participants, however, was 26.4% when compared to 16.2% in our study.¹¹

Diabetes mellitus is another prevalent comorbidity. The number of subjects with diabetes mellitus was far higher in the HTN-E group (73%) when compared to HTN-U group (20.6%) based on our study results. A large population-based study published recently reports that out of the 1,320,555 adults, the crude prevalence of diabetes and hypertension was 7.5% (95% CI, 7.3%-7.7%) and 25.3% (95% CI, 25.0%-25.6%), respectively.⁹

We also report that obesity / overweight was seen in 39% of our study participants. The global burden of obesity among adults in the year 2014 was quite high with 39% of all adults being overweight/obese and 13% obese¹⁸ and in India, 11.48% of adults were overweight/obese and 2.2% obese in 2005-06.¹⁹

Drug utilisation:

Some of the common drugs which have been used in the treatment of hypertension in the past were calcium channel blockers (amlodipine, cilnidipine), beta clockers (atenolol, metoprolol), angiotensin receptor blockers (losartan, telmisartan) and diuretics (frusemide, torsemide, hydrochlorothiazide) some of which were used as fixed dose combinations. We find that these were as per the existing guidelines which we follow in most of India. According to the Joint National Committee – 8 recommendations for non-Black population, including those with diabetes mellitus, the initial anti-hypertensive treatment should include a thiazide-type diuretic, calcium channel blocker, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker.²⁰

Table 1: Baseline demographic characteristics

*Assessed as per census of India report 2011 ²¹

Table 2: Initial clinical presentation of study subjects

*Overlapping symptoms were observed in 16 subjects: headache + nausea (n=4); palpitations + chest pain (n=2); dyspnoea + chest pain (n=2; weakness + altered sensorium (n=2); giddiness + epistaxis (n=1); headache + altered sensorium (n=1; blurred vision + altered sensorium (n=1); confusion + altered sensorium (n=1); confusion + dyspnoea (n=1); giddiness + confusion + blurred vision (n=1);

Table 3: Body mass index (BMI); distribution of study subjects

*as per WHO classification of BMI ²²

†Average age 24.29 years; range 17.6-33.6 years

‡Average age 23.16 years; range 18.7-34.9 years

Table 4: Blood pressure at presentation*

*Done bedside manually using a standard sphygmomanometer in both the arms in supine position using standard cuff

† Maximum SBP recorded 250 mmHg in HTN-E and 220 mmHg in HTN-U

† Minimum SBP recorded 180 mmHg in HTN-E and 180 mmHg in HTN-U

‡ Maximum DBP recorded 120 mmHg in HTN-E and 120 mmHg in HTN-U

‡ Minimum DBP recorded 80 mmHg in HTN-E and 80 mmHg in HTN-U

Table 5: Initial pharmacological intervention of HTN-U

* All medications were administered as oral tablets except labetelol was administered both as oral tablet (n=4) as well as intravenous injection (n=1)

† Dose: 10.0 mg (n=43)

‡Dose: 10 mg (n=7)

• Dose: 0.2 mg (n=7)

‖Dose: Tablet 100 mg (n=4), injection 20 mg (n=1)

¶Dose: 50 mg (n=1)

Table 6: Initial pharmacological intervention of HTN-E

* All medications were administered as oral tablets except labetelol intravenous injection and Nitroglycerin intravenous infusion.

†Dose: 2.5 mg (n=1); 10.0 mg (n=12)

‡Dose: 10 mg (n=5)

• Dose: 0.2 mg (n=5)

‖ FDC of tablet losartan 50 mg + amlodipine 5 mg (n=1)

¶Dose: 20 mg (n=12)

#Dose: 5mcg/min (n=1

 Figure 1: Change in mean BP over time in subjects with HTN-U with amlodipine as the initial management

Figure 2: Change in mean BP over time in subjects with HTN-U with cilnidipine as the initial management

Figure 3: Change in mean BP over time in subjects with HTN-E with labetalol as the initial management

When it comes to the treatment of hypertensive crises, hypertensive emergency almost always requires a prolonged hospital stay including an intensive care unit stay in most cases and requires the use of parenteral anti-hypertensive agents.²³ On the other hand, HTN-U can be successfully treated by initiation, re-initiation or titration of the oral anti-hypertensive agents.²⁵ For HTN-U, we report the predominant use of oral amlodipine or cilnidipine both of which are calcium channel blockers (Table 5). This is followed by the use of clonidine which is a centrally acting α₂ receptors agonist, metoprolol which is a selective β₁ receptor blocker or labetalol which is a dual alpha (α₁) and beta (β₁/β₂) adrenergic receptor blocker. As per the guidelines, all except for one patient just received an oral drug. For subjects with HTN-E, amlodipine or cilnidipine were the predominant initial intervention. However, there was much more frequent use of labetalol and nitroglycerine parenteral preparations (Table 6). It is also noted that though the number of participants with HTN-E were only 37, there has been 260 pharmacological interventions suggesting that each patient has received more than one intervention unlike in HTN-U. Also, the total number of participants with HTN-E who received an intravenous drug is 26/37. These management strategies are in line with the existing guidelines that guide the treatment of hypertensive crisis.²⁴ These guidelines allow the use of various agents like vasodilators (hydralazine, nitroglycerine), calcium channel blockers (amlodipine, cilnidipine, clevidipine), beta blockers (esmolol, labetalol, metoprolol), ACE inhibitors (enalaprilat), alpha antagonist (phentolamine) especially in cases of pheochromocytoma and dopamine D₁ receptor agonist (fenoldopam).²⁴

Effectiveness of amlodipine:

The sub-group analysis of participants who were initiated on amlodipine as a treatment option was done and this showed the efficacy of its use in hypertensive crisis. Within the first 6 hours, it has recorded a percentage fall of 40% in the SBP and 20% in the DBP in patient with HTN-U while it was a little delayed in subjects with HTN-E probably due to a much severe underlying pathophysiological mechanisms in HTN-E when compared to HTN-U (Figure 1). A study by Grassi et al, published in the year 2008 reports that a favourable response in blood pressure (2 hours after drug administration) was observed in 70.7% (94 of 133), 75.5% (105 of 139), and 84.3% (86 of 102)of the amlodipine, perindopril, and labetalol groups, respectively (amlodipine vs labetalol vs perindopril.²⁵

Effectiveness of cilnidipine:

Cilnidipine was another calcium channel blocker that was used in our setting. It achieved a maximum percentage fall of 40% in SBP and 25% fall in DBP similar to Amlodipine. The highest percentage fall was achieved much earlier in the HTN-U group when compared to the HTN-E group (Figure 2).  Cilnidipine has an advantage of causing less reflex tachycardia, less pedal oedema and better control of proteinuria in comparison to L-type CCB. By causing dilatation of efferent arteriole, it causes less damage to glomeruli and suppresses podocyte injury. Cilnidipine also increases insulin sensitivity.²⁶ A study by Zaman et al from India which compared the efficacy of Amlodipine and cilnidipine reported that both the drugs significantly reduced both SBP and DBP and cilnidipine was also associated with decreased reflex tachycardia and decreased urinary protein excretion.²⁷

Effectiveness of labetalol:

We report the use of labetalol in the oral form for HTN-U and in the injectable from for HTN-E. There was a 45% fall in SBP and 30% fall in DBP from baseline among participants those who were prescribed labetalol as the initial management strategy (Figure 3). In a study comparing labetalol with nitroprusside in 15 individuals with malignant hypertension, reported an equal attainment of target BP within 60 minutes in both groups with similar reductions in MAP With labetalol, lesser percent decrease in systemic vascular before and after therapy than with sodium nitroprusside (p<0.05).²⁸

Majority of the participants in the HTN-U group had oral pharmacological interventions and were discharged within 12 hours of hospital admission. Those with HTN-E had higher number of parenteral drugs that were used and had been in the hospital for a maximum of 5 days. With regards to the treatment of hypertensive crisis, we report the predominant use of oral amlodipine or cilnidipine followed by the use of clonidine which is a centrally acting α2 receptors agonist, metoprolol which is a selective β₁ receptor blocker or labetalol which is a dual alpha (α₁) and beta (β₁/β₂) adrenergic receptor blocker. Intravenous nitroglycerine and intravenous labetalol were commonly used in subjects with HTN-E. The sub-group analysis with the common drugs used like amlodipine, cilnidipine and labetalol showed that all are effective in reducing the blood pressure both SBP and DBP.

Strengths and limitations of the study:

The strength of our study is that it is a single centre first-of-a-kind study in our geographical region that allows us to compare the use of different anti-hypertensive medications among participants diagnosed with HTN-U and HTN-E in one study. A single centre study in this case avoided the bias arising out of multiple treatment protocols in place in different centres. The limitations of our study, however, included a sample size. Also, a randomized controlled design would have helped us in better comparing the efficacy of the different drugs used at the initiation of the treatment for hypertensive crisis.

1. Rodriguez MA, Kumar SK, De Caro M.  Hypertensive Crisis.  Cardiology in Review. 2010; 18(2): 102-3
2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289:2560–2572.
3. Muiesan ML, Salvetti M, Amadoro V, Di Somma S, Perlini S, Semplicini A, Borghi C, Volpe M, Saba PS, Cameli M, Ciccone MM. An update on hypertensive emergencies and urgencies. Journal of Cardiovascular Medicine. 2015 May 1;16(5):372-82.
4. Katz JN, Gore JM, Amin A, Anderson FA, Dasta JF, Ferguson JJ,etal.Practice patterns, outcomes, and end-organ dysfunction for patients with acute severe hypertension: The Studying the Treatment of Acute hypertension (STAT) Registry.  American Heart Journal 2009. doi: 10.1016/j.ahj.2009;07(20): 601-6
5. Dhadke SV, Dhadke VN, Batra DS. Clinical Profile of Hypertensive Emergencies in an Intensive Care Unit. Journal of The Association of Physicians of India. 2017; 65: 18 – 22.
6. Salagre SB, Itolikar SM, Gedam K. A Prospective Observational Study to Determine the Prevalence and Clinical Profile of Patients of Hypertensive Crisis in a Tertiary Care Hospital. J Assoc Physicians India 2017; 65:14-21.
7. Varun MS, Gangaram U, Nagabushana MV, Siddappa HG, Soren B. Clinical study of hypertensive crisis at a tertiary care hospital of South India. Int J Adv Med 2018; 5:1168-71.
8. Salkic S, Batic-Mujanovic O, Ljuca F, Brkic S. Clinical Presentation of Hypertensive Crises in Emergency Medical Services. Materia SocioMedica. 2014; 26:6-12
9. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996; 275:1557–1562
10. Lionakis N, Mendrinos D, Sanidas E, Favatas G, Georgopoulou M. Hypertension in the elderly. World J Cardiol. 2012;4(5):135-47.
11. Martin JF, Higashiama E, Garcia E, Luizon MR, Cipullo JP. Hypertensive crisis profile. Prevalence and clinical presentation. Arq Bras Cardiol. 2004;83(2):131-6
12. Epstein M. Aging and the kidney. J Am SocNephrol. 1996; 7:1106–1122
13. Beck LH. The aging kidney. Defending a delicate balance of fluid and electrolytes. Geriatrics. 2000; 55:26–28, 31-32
14. Office of the Registrar General & Census Commissioner, India. Census 2011. Available at URL: http://www.censusindia.gov.in/2011-Common/CensusInfo.html, [accessed on 25 oct, 2018]
15. Pacheco HG, Victorino NM, Urquiza JP, Castillo AA, Herrera UJ, Mendoza AA, et al. Patients with hypertensive crises who are admitted to a coronary care unit: clinical characteristics and outcomes. J ClinHypertens. 2013 Mar;15(3):210-4
16. Zampaglione B, Pascale C, Marchisio M, Cavallo-Perin P. Hypertensive urgencies and emergencies. Prevalence and clinical presentation. Hypertension. 1996 Jan;27(1):144-7.
17. Shao PJ, Sawe HR, Murray BL, Mfinaga JA, Mwafongo V, Runyon MS. Profile of patients with hypertensive urgency and emergency presenting to an urban emergency department of a tertiary referral hospital in Tanzania. BMC Cardiovascular Disorders (2018) 18:158
18. World Health Organization (WHO). Obesity and Overweight factsheet from the WHO. World. 2015. Available from http://www.who.int/mediacentre/factsheets/fs311/en/ [[last accessed on 25th Nov, 2018]
19. International Institute for Population Sciences (IIPS) and Macro International. 2007. National Family Health Survey (NFHS-3), 2005–06: India: Volume I. Mumbai: IIPS. Accessed from http://rchiips.org/nfhs/NFHS-3%20Data/VOL-1/India_volume_I_corrected_17oct08.pdf on 25-02-2016 [accessed on 13oct 2018]
20. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J,et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). Jama. 2014 Feb 5;311(5):507-20
21. Census of India report 2011 http://censusindia.gov.in/2011-prov-results/paper2/data_files/India2/1.%20Data%20Highlight.pdf [ accessed on 1nov 2018]
22. BMI-WHO http://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi [ accessed on 13-nov 2018 ]
23. Mako K, Ureche C, Jeremias Z. An Updated Review of Hypertensive Emergencies and Urgencies. Journal of Cardiovascular Emergencies 2018;4(2):73-83
24. Benken ST. Acute cardiac care. In: Abel EE, Bauer SR, Benken ST, et al, eds. Updates in Therapeutics: Critical Care Pharmacy Preparatory Review Course, 2017 ed. Lenexa, KS: American College of Clinical Pharmacy, 2017 p7-30
25. Grassi D, O’Flaherty M, Pellizzari M, Bendersky M, Rodriguez P, Turri D, Forcada P, Ferdinand KC, Kotliar C, Group of Investigators of the REHASE Program6. Hypertensive urgencies in the emergency department: evaluating blood pressure response to rest and to antihypertensive drugs with different profiles. The Journal of Clinical Hypertension. 2008 Sep;10(9):662-7.
26. Shete MM. Cilnidipine: Next Generation Calcium Channel Blocker. Journal of The Association of Physicians of India. 2016; 64: 95 – 99
27. Zaman ZA, KumariV.Comparison of the effects of amlodipine andcilnidipine on blood pressure, heart rate, proteinuriaand lipid profile in hypertensive patients. Int J BasicClin Pharmacol2013; 2:160-4.
28. 28. Immink RV, van den Born BJ, van Montfrans GA, Kim YS, Hollmann MW, van Lieshout JJ. Cerebral hemodynamics during treatment with sodium nitroprusside versus labetalol in malignant hypertension. Hypertension. 2008 Aug 1;52(2):236-40.