1 INTRODUCTION

Hypertension (HTN) is common in hospitalized patients with prevalence rates up to 72%.1 In patients who are admitted for severe HTN (systolic/diastolic blood pressure [SBP/DBP] > 180/110 mm Hg) with acute end organ damage, that is, hypertensive emergency, immediate intravenous (IV) pharmacotherapy under intensive care monitoring is recommended to limit progressive injury.2 However, far more common is incident severe HTN in already hospitalized patients occurring during an admission unrelated to HTN.3-5 Increased blood pressure (BP) in ambulatory patients is associated with increased risk of cardiovascular disease (CVD) related outcomes including stroke, myocardial infarction and coronary artery disease increases, but treatment of severe inpatient HTN in the absence of acute target organ injury is currently not directed by guidelines.6, 7 Additionally, recent studies have found that treatment of severe inpatient HTN resulted in greater BP drops, and higher rates of acute kidney injury and myocardial injury.5, 8 However, these studies used different study populations (Rastogi and coworkers excluded cardiac admissions), used a wide range of blood pressure (BP) thresholds, and did not account for patient level factors (eg, pain, anxiety).1, 5, 8

Because severe HTN that develops during hospitalization is poorly studied and management remains arbitrary, understanding the actual real-world practice of identifying and treating severe HTN is essential. To address this evidence gap and limitations of previous study, we conducted a retrospective cohort study of adults admitted to five teaching hospitals in Connecticut. Our goal was to leverage data from this large healthcare system to determine prevalence of severe inpatient HTN, to characterize how severe HTN is managed, and to understand how often antihypertensive treatment leads to excessive BP reduction (Figure 1).

 

2 METHODS 2.1 Study population

We included adult patients admitted to one of the five Yale New Haven Health System (YNHHS) Network hospitals between January 1, 2016 and March 31, 2020 with a length of stay ≥2 days and ≤30 days. We excluded patients hospitalized with hypertensive emergency (based on International Classification of Diseases-10 codes [ICD-10]: I16.0, I16.1, I16.9), or to the maternity ward, intensive care unit, or research unit. Patients opting out of research studies were excluded (< 1% of YNNHS). For patients with multiple admissions during the study period, we only included data from their first admission. Patients who received vasopressors 0–6 hours before developing severe HTN were excluded in analysis of antihypertensive therapy (Figure 2). We used a longitudinal dataset with time varying BP measurements and antihypertensive medication administration. This study was approved by the Yale Human Investigation Committee (HIC # 2000028801). Electronic health record data (EHR) was collected from the YNNHS data warehouse (EPIC, Verona WI, USA).

Study flow diagram. YNHHS: Yale New Haven Health System; ICU: intensive care unit; BP: blood pressure

2.2 Severe inpatient HTN definition

Severe inpatient HTN was defined as the first documented severe BP elevation (SBP > 180 or DBP > 110 mm Hg) reported after admission to the floor and did not include BPs captured in the emergency department. To exclude falsely elevated measures, we excluded patients whose BP dropped to SBP < 180 mm Hg or DBP < 110 mm Hg within 1 hour of the index severe BP elevation without administration of antihypertensive medications over the same interval. If no repeat BP measurement was available within 1 hour of severe BP elevation, we considered the patient to have severe HTN.

2.3 Covariates

Demographics, vital signs, body mass index, comorbidities prior to admission (defined per the Elixhauser comorbidity index based on ICD-10 codes9), antihypertensive medications, and laboratory results were extracted from the EHR. We defined mean arterial pressure (MAP) as 1/3 SBP + 2/3 DBP. We included coefficient of variation (standard deviation of BP/ mean BP of BP measurements obtained before severe HTN developed) of MAP, SBP, and DBP to account for BP variability. We also included narcotics, sedatives, benzodiazepines, non-steroidal anti-inflammatory drugs (NSAID), corticosteroids, and crystalloid IV fluids; these are markers of pain, anxiety, inflammation, or hypovolemia and have been associated with BP effects.10-13 Race and ethnicity were extracted from the patient-reported demographic information in the EHR and were included as they have been independently associated with HTN.14

2.4 Antihypertensive treatment definition

Antihypertensive treatment was defined as receiving any oral or IV medication class (angiotensin converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, beta blockers, diuretics, renin inhibitors and vasodilators) within 6 hours of developing severe HTN. Antihypertensive treatment and route were assigned as time-varying covariates within the longitudinal dataset.

2.5 Outcome

The primary study outcome was time to MAP drop ≥30% within 6 hours from the time of developing severe HTN. For most hypertensive emergencies (patients admitted for severe HTN), guidelines recommend that MAP be decreased gradually by 10–20% in the first hour and a further 5–15% over the next 23 hours to conserve cerebral perfusion and avoid ischemic damage to the vascular beds that have been habituated to elevated BPs.2, 14-16 Additionally, severe BP reductions have been associated with increased risk of death.17, 18 Therefore, we used a MAP cutoff of 30% to reflect a clinically relevant BP drop that is better avoided. The secondary outcome was the slope of MAP over 6 hours from the time of initial development of severe HTN.

2.6 Statistical analysis

Characteristics between patient groups were compared using the χ2 test for proportions and Wilcoxon rank sum test for continuous variables. Class and number of antihypertensive medications were described. We used Cox proportional hazards models with time-varying covariates to study the association between antihypertensive treatment and time to MAP drop ≥30%. Secondary outcomes included time to SBP drop ≥30% and DBP drop ≥30%. All time-to-event comes were administratively censored at 6 hours. We fit an unadjusted model, reduced adjusted model (with covariates previously shown to be confounders2, 10-14, 19 and having a p value ≤.05 in our data) and a fully adjusted model (all covariates). We performed similar analysis using the following exposures: (1) treatment with IV antihypertensives versus untreated, (2) treatment with oral antihypertensives versus untreated, and (3) treatment with IV versus oral antihypertensives. For secondary outcomes, we used a linear mixed effect model with random intercept and random slope at the patient level to study the association between treatment and slope of MAP, SBP and DBP change over 6 hours from the time of severe HTN development in unadjusted and adjusted models.

2.7 Sensitivity analysis

We conducted several sensitivity analyses. First, severe inpatient HTN was defined as having two consecutive severe BP measurements (SBP > 180 mm Hg or DBP > 110 mm Hg) within 3 hours [sustained BP elevation]. If no repeat BP measurement was available within 3 hours, patient was not considered to have severe inpatient HTN. Second, knowing that antihypertensive medications are required in patients who are admitted with CVD diagnosis such as acute coronary symptoms (ACS) or stroke,20-22 and patients with heart failure and atrial fibrillation may be treated with antihypertensive medications such as loop diuretics and beta blockers23-25; we excluded loop diuretics and betablockers from antihypertensive medication list and subsequently stratified by whether patients were admitted for CVD diagnosis (ACS, stroke, heart failure, or atrial fibrillation) or not. Third, treatment was defined as receiving a new antihypertensive medication (ie, not a standing medication: medication not prescribed/day ≥90% of their hospital stay). Fourth, we excluded patients admitted to the surgical wards and thus excluded BPs obtained preoperatively and postoperatively. Fifth, we limited our analysis to patients admitted to the medical ward with sustained hypertension and defined treatment as receiving a new medication. Finally, we manually reviewed 100 charts to validate BP measurements, medications and other covariates recorded in our dataset.

Statistical significance was defined by a 2-sided P < .05. We conducted our analyses using R, version 4.0.0 (R Project for Statistical Computing).

3 RESULTS 3.1 Cohort characteristics

Of the 304 695 adult patient encounters within YNHHS, we identified 224 265 unique patient encounters of which 23 147 developed severe HTN (Figure 3). The median number of BP measurements available was 33 [interquartile range (IQR): 22, 57] during a median length of stay of 4.7 [3.1, 7.4] days. Compared to patients who did not develop severe HTN, those who did were older and more likely to be female, black and be admitted to a medical ward (Table 1). Additionally, those with severe HTN had higher prevalence of comorbidities (Elixhauser score: 6[3, 9] vs. 5[2,9]). Baseline laboratory values were similar though patients with severe HTN had lower estimated glomerular filtration rate (eGFR) [63 vs. 80 ml/min/1.73m2].26, 27 Admission BPs were higher among patients who developed severe HTN compared to those who did not (MAP: 105 [93, 117] vs. 95 [84, 105]).

(A). Absolute change in blood pressure following severe hypertension development by treatment status. MAP: mean arterial pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure, Tx: treated within 6 hours of developing severe hypertension; Untx: untreated within 6 hours of developing severe hypertension. *: statistically significant difference between treated and untreated (p < .001). Median values of absolute change are shown in the figure. Absolute change in blood pressure (MAP, SBP, DBP) 0–6 hours from developing severe inpatient hypertension: blood pressure at time of severe inpatient hypertension – minimum blood pressure recorded within 0–6 hours of developing severe inpatient hypertension. (B). Percent Change in Blood Pressure following Severe Hypertension Development by Treatment Status. MAP: mean arterial pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure, Tx: treated within 6 hours of developing severe hypertension; Untx: untreated within 6 hours of developing severe hypertension. *: statistically significant difference between treated and untreated (p < .001). All values on y-axis refer to percent change in blood pressures. Median values of percent change are shown in the figure. Percent change in blood pressure (MAP, SBP, DBP) 0–6 hours from developing severe inpatient hypertension: blood pressure at time of severe inpatient hypertension – minimum blood pressure recorded within 0–6 hours of developing severe inpatient hypertension

TABLE 1. Baseline characteristics of study cohort on admission overall and among those who did and did not develop severe inpatient hypertension Overall N = 224 265 Among inpatients who developed severe hypertension N = 23 147 (10.3%) Among inpatients who did not develop severe hypertension N = 201 118 (89.7%) Demographics Age, years 64.7 (18.4) 71.4 (16.3) 63.9 (18.5) Male 107 130 (47.8) 10 316 (44.6) 96 814 (48.1) Black 37 441 (16.7) 4576 (19.8) 32 865 (16.3) Hispanic or Latino 25 839 (11.5) 2341 (10.1) 23 498 (11.7) Service admitted to Medical 178 917 (79.8) 19 021 (82.2) 159 896 (79.5) Surgical 45 348 (20.2) 4126 (17.8) 41 222 (20.4) Comorbidities Congestive heart failure 59 559 (26.6) 7163 (30.9) 52 396 (26.1) Cardiac arrhythmia 87 137 (38.9) 9546 (41.2) 77 591 (38.6) Valvular disease 46 083 (20.5) 4976 (21.5) 41 107 (20.4) Pulmonary circulation disorder 28 282 (12.6) 2835 (12.2) 25 447 (12.7) Peripheral vascular disease 49 986 (22.3) 6036 (26.1) 43 950 (21.9) Hypertension 146 976 (65.5) 18 493 (79.9) 128 483 (63.9) Paralysis 8938 (4.0) 1122 (4.8) 7816 (3.9) Other neurological disorder 46 929 (20.9) 6440 (27.8) 40 489 (20.1) Chronic pulmonary disorders 82 129 (36.6) 8581 (37.1) 73 548 (36.6) Diabetes 73 770 (32.9) 9791 (42.3) 63 979 (31.8) Hypothyroidism 43 942 (19.6) 5222 (22.6) 38 720 (19.3) Renal failure 53 097 (23.7) 7578 (32.7) 45 519 (22.6) Liver disease 35 717 (15.9) 3390 (14.6) 32 327 (16.1) Peptic ulcer disease (no bleeding) 10 411 (4.6) 1263 (5.5) 9148 (4.5) AIDS/HIV 3290 (1.5) 346 (1.5) 2994 (1.5) Malignancy 51 275 (22.9) 4600 (19.9) 46675 (23.2) Rheumatoid arthritis /collagen disorders 17 565 (7.8) 1894 (8.2) 15 671 (7.8) Coagulopathy 34 507 (15.4) 3133 (13.5) 31 374 (15.6) Obesity 57 692 (25.7) 5870 (25.4) 51 822 (25.8) Weight loss 40 080 (17.9) 4250 (18.4) 35 830 (17.8) Fluid and electrolyte disorders 103 802 (46.3) 12 244 (52.9) 91 558 (45.5) Blood loss anemia 15 447 (6.9) 1748 (7.6) 13 699 (6.8) Iron deficiency anemia 42 258 (18.8) 4965 (21.4) 37 293 (18.5) Alcohol use disorder 28 829 (12.9) 3034 (13.1) 25 795 (12.8) Drug abuse 30 101 (13.4) 3245 (14.0) 26 856 (13.4) Psychosis 11 526 (5.1) 1413 (6.1) 10 113 (5.0) Depression 68 409 (30.5) 7829 (33.8) 60 580 (30.1) Elixhauser score 5 [2, 9] 6 [3, 9] 5 [2, 9] Admission characteristics, median [IQR] MAP 95.7 [85.0, 106.3] 105.3 [93.0, 117.0] 94.7 [84.3, 105.0] SBP (mm Hg) 134.0 [118.0, 150.0] 153.0 [134.0, 172.0] 132.0 [117.0, 147.0] DBP (mm Hg) 76.0 [66.0, 86.0] 80.0 [69.0, 92.0] 76.0 [66.0, 85.0] Heart Rate (bpm) 85.0 [73.0, 100.0] 82.0 [70.00, 97.00] 85.0 [73.0, 100.0] BMI (kg/m2) 27.6 [23.5, 32.9] 27.4 [23.3, 32.5] 27.6 [23.6, 32.9] Admission laboratory values median [IQR] Serum sodium (meq/L) 139.0 [136.0, 141.0] 139.0 [136.0, 141.0] 139.0 [136.0, 141.0] Serum potassium (meq/L) 4.1 [3.8, 4.05] 4.2 [3.8, 4.6] 4.1 [3.8, 4.5] Serum chloride (meq/L) 102.0 [98.0, 105.0] 102.0 [98.0, 105.0] 102.0 [98.0, 105.0] Serum bicarbonate (meq/L) 24.0 [22.0, 27.0] 24.7 [22.0, 27.0] 24.0 [22.0, 27.0] BUN (mg/dl) 18.0 [12.0, 27.0] 21.0 [14.0, 32.0] 17.0 [12.0, 26.0] Serum creatinine (mg/dl) 0.9 [0.7, 1.3] 1.1 [0.8, 1.6] 0.9 [0.7, 1.3] eGFR (ml/min/1.73m2) 78.5 [49.7, 108.7] 63.3 [38.3, 91.7] 80.3 [51.4, 110.4] White blood cell count (x1000/ul) 9.1 [6.8, 12.3] 9.0 [6.8, 12.4] 9.2 [6.8, 12.4] Platelet count (x1000/ul) 223.0 [171.0, 285.0] 224.0 [174.0, 284.0] 223.0 [171.0, 286.0] Hemoglobin, g/dl 12.0 [10.4, 13.5] 12.0 [10.4, 13.5] 12.0 [10.4, 13.5] Hematocrit, % 36.9 [32.3, 41.0] 37.0 [32.5, 41.2] 36.9 [32.2, 41.0] Values are presented as count (percent) or median (IQR). Abbreviations: BMI, body mass index; BP, blood pressure; MAP, mean arterial pressure; SBP, systolic BP; DBP, diastolic BP; bpm, beats per minute; BUN, Blood Urea Nitrogen; eGFR, Estimated glomerular filtration rate. p-values are < .0001 for all covariates except chronic pulmonary disorders (p-value = .135), obesity (p = .182), iron deficiency anemia (p-value = .229), AIDS/HIV (p-value = .732), alcohol use disorder (p-value = .229), drug abuse (.005), and platelet count (p-value = .02).

After excluding 228 patients who received vasopressors, 9166 received antihypertensive medications while 13 753 were left untreated within 6 hours following severe BP elevation. Median time from admission to first recorded severe BP elevation was 8 [1.3, 49.4] hours overall, 10 [2.2, 53.1] hours among those treated and 7 [1.0, 47.6] among those untreated. Patients who developed severe HTN and received treatment were older, had similar BPs on admission, and had more comorbidities compared to those who were not treated (Table S1). Additionally, treated compared to untreated severe hypertensive patients had similar MAP at time of diagnosis (122 [115, 129]; p-value = .04) and were less likely to have received steroids, NSAIDs, crystalloids, or narcotics before severe BP elevation. Moreover, MAP and SBP drop after 6 hours of developing severe BP elevation was higher in untreated than treated inpatients (Figure 3, Table S2). Moreover, treated patients received overall a median of 1 [1, 1.75] antihypertensive; and a median of 0 [0, 1] of new antihypertensives. The most commonly used agents were beta blockers, calcium channel blockers, and angiotensin converting enzyme inhibitors/angiotensin receptor blockers (Table S3). Of the 9166 inpatients who developed severe HTN and were treated within 6 hours, 1912 received IV medications, 5756 received oral medications; and 1498 received both.

3.2 Antihypertensive treatment and severe BP drop (≥30%)

Incident MAP drop ≥30% among treated and untreated patients with severe HTN was 2.22/1000 person-hours versus 5.73/1000 person-hours (p-value < .001) (Table S2). Among inpatients who developed severe HTN, treatment was associated with lower rates of MAP and DBP drop ≥30% (Table 2) in the fully adjusted model. This is consistent for patients treated with oral medications versus untreated. However, patients who were treated with IV only medications had a 38% (HR, 95%CI: 1.4 [1.2, 1.7]), 43% (1.4 [1.2, 1.7]), and 32% (1.3 [1.1, 1.6]) greater rate of MAP, SBP and DBP drop ≥30% compared to untreated inpatients, respectively, after adjusting for demographic and clinical characteristics. Severe BP drop (≥30%) was also greater among patients treated with IV versus oral medications. The following patient characteristics were associated with greater risk of MAP drop ≥30%: increase in age, congestive heart failure, cardiac arrythmia, peripheral vascular disease, and receiving crystalloids or sedatives.

TABLE 2. Association of treatment with MAP, SBP, DBP drop ≥30% over 0–6 hours from time of severe inpatient HTN development HR (95% CI) Model 1 (Unadjusted) Model 2 Model 3 MAP drop ≥ 30% Treated versus untreated 0.86 [0.80, 0.94] 0.89 [0.82, 0.96] 0.89 [0.80, 0.99] Treated with IV only versus untreated 1.49 [1.33, 1.68] 1.49 [1.32, 1.68] 1.38 [1.15, 1.67] Treated with oral only versus untreated 0.59 [0.53, 0.66] 0.61 [0.54, 0.68] 0.69 [0.61, 0.79] Treated with IV only versus oral only 2.57 [2.22, 2.98] 2.48 [2.13, 2.91] 2.06 [1.65, 2.57] SBP drop ≥ 30% Treated versus untreated 0.92 [0.86, 0.99] 0.93 [0.86, 1.00] 0.96 [0.87, 1.05] Treated with IV only versus UNTREATED 1.44 [1.29, 1.62] 1.42 [1.26, 1.59] 1.43 [1.19, 1.71] Treated with oral only versus untreated 0.69 [0.62, 0.76] 0.69 [0.63, 0.77] 0.78 [0.69, 0.88] Treated with IV only versus oral only 2.11 [1.84, 2.42] 2.08 [1.80, 2.41] 1.87 [1.53, 2.29] DBP drop ≥ 30% Treated versus untreated 0.79 [0.74, 0.85] 0.82 [0.76, 0.89] 0.79 [0.72, 0.88] Treated with IV only versus untreated 1.34 [1.20, 1.50] 1.37 [1.22 1.54] 1.32 [1.11, 1.58] Treated with oral only versus untreated 0.52 [0.47, 0.58] 0.55 [0.49, 0.61] 0.60 [0.53, 0.69] Treated with IV only versus oral only 2.66 [2.30, 3.08] 2.59 [2.22, 3.02] 2.25 [1.82, 2.78] Of the 9166 inpatients who developed severe HTN and were treated, 1912 were treated only with IV medications, 5756 were treated only with oral medications and 1498 were treated with a combination of IV and oral medications. 13 753 inpatients developed severe HTN and were not treated. Model 1: unadjusted; Model 2: age, sex, race, ethnicity, ward, comorbidities (congestive heart failure, cardiac arrythmia, peripheral vascular disease, hypertension, diabetes, hypothyroidism, renal failure, AIDS/HIV, cancer, alcohol abuse, drug abuse, psychosis, depression), baseline laboratory values (sodium, potassium, chloride, bicarbonate, BUN, eGFR, WBCC, platelet count, hemoglobin, hematocrit), NSAID use 0–6 hours before time of severe inpatient HTN, crystalloid use 0–6 hours before time of severe inpatient HTN, steroid use 0–6 hours before time of severe inpatient HTN, narcotic use 0–6 hours before time of severe inpatient HTN, sedative use 0–6 hours before time of severe inpatient HTN, hospital. Model 3: age, sex, race, ethnicity, ward, comorbidities (congestive heart failure, cardiac arrythmia, valvular disease, pulmonary circulation disorder, peripheral vascular disease, hypertension, paralysis, other neurological disorders, chronic pulmonary disease, diabetes, hypothyroidism, renal failure, liver disease, peptic ulcer disease excluding bleeding, AIDS/HIV, lymphoma, cancer, rheumatoid arthritis/collagen disorder, coagulopathy, obesity, weight loss, fluid and electrolyte disorders, blood loss anemia, deficiency anemia, alcohol abuse, drug abuse, psychosis, depression), baseline laboratory values (sodium, potassium, chloride, bicarbonate, BUN, eGFR, WBCC, platelet count, hemoglobin, hematocrit), NSAID use 0–6 hours before time of severe inpatient HTN, crystalloid use 0–6 hours before time of severe inpatient HTN, steroid use 0–6 hours before time of severe inpatient HTN, narcotic use 0–6 hours before time of severe inpatient HTN, sedative use 0–6 hours before time of severe inpatient HTN, maximum MAP before time of severe inpatient HTN development, minimum MAP before time of severe inpatient HTN development, coefficient of variation of MAP before time of severe inpatient HTN development, hospital. Abbreviations: HR, hazard ratio; CI, confidence interval; MAP, mean arterial pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure, HTN, hypertension; IV, intravenous.

In sensitivity analysis, in which severe HTN was defined as having sustained BP elevation, we similarly observed that patients who were treated with IV antihypertensives had greater rate of MAP, SBP, and DBP drop ≥30% compared to other groups (Table S4). We then defined treatment as receiving any class of antihypertensive medications except loop diuretics and beta blockers and subsequently stratified our analysis by CVD admission diagnosis (Table S5). In CVD and non-CVD admissions, treatment was associated with a lower rate of DBP drop ≥30% in the fully adjusted models. Treatment with IV medications was associated with greater severe BP drops when compared to other groups. The following sensitivity analyses yielded similar results to the primary analysis: defining treatment as having received a new antihypertensive medication (Table S6), excluding patients admitted to the surgical ward (Table S7), and when considering only patients admitted to the medical ward with sustained hypertension treated with new antihypertensives and adjusting for CVD admission (Table S8).

3.3 Antihypertensive treatment and BP response

Patients who develop severe HTN and were treated had greater absolute decrease in MAP (-0.6 [−1.0, −0.2]) and DBP (-1.2 [−1.6, −0.8]) compared to untreated inpatients in the fully adjusted model (Table 3). Similarly, patients who received oral antihypertensives compared to no treatment had greater reduction in MAP and DBP after adjusting for demographic and clinical characteristics. Being older, obese, and having valvular disease were associated with lower MAP drop over time.

TABLE 3. Association of antihypertensive treatment among those who developed severe inpatient hypertension with MAP, SBP, and DBP change within 6 hours of developing severe inpatient hypertension β (95%CI) Model 1 (Unadjusted) Model 2 Model 3 Slope of MAP Treated versus Untreated −0.78 [−1.13, −0.43] −0.61 [−0.98, −0.25] −0.56 [−0.97, −0.16] Treated with IV only versus untreated −0.93 [−1.73, −0.13] −0.57 [−1.39, 0.25] 0.42 [−1.49, 0.65] Treated with oral only versus untreated −1.02 [−1.47, −0.58] −0.78 [−1.24, −0.32] −0.56 [−1.04, −0.08] Treated with IV only versus oral only 0.51 [−0.31, 1.33] 0.45 [−0.39, 1.29] 0.23 [−0.03, 0.86] Slope of SBP