Day‐by‐day blood pressure variability in hospitalized patients with COVID‐19

Abstract In a retrospective analysis, the authors investigated day‐by‐day blood pressure variability (BPV) and its association with clinical outcomes (critical vs. severe and discharged) in hospitalized patients with COVID‐19. The study participants were hospitalized in Tongji Hospital, Guanggu Branch, Wuhan, China, between February 1 and April 1, 2020. BPV was assessed as standard derivation (SD), coefficient of variation (CV), and variability independent of mean (VIM). The 79 participants included 60 (75.9%) severe patients discharged from the hospital after up to 47 days of hospitalization, and 19 (24.1%) critically ill patients transferred to other hospitals for further treatment (n = 13), admitted to ICU (n = 3) or died (n=3). Despite similar use of antihypertensive medication (47.4% vs. 41.7%) and mean levels of systolic/diastolic blood pressure (131.3/75.2 vs. 125.4/77.3 mmHg), critically ill patients, compared with severe and discharged patients, had a significantly (p ≤ .04) greater variability of systolic (SD 14.92 vs. 10.84 mmHg, CV 11.39% vs. 8.56%, and VIM 15.15 vs. 10.75 units) and diastolic blood pressure (SD 9.38 vs. 7.50 mmHg, CV 12.66% vs. 9.80%, and VIM 9.33 vs. 7.50 units). After adjustment for confounding factors, the odds ratios for critical versus severe and discharged patients for systolic BPV were 3.41 (95% confidence interval [CI] 1.20‐9.66, p = .02), 4.09 (95% CI 1.14‐14.67, p = .03), and 2.81 (95% CI 1.12‐7.05, p = .03) for each 5‐mmHg increment in SD, 5% increment in CV, and 5‐unit increment in VIM, respectively. Similar trends were observed for diastolic BPV indices (p ≤ .08). In conclusion, in patients with COVID‐19, BPV was greater and associated with worse clinical outcomes.

Early studies repeatedly showed that, in the presence of hypertension, the disease of COVID-19 was more severe and associated with a higher fatality. 1 Because angiotensin converting enzyme (ACE) 2 behaves as a mediator of the COVID-19 infection, early views focused on the use of ACE inhibitors or angiotensin receptor blockers that may potentially increase the expression of ACE2 in several tissues, though not necessarily the lungs. 2 Most studies on this topic did not show any significant association. 3,4 The results of subsequent studies suggested that hypertension itself and its target organ damage and complications might be the cause of high risk and fatality. 5 We hypothesize that blood pressure fluctuates on critical conditions, such as COVID-19, and increases the severity and fatality of the disease. There is some evidence on the negative health consequences of the day-by-day blood pressure variability (BPV) during hospitalization on critical disease conditions. 6 In the present study, we investigated the day-by-day clinic BPV and its association with clinical outcomes in hospitalized patients with COVID-19.

METHODS
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study population
The study participants were hospitalized patients with COVID-19 in During the whole study period, a total of 90 patients were hospitalized. In this retrospective analysis, we attempted to include as many patients as possible. We did not apply any exclusion criteria except for the minimum required number of blood pressure readings for the computation of BPV indices. We had to exclude 11 patients with less than three blood pressure readings obtained during the whole hospitalization period. Thus, the present analysis included 79 patients.

Blood pressure and other clinical, anthropometric and biochemical measurements
Blood pressure was measured in the morning usually at 06:00-10:00 in the supine position by a doctor or nurse using a validated electronic blood pressure monitor (Omron J30, an equivalence of HEM-7130 in the China market, Omron Healthcare, Kyoto, Japan) 8 before breakfast and intake of antihypertensive drugs. One reading was obtained on each occasion. Mean arterial pressure was calculated as the sum of a third of systolic blood pressure plus two thirds of diastolic blood pressure.
Information on other clinical, anthropometric, and biochemical measurements was also collected from the medical records. Body height and body weight were self-reported. Body mass index was calculated as the body weight in kilograms divided by the body height in meters squared. Estimated glomerular filtration rate (eGFR) was calculated by the use of the CKD-EPI formula. 9

Symptoms, treatment, and clinical outcomes of COVID-19
Information on the diagnosis, symptoms, disease severity, treatment, and clinical outcomes of COVID-19 was collected from medical records. Oxygen saturation was measured with pulse oximetry.
Hypoxia was defined as an oxygen saturation of ≤93%. 7 Adverse clinical outcomes included transfer to other hospitals for further treatment, ICU admission or death due to COVID-19 exacerbation. Patients were discharged at doctor's discretion when the discharge requirements were met, including (1) normothermia, (2) significant recovery of respiratory symptoms, (3) significant improvement of acute diffusive lesion of the lung identified by imaging, and (4) two consecutive negative results of COVID-19 nucleic acid testing within an interval of at least one day. Patients were classified as "severe" if discharged and "critical" if transferred to other hospitals for further treatment, admitted to ICU, or died. Values are mean ± SD, median (interquartile range) or number of patients (% of column total). Abbreviations: eGFR, estimated glomerular filtration rate; HDL, high density lipoprotein; LDL, low density lipoprotein.

BPV and clinical outcomes
In a logistic regression model, we included age and sex and the confounding factors with a significant between-group difference identified in Tables 1 and 2 Values are mean ± standard deviation (SD) or number of patients (% of column total), unless indicated otherwise. Abbreviations: COVID-19, coronavirus disease 2019; CV, coefficient of variation.

F I G U R E 1
Day-by-day clinic blood pressure variability of standard deviation (A), coefficient of variation (B), and variability independent of mean (C) by clinical outcome. Symbols represent mean values in severe (dots) and critically ill (squares) patients, adjusted for age, sex, and the mean level of systolic and diastolic blood pressure and pulse rate, and presence of hypoxia during treatment. p values for the comparison between severe and critically ill patients are given

DISCUSSION
The key finding of the present study was that the critically ill patients had increased systolic and diastolic BPV, which was associated with reported that higher mean arterial pressure variability was associated with a higher risk of mortality as outcome and with older age, higher C reactive protein concentration, and markers of cardiac and renal injury as the related risk factors. 14 However, it is also possible that the disrupted blood pressure regulation or the too high or too low blood pres-sure as indicated by increased BPV directly caused worse clinical outcomes, such as shock.
The study should be interpreted within the context of its limitations.
The sample size was rather small and hence inadequately powered, but nevertheless allowed detection of significant associations between BPV and clinical outcomes. In addition, for the sake of minimum intervention, only one blood pressure reading was obtained on each measurement occasion. However, blood pressure was measured for the whole study period.
In conclusion, in hospitalized patients with COVID-19, day-by-day clinic BPV was higher and associated with worse clinical outcomes.
The finding pinpoints the importance of blood pressure monitoring and further investigation for the underlying causes of increased BPV in patients with COVID-19.