Blood pressure variability as an indicator of sepsis severity in adult emergency department patients

Accepted Manuscript Blood pressure variability as an indicator of sepsis severity in adult emergency department patients

Jacob E. Nouriel, Scott R. Millis, Jonathon Ottolini, John M. Wilburn, Robert L. Sherwin, James H. Paxton PII: DOI: Reference:

S0735-6757(17)30742-8 doi: 10.1016/j.ajem.2017.09.017 YAJEM 56962

To appear in: Received date: Revised date: Accepted date:

21 April 2017 11 September 2017 13 September 2017

Please cite this article as: Jacob E. Nouriel, Scott R. Millis, Jonathon Ottolini, John M. Wilburn, Robert L. Sherwin, James H. Paxton , Blood pressure variability as an indicator of sepsis severity in adult emergency department patients, (2017), doi: 10.1016/ j.ajem.2017.09.017

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Blood Pressure Variability as an Indicator of Sepsis Severity in Adult Emergency Department Patients Jacob E. Nouriel1, BA Scott R. Millis2, PhD Jonathon Ottolini1, BA

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John M. Wilburn1, MD

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Robert L. Sherwin1, MD

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Corresponding Author: Jacob E. Nouriel Wayne State University School of Medicine 540 E. Canfield St. Detroit, MI 48201 [email protected]

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James H. Paxton1, MD, MBA

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Funding: Funding for this study was provided by Wayne State University School of Medicine and Vidacara / Teleflex Corporation.

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Conflicts of Interests: There are no conflicts of interest for the primary author or any of the co-authors.

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Prior abstract publication/presentation: This research has been presented (abstract) at the 2017 meeting for the Society of Critical Care Medicine, Honolulu, Hawaii, on January 23, 2017.

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Keywords: Sepsis, hemodynamic monitoring, and fluid resuscitation

Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI USA Department of Physical Medicine and Rehabilitation, Wayne State University School of Medicine, Detroit, MI USA 2

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Abstract

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Study objective: Quantify the correlation between blood pressure variability (BPV) and markers of

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illness severity: serum lactate (LAC) or Sequential Organ Failure Assessment (SOFA) scores.

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Methods: We performed a secondary analysis of data from a prospective, observational study evaluating fluid resuscitation on adult, septic, ED patients. Vital signs and fluid infusion volumes were recorded

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every 15 minutes during the 3 hours following ED arrival. BPV was assessed via average real variability (ARV): the average of the absolute differences between consecutive BP measurements. ARV was

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calculated for the time periods before and after 3 fluid infusion milestones: 10-, 20-, and 30-mL/kg total body weight (TBW). Spearman's rho correlation coefficient analysis was utilized. A p-value < 0.05 was

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considered statistically significant.

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Results: Forty patients were included. Mean fluid infusion was 33.7 mL/kg TBW (SD 22.1). All patients received fluid infusion≥10 mL/kg TBW, 25 patients received fluid infusion >20 mL/kg TBW, and 16

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patients received fluid infusion > 30 mL/kg TBW. Mean initial LAC was 4.0 mmol/L (SD 3.2). Mean

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repeat LAC was 3.1 mmol/L (SD 3.2), obtained an average of 6.6 hours (SD 5.3) later. Mean SOFA score was 7.0 (SD 4.4). BPV correlated with both follow-up LAC (r=.564; p=.023) and SOFA score (r=.544;

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p=.024) among the cohort that received a fluid infusion> 20-mL/kg TBW. Conclusion: With the finding of a positive correlation between BPV and markers of illness severity (LAC and SOFA scores), this pilot study introduces BPV analysis as a real-time, non-invasive tool for continuous sepsis monitoring in the ED.

Keywords: Sepsis, hemodynamic monitoring, and fluid resuscitation

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Abbreviations: Average real variability: ARV, the average of the absolute differences between consecutive

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measurements within a series (mmHg for BPV; beats per minute for HRV)

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Blood pressure: BP (mmHg)

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Blood pressure variability: BPV, the change in blood pressure over time Heart rate variability: HRV, the change in heart rate over time

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Serum lactate: LAC (mmol/L)

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Introduction Sepsis is the 11th leading cause of death in the United States.1-2 Early detection and treatment of sepsis can significantly improve clinical outcomes.3-4 Because a large proportion of septic patients present

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initially to the emergency department (ED), ED providers have a unique opportunity to alter the course of

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non-invasive tools for monitoring early sepsis management are needed.

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disease.5 However, identifying sepsis and its severity at the time of ED arrival can be challenging. Rapid,

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Blood pressure (BP) control is an essential component of sepsis treatment. The 2016 Surviving Sepsis Campaign (SSC) guidelines recommend maintaining a mean arterial pressure (MAP) ≥ 65 mmHg

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throughout the first 6 hours of resuscitation.6 Additionally, recent definitions of sepsis have placed a great deal of emphasis on the patient‟s presenting BP, categorizing those patients with a persistent SBP < 90

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mmHg and serum lactate level greater than 2 mmol/L despite adequate fluid resuscitation as having septic

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shock.7 Septic shock represents an advanced state of sepsis with increased mortality.8 Therefore, blood pressure measurement may serve a prognostic role in the evaluation of sepsis and can help to guide

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therapy.

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The majority of previous studies evaluating the prognostic value of BP among septic patients have focused on determining the optimal MAP.9 However, BP is sensitive to neuronal and hormonal

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systems, and oscillates in both short- (minutes to hours) and long-term (days to months) periods.10 Blood pressure variability (BPV) is a measure of this oscillation of BP over time. High BPV has been shown to be independently associated with and prognostic for greater levels of multi-organ damage (MOD).11-14 Hence, it is reasonable to expect that septic patients, who by definition suffer MOD, would also have high BPV. In a study of septic patients within the first 48 hours of hospital admission, Pandey et al found that a greater severity of illness was associated with statistically significant greater systolic and diastolic BPV.15 In contrast, Berg et al found that BP oscillation occurred at reduced frequencies in mechanically-

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ventilated septic patients, as compared to healthy, spontaneously breathing patients.16 Thus, it is not clear whether septic patients suffer from labile BP. Characterization of the relationship between BPV and “traditional” makers of sepsis severity (e.g., lactate, Sequential Organ Failure Assessment (SOFA) scores) could provide clinicians with a non-

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invasive tool to monitor sepsis management. Although tissue hypoperfusion is only one possible

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mechanism for lactemia, high serum lactate and low lactate clearance values are associated with worse

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clinical outcomes among septic patients.17-20 Current SSC guidelines recommend that resuscitation should aim to normalize lactate (to a level < 1mmol/L) as rapidly as possible.6 However, serial lactate

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measurement represents static indicators of perfusion, and occurs over a period of many hours, which may not be able to provide clinicians with adequate “real-time” feedback on the efficacy of their care for

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septic patients. While the SOFA score evaluates septic patients for the presence of MOD, thereby

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assisting clinicians in estimating illness severity and mortality risk, these scores are not generally available early in the patient‟s resuscitation.21 Consequently, it is necessary to develop additional tools

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that would be available to the emergency physician in “real-time” during the first few hours following ED

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arrival. Such tools are likely to help lower the high mortality rate associated with sepsis. 22-23 Previous data characterize some of these relationships, but only at a more advanced stage in the

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patient‟s illness. Our study sought to evaluate BPV at an earlier time point in the course of the disease – within the first three hours following ED arrival. Our objectives were to quantify both the correlation

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between BPV and serum lactate levels and the correlation between BPV and SOFA scores. We hypothesized that a positive relationship exists between BPV and these established markers of sepsis severity. Methods We conducted a secondary analysis of data obtained from an on-going multi-center prospective, observational study, Shock Access For Emergent Resuscitation (SAFER). SAFER is designed to evaluate

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the relationship between early fluid resuscitation and clinical outcomes in patients with undifferentiated hypotension (SBP < 90 mmHg). Our sub-analysis of SAFER data includes only septic patients, retrospectively identified by the presence of hypotension on ED arrival with a positive laboratory or other diagnostic test finding of bacterial infection. All patients were diagnosed with sepsis by the admitting

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physician, and all had documented sources of bacterial infection. All patients were enrolled from

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December 2014 to August 2016 at Sinai-Grace Hospital and Detroit Receiving Hospital (Detroit, MI).

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Both are large, tertiary care hospitals staffed by emergency medicine resident physicians supervised by emergency medicine attending physicians. This protocol was approved by the Institutional Review Board

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at Wayne State University (WSU), the affiliated academic institution for both hospitals. Patients were eligible for enrollment if they were at least 18 years old, presented with a SBP < 90

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mmHg, and had intravascular volume-depletion requiring fluid bolus administration of at least 1 liter of

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IV fluid within the first hour following ED arrival (per discretion of treating ED physician). Patient vital signs (BP, HR, RR, temperature) were recorded initially at presentation and again at 15 minute intervals

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throughout the first 3 hours following ED arrival. The relevant SAFER data for our secondary analysis included details on blood, crystalloid and colloid fluid resuscitation: fluid administration start time, fluid

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administration conclusion time, and volume of fluid infused during each 15-minute interval. Patients were

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followed from the time of ED arrival, but patient identifiers were only paired with the anonymouslycollected data if the patient or their legally-authorized representative consented to study inclusion.

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Patients who did not consent to enrollment had their data used anonymously, without patient identifiers. Data collected following obtainment of informed consent included: comorbidities, results of all laboratory and diagnostic tests during the hospitalization, pharmacologic therapy, and discharge diagnoses at time of both ED disposition and hospital discharge. At the time of enrollment, study participants were assigned a unique Study Number. All HIPAA regulations were strictly followed in order to maintain the privacy of study participants. Extracted data was compiled in a Microsoft© Excel spreadsheet, maintained on a

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password-protected institutional webserver. For this subgroup analysis, only consented patient charts were included. We assessed systolic BPV via a previously established statistical tool for BPV, average real variability (ARV) which is calculated as the average of the absolute differences between consecutive BP

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measurements within a series:24

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ARV was calculated for systolic blood pressure (SBP) measurements during the time periods before and after three milestones of intravenous fluid infusion: 10 mL/kg of total body weight (TBW), 20

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mL/kg TBW, and 30 mL/kg TBW. (N) represents the number of SBP measurements within a given series. Hemodynamic data was not used once vasopressor therapy was initiated, due to the direct alteration on

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vasomotor activity. ARV was additionally utilized to assess heart rate oscillation.

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SOFA scores were calculated for all patients and were calculated from the worst values for the

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indicated parameters during the initial 24 hours following ED arrival. When patients lacked a measurement of PaO2, the respiratory component of SOFA scores was calculated via a previously

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validated method that utilized pulse oximetry (SpO2/FiO2 ratio) in lieu of an arterial blood gas analysis (PaO2/FiO2 ratio).25-26 Bilirubin data was not available for 15 patients and normal bilirubin values were

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imputated for the SOFA score calculation. Serum lactate measurements included both an initial specimen and the next subsequent specimen sampled within 24 hours of the initial specimen. Lactate clearance was calculated as the percentage of the difference between initial and final lactate divided by initial lactate. A positive value indicated a decrease in serum lactate, while a negative value indicated an increase in serum lactate. Spearman‟s rank-order correlation coefficient analysis was utilized to calculate the association between a hemodynamic variable (BPV or HRV) and a marker for illness (serum lactate or SOFA scores).

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Any p-value < .05 was considered statistically significant. Statistical analysis of the data was performed using IBM SPSS Statistics, Version 23 (Armonk, NY, USA). Results Forty patients from among the 181 consented SAFER patients qualified for inclusion in this sub-

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within the BPV sub-analysis (1.B). Table 1 provides a patient summary.

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analysis. Figure 1 is a flow chart for the protocol of patient enrollment within the SAFER study (1.A) and

Figure 1: (A) Flowchart of SAFER enrollment protocol; (B): Flow chart of BPV sub-analysis enrollment protocol

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(A)

(B)

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Blood Pressure Variability in Early Sepsis Management

Table 1: Patient summary

Value 59

SD 15

58 78

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Mean fluid administration mL/kg TBW Number of patients who received fluid administration 10 mL/kg TBW

33.7 40

22.1 -

Number of patients who received fluid administration 20 mL/kg TBW

25

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Number of patients who received fluid administration 30 mL/kg TBW

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Mean initial lactate mmol/L (n=39)

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3.2

Mean subsequent lactate mmol/L (n=31) Mean lactate clearance (%)

3.1 20

3.2 58

Mean time between initial and subsequent lactate (hours)

6.6

5.3

Sequential Organ Failure Assessment score (n=15)

7.0

4.4

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Parameter Mean age (years)

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Female (%) Mean TBW (kg)

TBW: total body weight

For patients who received a fluid infusion of 10 mL/kg TBW, the average BPV before and after the 10 mL/kg TBW fluid infusion was 13.6 mmHg and 10.4 mmHg, respectively. Three patients with subject numbers of 28, 40, and 27 were outliers for the BPV after receiving 10 mL/kg TBW fluid 10

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infusion, demonstrated by BPV values equal to 24.6 mmHg, 26.3 mmHg, and 26. 6 mmHg, respectively. For patients who received a fluid infusion of 20 mL/kg TBW, the average BPV before and after the 20 mL/kg TBW fluid infusion was 13.7 mm Hg and 10.2 mmHg, respectively. Patient with subject number 27 was an outlier for BPV before receiving 20 mL/kg TBW fluid infusion, with a BPV value of 33.8

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mmHg. Patients with subject numbers 28 and 40 were outliers for BPV after receiving 20 mL/kg TBW

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fluid infusion, with a BPV value equal to 24.7 mmHg. For patients who received a fluid infusion of 30

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mL/kg TBW, the average BPV before and after the 30 mL/kg TBW fluid infusion milestone was 15.5

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mmHg and 12 mmHg, respectively. See Figure 2.

Figure 2: Boxplot reflecting the interquartile range (25th to 75th percentile range) for the variability in systolic BPV determined by ARV. Variations were determined for SBP measurements before and after 3

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grades of fluid infusion milestones 10-, 20-, and 30-mL/kg TBW. Patients with subject numbers of 27,

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28, and 40 were outliers.

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Of the 25 patients who received a fluid replacement of 20 mL/kg TBW, an ARV calculation for BPV following a fluid administration of 20 mL/kg TBW was possible for 17 patients (because the ARV calculation requires 2 data points). All 17 patients, who both received 20 mL/kg TBW fluid infusion and had a post-fluid infusion ARV calculation also had an initial lactate measurement versus 16 out of these

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17 patients had a subsequent lactate measurement. BPV during the time period following a fluid infusion

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> 20 mL/kg TBW positively correlated with follow-up lactate levels (r=.564; p=.023).. BPV following a

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fluid infusion > 20 mL/kg TBW positively correlated with SOFA scores (r=.544; p=.025). The correlation between BPV following a fluid infusion > 20 mL/kg TBW and initial lactate levels approached statistical

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significance (r=.474; p=.055). Out of the 16 patients who received a fluid infusion of 30 mL/kg TBW, BPV prior to achieving this fluid milestone positively correlated with SOFA scores (r=.794, p=.000). Out

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of the 16 patients who received a fluid infusion of 30 mL/kg TBW, 15 patients had a subsequent lactate measurement. For these 15 patients, the positive correlation between BPV prior to the 30 mL/kg TBW

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fluid milestone and subsequent lactate approached statistical significance (r=.488, p=.065). 36 patients

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had both an ARV calculation for BPV following a fluid infusion of 10 mL/kg TBW and an initial lactate measurement. For these 36 patients, the correlation between BPV following fluid infusion of 10 mL/kg

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TBW and initial lactate measurements was not statistically significant (r=.288, p=.088). SeeTable 2.

Table 2: Correlation coefficients between blood pressure variability (BPV) and markers of illness severity Patient cohort

Post fluid administration of 10 mL/kg TBW

Correlation coefficients between BPV (mmHg) and initial lactate (mmol/L) .288 (p = 0.088)

Correlation coefficients between BPV (mmHg) and subsequent lactate (mmol/L) -

Correlation coefficient between BPV (mmHg) and SOFA score -

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(n=36)

Post fluid administration of 20 mL/kg TBW

.474 (p = 0.055)

.564 (p =0.023)

.544 (p = .024) (n=17)

(n=16)⁕ .488 (p = 0.065)

.794 (p=.000)

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n=16

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Prior to fluid administration of 30 mL/kg TBW

(n=15)◊

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TBW: total body weight; SOFA: Sequential Organ Failure Assessment ⁕one patient lacked a subsequent lactate

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◊one patient lacked a subsequent lactate

Out of the 40 patients who received a fluid infusion of 10 mL/kg TBW, an HRV calculation was possible for 37 patients for the time period after achieving this fluid milestone. Of these 37 patients, 36 patients had an initial lactate versus 29 patients had a subsequent lactate. Heart rate variability (HRV) following a fluid infusion of 10 mL/kg TBW correlated with both initial (r=.345; p=.039) and follow-up 14

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lactate (r=.419; p=.024). The correlation between HRV following 10 mL/kg TBW and SOFA score was not statistically significant (r=.281; p=.092). Out of the 25 patients who received a 20 mL/kg TBW fluid infusion, an ARV calculation for HRV prior to achieving this fluid milestone was possible for 24 patients. HRV prior to receiving a fluid infusion of 20 mL/kg TBW positively correlated with SOFA scores

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(r=.456;p=.025) . The correlation between HRV prior to receiving a fluid infusion of 20 mL/kg TBW and

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initial lactate approached statistical significance (r=.036; p=.069). Out of the 40 patients who received a

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fluid infusion of 10 mL/kg TBW, an ARV calculation for HRV prior to receiving fluid infusion 10 mL/kg TBW was possible for 36 patients. Of these 36 patients, 35 patients had an initial lactate versus 29 had an

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additional subsequent lactate. Both the correlation between HRV prior to receiving 10 mL/kg TBW fluid infusion and initial lactate (r=.298; p=.0.82) and the correlation between HRV prior to receiving 10

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mL/kg TBW fluid infusion and subsequent lactate were not statistically significant (r=.328; p=.089). See

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Table 3.

Table 3: Correlation coefficients between heart rate variability (HRV) and markers of illness severity Patient cohort

Prior to fluid administration of 10 mL/kg TBW

Correlation coefficient between HRV (bpm) and initial lactate (mmol/L) .298 (p = .082) n = 35

Correlation coefficient between HRV (bpm) and subsequent lactate (mmol/L) .328 (p = .089) n = 28

Correlation coefficient between HRV (bpm) and SOFA score -

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.281 (p = .092) n = 37

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.456 (p = .025) n = 24

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Post fluid .345 (p = .036) administration of 10 n = 36 mL/kg TBW Prior to fluid .386 (p = .069) administration of 20 n = 23a mL/kg TBW a one patient lacked an initial lactate

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Discussion To the best of our knowledge, this is the first study designed to examine the clinical utility of BPV in monitoring the progression of early sepsis management in the ED. We assessed BPV via ARV, a previously established statistical tool for quantifying BPV.24 Within the context of assessing the

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prognostic significance of BPV for cardiovascular events (coronary artery disease, stroke and congestive heart failure), Mena et al developed ARV against standard deviation as a measure of variability and derived ARV from the total variability concept of real analysis in mathemathics.27 We found that the average BPV decreased after each grade of fluid resuscitation (10mL/kg TBW, 20 mL/kg TBW, and 30

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mL/kg TBW), indicating that patients experienced a more volatile blood pressure prior to clinical

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intervention. In addition to a decrease in the average BPV, the interquartile range of BPV decreased after

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a fluid resuscitation of 10- and 20-mL/kg TBW in comparison to the interquartile range of BPV pre-fluid resuscitation. However, the interquartile range of BPV increased after a fluid resuscitation of 30 mL/kg

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TBW in comparison to the interquartile range of BPV pre-fluid resuscitation. 3 patients were consistent outliers from the interquartile range of BPV. Our study suggests that SBP is less volatile after fluid

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resuscitation.

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In order to assess the significance of BPV, we investigated the correlation between BPV and markers of illness severity (lactate and SOFA scores). In our analysis, serum lactate is the “gold standard”

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to which BPV is compared. Similar to the decrease in BPV identified following clinical intervention, mean initial lactate decreased from 4 mmol/L (SD 3.2) to 3.1 mmol/L (SD 3.2) for mean subsequent

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lactate, which was obtained an average of 6.6 hours (SD 5.3) later. We found a positive correlation

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between BPV and serum lactate levels, suggesting that persistently increased BPV may indicate hyperlactemia. This propensity to predict hyperlactemia via BPV analysis promotes early clinical

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intervention, which has been shown to improve clinical outcomes.3-4 Mean SOFA score was 7.0 (SD 4.4), which approximately represents a 15% mortality risk.21 Our main secondary finding was that BPV positively correlated with SOFA scores, which further supports our hypothesis that a positive relationship exists between BPV and illness severity. Jones et al found that applying to SOFA scores to patients with severe sepsis with evidence of hypoperfusion at the time of ED presentation functioned with fair to good accuracy at predicting in-hospital mortality, which consequently suggests that SOFA scores at ED presentation is an acceptable method for risk stratification and prognosis 17

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determination.28 However, SOFA scores are not readily available during the patient‟s early management in the ED versus BP measurement is a standard non-invasive monitor of a patient‟s hemodynamic status. Additionally, calculation of a SOFA score over a short time interval (<1 hour) is not practical within the clinical setting and are unlikely to be altered over such a short time period. Therefore, for a parameter that is readily available at the patient‟s bed-side, can be monitored for changes over short time intervals and is

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strongly correlated with and potentially predicts the patient‟s SOFA score, the monitoring of such a

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parameter likely has a high degree of clinical utility for the management of the septic patients within the ED.

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Sepsis is characterized as a complex state of systemic inflammation following an infection, with a resultant increase in inflammatory mediators (TNF-alpha) that elicits diffuse vasodilation.29 Conflicting

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vasodilatory and vasoconstricting influences (lactic acidemia versus reflex sympathetic activity) may

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explain our finding that hyperlactemia positively correlated with labile SBP. Although inflammation appears to be the primary mechanism underlying the altered vasomotor tone seen in sepsis, other factors

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are being discovered. Sharshar et al found an association between septic shock and apoptosis of neurons in the cardiovascular autonomic centers.30 Autonomic imbalance with increased activity in the

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parasympathetic arm and an uncoupling of cardiac tissue to autonomic influence have also been proposed

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as explanations for the hemodynamic changes in sepsis.31-32 It should be noted that the parasympathetic arm does not significantly innervate human vasculature. Clarifying this multifactorial regulation of BP

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will aid future clinical investigations of BPV. The clinical significance of BPV may relate to autoregulation which normally maintains a constant blood flow when BP changes. Such mechanisms are uniquely present for cerebral and renal blood flow.33-34 Recent data suggest that sepsis represents a state of dysregulation in cerebral autoregulation.35-36 Since cerebral autoregulation mechanisms are arguably active during changes in BP, a highly volatile BP may stress impaired autoregulation mechanisms. This potentially introduces a deleterious effect. Acute kidney injury (AKI) is a common problem following sepsis.37 Renal 18

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autoregulation also appears to be dysregulated during sepsis.38 We speculate a theoretical harm from a volatile BP, particularly when autoregulation of renal perfusion is impaired or has diminished functional capacity. . According to our findings, BPV analysis provides a means to mitigate septic patients who are at risk for tissue hypoperfusion.

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The small sample size was the primary limitation to our study. Furthermore, 15 out of 40 patients

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(38%) had all 13 systolic blood pressure measurements (ED triage BP plus a BP every 15 minutes over

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the first 3 hours of ED admission); 13 patients (33%) had 1 missing SBP measurement; 4 patients (10%) had 2 missing SBP measurements; and 4 patients (10%) had 3 missing SBP measurements; and 4 patients

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(10%) had more than 3 missing SBP measurements. Additionally, our study lacked a control group. A planned larger study involving both septic and non-septic patients may provide stronger evidence on the

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relationship between BPV and illness severity. Furthermore, blood pressure is influenced by many

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different factors, including time of day, posture, respiratory rate, pre-existing pathophysiology and home pharmacologic therapy. Within a clinical setting, it is virtually impossible to account for all of these

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variables fully. Since patients with a history of chronic hypertension are in a state of increased basal sympathetic activity, future studies on BPV in sepsis patients may compare pre-existing conditions that

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are likely to be hemodynamically significant to those that are less likely to impact patient hemodynamics.

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Home medications with hemodynamic significance will also need to be studied, including serum

substances.

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concentrations to fully understand the interplay between native hormonal regulators and exogenous

We designated three milestones of fluid infusion with the maximum milestone equal to 30 mL/kg TBW, based upon the 2016 SSC guidelines recommendation of a fluid resuscitation of 30 mL/kg TBW within the first 3 hours of ED admission.6 We added the 10 mL/kg and 20 mL/kg fluid administration milestones in order to improve the granularity of the data, and because preliminary data suggested that not all patients would receive the requisite 30 mL/kg TBW fluid infusion during the 3-hour study period.39-40 As such, less than half of our included patients received the amount of crystalloid fluid resuscitation 19

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recommended by current SCC guidelines. A study period extending beyond the first three hours of ED admission may have increased the number of patients receiving this obligatory fluid volume of 30 mL/kg TBW. The necessary information for a sepsis diagnosis is not always available to the treating physician.

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Our enrolled patients were retrospectively identified as septic by the presence of a positive laboratory or

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other diagnostic test finding of bacterial infection. This method limits the generalizability of our findings,

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because this laboratory result of a bacterial infection would not be known to the treating physician at the time of the decision to initiate a fluid resuscitation for shock. However, all patients were known to be

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hypotensive at the time of ED arrival and sepsis was a likely primary consideration for the treating physician considering a perceived high acuity of illness requiring aggressive fluid resuscitation.

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Additionally, our data set is not intended to contribute to the diagnostic process. Rather, our investigation

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sought to identify a non-invasive tool that indicated patient improvement or decompensation during the treatment process. Future studies may compare BPV between septic and non-septic patients in order to

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evaluate the utility of BPV analysis as a tool that could contribute to identifying multi-organ dysfunction,

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an integral component of a sepsis diagnosis.

Blood pressure variability, specifically among septic patients, is a largely under-studied concept.

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Pandey et al found BPV was significantly higher in septic patients with increased severity of disease measured by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.15 In that study, BP

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was measured at 30-minute intervals during the day and 60-minute intervals at night, over a 24 hour period within the first 48 hours of hospital admission. Our study differs in regards to both the frequency of BP measurement (15 minutes) and the study time period relative to admission (within first 3 hours of ED admission). This underscores the need for data that can be used early in the management of the disease, rather than several days into hospital admission. That study also assessed BPV via standard deviation while our study assesses BPV via ARV. ARV has demonstrated superior prognostic value in the

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setting of organ damage when compared to the standard deviation method, which does not account for the sequence of values within a data set.24,41 Just as BPV is an under-studied concept, ARV is a novel statistical tool for measuring BPV. Increasing or decreasing the time interval between BP measurements will result in less or more BP

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measurements, which consequently can increase or decrease ARV. Our time intervals between BP

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measurements were determined by expert clinicians. Other experts may disagree with a 15 minute interval

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between BP measurements. SSC guidelines recommend frequent BP measurements to guide fluid resuscitation.6 How frequent is unclear. A more in-depth understanding of BPV can help determine the

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optimal frequency of BP measurements necessary to guide clinical intervention for sepsis. Although ARV calculations account for the number of data points included within a series and involve a summation, it is

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more a measure of variability than an average value as the summation is calculated utilizing the difference

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between consecutive values within a series, thereby accounting for how data points change or vary over time. A limitation we encountered with ARV was that ARV calculation is not possible if a patient has one

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BP measurement during a designated time period (before or after receiving a fluid infusion milestone), because ARV is based upon the difference between consecutive measurements, requiring two BP values.

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Ultimately, the primary purpose of our study was to investigate whether BPV is associated with clinical

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improvement or deterioration. Many questions remain on BPV and on what is a high or low BPV. Future studies may establish target values for BPV determined by ARV to help guide sepsis management.

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In contrast to the finding of an association between elevated BPV and disease, another study found that mechanically-ventilated septic patients in an intensive care unit-based study exhibited BP oscillation at reduced frequencies, compared to previous reports on healthy, spontaneously breathing patients.16 The authors explained that the identified reduction in BP oscillations may be due to reduced sympathetic autonomic activity. By contrast, the majority of patients in our data set were spontaneously breathing. Only nine of the 40 septic patients (23%) were mechanically-ventilated during the study

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period. Given that positive-pressure ventilation can influence BP, mechanically-ventilated patients are exposed to an additional confounding variable, as compared to spontaneously breathing patients. The altered vasomotor tone in sepsis pathophysiology is accompanied by myocardial depression.42 Given this change in cardiac function, we also investigated HRV in our septic patient

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population, finding a positive correlation between HRV and lactate in patients who received fluid

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administration > 10 mL/kg TBW. Notably, this patient cohort (fluid administration > 10 mL/kg TBW)

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represents a slightly earlier point in time than the patient cohort (fluid administration > 20 mL/kg TBW) that demonstrated a positive correlation between BPV and lactate. We also discovered that HRV prior to

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receiving 20 mL/kg TBW fluid infusion positively correlated with SOFA scores. Similarly, Bohanon et al found that HRV analysis was more sensitive than conventional vital signs (cardiac output and mean

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arterial pressure) in confirming a diagnosis of sepsis in neonates.43 We also found that the correlation

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between HRV and lactate was less than the correlation between BPV and lactate, suggesting a weaker relationship between HRV and lactate than the relationship between BPV and lactate. This finding is

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supported by previous studies, which have shown that illness severity has been associated with low HRV, a contrast with the association between illness severity and high BPV.44-45 Future studies may investigate

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the utility of analyzing BPV and HRV conjointly to monitor sepsis management.

Conclusion

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Despite advances within the medical field, mortality from sepsis remains high, especially among patients with associated systolic hypotension and shock.22-23 Identifying tools that can aid ED clinicians in the early risk-stratification and monitoring of septic patients is likely to have a high impact on clinical outcomes.3-4 With the finding of a positive correlation between BPV and both lactate levels and SOFA

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score, this pilot study introduces BPV analysis as a real-time, non-invasive tool for continuous sepsis

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reproducibility in a larger and more heterogeneous cohort of patients.

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monitoring in the ED. Further study is needed to verify the significance of these findings and their

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