Bao et al.

Perioperative Medicine (2024) 13:13 Perioperative Medicine

https://doi.org/10.1186/s13741-024-00369-9

RESEARCH Open Access

AcumenTM hypotension prediction index

guidance for prevention and treatment
of hypotension in noncardiac surgery:
a prospective, single‑arm, multicenter trial
Xiaodong Bao1*, Sathish S. Kumar2, Nirav J. Shah2, Donald Penning3, Mitchell Weinstein4, Gaurav Malhotra4,
Sydney Rose5, David Drover6, Matthew W. Pennington7, Karen Domino7, Lingzhong Meng8, Mariam Treggiari9,
Claudia Clavijo10, Gebhard Wagener11, Hovig Chitilian1, Kamal Maheshwari12 and The HPI Study Team

Abstract
Background Intraoperative hypotension is common during noncardiac surgery and is associated with postoperative
myocardial infarction, acute kidney injury, stroke, and severe infection. The Hypotension Prediction Index software
is an algorithm based on arterial waveform analysis that alerts clinicians of the patient’s likelihood of experiencing
a future hypotensive event, defined as mean arterial pressure < 65 mmHg for at least 1 min.
Methods Two analyses included (1) a prospective, single-arm trial, with continuous blood pressure measurements
from study monitors, compared to a historical comparison cohort. (2) A post hoc analysis of a subset of trial partici-
pants versus a propensity score-weighted contemporaneous comparison group, using external data from the Multi-
center Perioperative Outcomes Group (MPOG). The trial included 485 subjects in 11 sites; 406 were in the final effec-
tiveness analysis. The post hoc analysis included 457 trial participants and 15,796 comparison patients. Patients were
eligible if aged 18 years or older, American Society of Anesthesiologists (ASA) physical status 3 or 4, and scheduled
for moderate- to high-risk noncardiac surgery expected to last at least 3 h. Measurements: minutes of mean arterial
pressure (MAP) below 65 mmHg and area under MAP < 65 mmHg.
Results Analysis 1: Trial subjects (n = 406) experienced a mean of 9 ± 13 min of MAP below 65 mmHg, compared
with the MPOG historical control mean of 25 ± 41 min, a 65% reduction (p < 0.001). Subjects with at least one episode
of hypotension (n = 293) had a mean of 12 ± 14 min of MAP below 65 mmHg compared with the MPOG historical
control mean of 28 ± 43 min, a 58% reduction (p< 0.001). Analysis 2: In the post hoc inverse probability treatment
weighting model, patients in the trial demonstrated a 35% reduction in minutes of hypotension compared to a con-
temporaneous comparison group [exponentiated coefficient: − 0.35 (95%CI − 0.43, − 0.27); p < 0.001].
Conclusions The use of prediction software for blood pressure management was associated with a clinically mean-
ingful reduction in the duration of intraoperative hypotension. Further studies must investigate whether predictive
algorithms to prevent hypotension can reduce adverse outcomes.

*Correspondence:
Xiaodong Bao
[email protected]
Full list of author information is available at the end of the article

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Bao et al. Perioperative Medicine (2024) 13:13 Page 2 of 12

Trial registration Clinical trial number: NCT03805217. Registry URL: https://​clini​caltr​ials.​gov/​ct2/​show/​NCT03​805217.

Principal investigator: Xiaodong Bao, MD, PhD. Date of registration: January 15, 2019.
Keywords Hypotension, Hypotension Prediction Index, Clinical decision support, Blood pressure monitor

Background clinically relevant amount. We also conducted a post hoc

A constant supply of oxygen and nutrients is needed to analysis to assess the duration of hypotension and inci-
support cellular metabolism. Adequate blood flow, blood dence of AKI in patients who participated in the trial
pressure, and autoregulation help maintain organ perfu- versus a propensity-score-weighted contemporaneous
sion. However, only blood pressure measurement is uni- comparison group.
versally available and is a key component affecting clinical
decision-making to ensure optimal organ perfusion. Dur- Methods
ing noncardiac surgery, blood pressure is routinely meas- Trial design and ethics
ured intermittently every 3–5 min (American Society of The single-arm, prospective multi-center study was a
Anesthesiologists, n.d.). Nevertheless, even with continu- post-market clinical study to further assess the safety and
ous monitoring of arterial blood pressure, intraoperative effectiveness of HPI. The trial was approved by a central
hypotension is common, with the incidence varying from Institutional Review Board (IRB; Western IRB approval
5 to 90%, depending on the chosen definition and the #1-1131056-1) and 8 local IRBs. It was registered with
context (Bijker et al., 2007). For example, 20% of patients clini​caltr​ials.​gov (NCT03805217, registered 1/15/19,
have at least one episode of mean arterial blood pressure first participant enrolled 5/16/19, PI: Bao). Written
(MAP) less than 65 mmHg during noncardiac surgery, informed consent was obtained from each subject in the
and the incidence is over 88% in moderate- to high-risk prospective trial, but not from subjects who were retro-
patients (Gregory et al., 2021; Shah et al., 2020). Intraop- spectively included in the comparison groups. Adverse
erative hypotension is associated with perioperative mor- events were reported by the trial sites, and an independ-
bidity and mortality, including acute kidney injury (AKI), ent Clinical Events Committee reviewed event narratives,
myocardial injury, and stroke (Hallqvist et al., 2021; Sal- patient profiles, and hemodynamics to adjudicate all
masi et al., 2017; Sessler et al., 2018; van Waes et al., 2016; adverse events for attribution, severity, and relatedness
Wesselink et al., 2018; Wijnberge et al., 2021a). In addi- to fluid management recommendations; classified as “not
tion, intraoperative hypotension increases hospital costs related”, “possibly related” or “related” to the software
(Keuffel et al., 2019; Nanji et al., 2021). However, reactive use, per FDA guidelines.
clinical management delays the delivery of corrective
intervention, making intraoperative hypotension difficult
Subject selection
to prevent.
Trial subjects were recruited from 11 academic hospitals
The AcumenTM Hypotension Prediction Index algo-
across the USA, with no site exceeding 20% of the total
rithm uses arterial pressure waveform information to
enrollment. Three pilot subjects (pilot cohort) were per-
alert clinicians of the patient’s likelihood of experiencing
mitted per site for training purposes before formal data
a future hypotensive event, defined as MAP < 65 mmHg
acquisition began. We included adults ≥ 18 years old
for at least 1 min (Hatib et al., 2018). This proactive man-
who were scheduled for elective moderate- or high-risk
agement may help clinicians treat hypotension effec-
(defined by the primary anesthesia team), noncardiac
tively. The algorithm performance is validated in several
surgical procedures, including orthopedic surgery, spine
small and mostly single-center studies (Hatib et al., 2018;
surgery, abdominal/pelvic surgery, or major periph-
Davies et al., 2020; Frassanito et al., 2022a; Frassanito
eral vascular surgery, expected to last 3 h or longer. All
et al., 2022b; Maheshwari et al., 2021; Ranucci et al., 2019;
subjects were American Society of Anesthesiologists
Shin et al., 2021; van der Ven et al., 2022; Wijnberge et al.,
(ASA) physical status 3 or 4 and required intra-operative
2021b). We conducted a single-arm multicenter pro-
mechanical ventilation and arterial catheterization for
spective trial to evaluate the safety and effectiveness of
continuous blood pressure monitoring as part of their
the hypotension prediction algorithm to decrease hypo-
anesthetic care plan. Patients were excluded if they had
tension in moderate- and high-risk noncardiac surgery
significant cardiac valvular disease including aortic ste-
patients, as compared to a historical comparison group.
nosis ≤ 1.5 ­ cm2, moderate-to-severe mitral stenosis,
We hypothesized that the alert function of the predic-
moderate-to-severe aortic or mitral regurgitation; intra-
tion software would reduce the duration of hypoten-
cardiac shunt; atrial fibrillation; acute heart failure; on
sion, defined as minutes of MAP below 65 mmHg, by a
support by intra-aortic balloon pump or ventricle assist
Bao et al. Perioperative Medicine (2024) 13:13 Page 3 of 12

device or multiple vasoactive agents; sepsis; planned ven- the monitor to alert anesthesia providers. The care team
tilation with tidal volume below 8 ml/kg of ideal body could administer fluid and/or vasoactive agents using
weight; as well as those scheduled for burn surgery, neu- advanced hemodynamic data or could choose to ignore
rosurgical procedures, open-chest procedures or urgent/ alerts based on their clinical assessment after coaching
emergent surgery. from the research team about the software.

Trial protocol
Subjects were enrolled after signing informed consent Trial endpoints
and having an arterial catheter connected to FloTrac IQ The primary endpoint for the trial was a cumulative dura-
sensor and EV1000 platform containing the predictive tion of intraoperative hypotension. The secondary end-
software. The software was activated after confirming point was the area under MAP of 65 mmHg. Data for the
a good-quality arterial waveform signal using a square trial endpoints were downloaded from the EV1000 moni-
wave test. The predictive index, ranging from 0 to 100, tor, which records vitals and the predictive index every 20
was displayed on the monitor, indicating the likelihood of s during the monitoring time. An episode of intraopera-
patients having a hypotensive event. A secondary screen tive hypotension was defined as three or more consecu-
with quantitative hemodynamic parameters including tive 20-s observations of MAP < 65 mmHg. Duration of
cardiac output, stroke volume variation, change of pres- hypotension was calculated as the sum of episodes where
sure over the change of time, systemic vascular resist- MAP < 65 mmHg for at least 1 min during the monitor-
ance, and dynamic arterial elastance aided clinician ing period. The area under MAP of 65 mmHg was cal-
assessment of physiological conditions (Fig. 1). When culated using the trapezoidal rule to estimate the area of
the hypotension prediction index exceeded 85 for two pressure and time. The total area was obtained using the
consecutive 20-s updates, a popup alert appeared on formula below.

Fig. 1 HPI Secondary Screen

Bao et al. Perioperative Medicine (2024) 13:13 Page 4 of 12

k l
pij + p(i−1)j sites from May 2019 to October 2020 and who did not
Total AUC = tij − t(i−1)j ∗ 65 −
2 participate in the trial (“Comparison”). Data were not
1 1
available from MPOG for the 11th trial site for that time
where tij is the measurement time of the ­ith hypoten- period. To maintain the inclusion and exclusion crite-
sion increment of the jth hypotension episode for the ria from the trial, similar eligibility criteria were applied
patient and p
­ ij is the mean pressure in mmHg for the ith using definitions that could be applied to retrospective
hypotension increment of the jth hypotension episode. data, as specified in Appendix 2.
The episode for each patient begins, t0j, with the first This post hoc analysis was conducted in collaboration
of two successive pressure measurements below MAP with the MPOG consortium. The MPOG Site Primary
65 mmHg and continues until the MAP raises to 65 Investigators at the HPI participating sites approved
mmHg or above. The trapezoidal rule sums the average the use of the dataset for this project, and the analytic
decreases in pressure from 65 mmHg between two meas- plan was presented at the MPOG Perioperative Clinical
urement times and multiplies that by the difference of the Research Committee. As has been previously described,
time increment between. Then, the areas per episode are the MPOG consortium (see www.​mpog.​org) maintains a
summed across the total number of episodes. detailed clinical and administrative data repository from
participating hospitals across the United States. MPOG
Statistical analysis data include automated extraction of both device-cap-
Single‑arm trial with historical comparison group tured and manually entered Electronic Health Record
A statistical analysis plan for the single-arm trial was (EHR) data, including patient and procedural character-
written, date-stamped, and recorded in the investigators’ istics, anesthetic medications, physiologic parameters,
files before data were accessed (Appendix 1). The analy- and key surgical events for patients undergoing anesthe-
sis excluded subjects in the pilot cohort. Mean duration sia care at contributing institutions. Monthly site-specific
of hypotension was calculated with a weighted average case validation for a random sample of submitted data
of site means and standard deviations as described in by subject-matter experts is required of all contribut-
Appendix 1. The standard deviation of the duration of ing sites, and additional quality checks are conducted
hypotension is the square root of the pooled variance at the coordinating center to monitor each center’s data
with each study site’s hypotension variance. The trial uploads and to remove artifacts from machine-captured
participants were compared to a historical comparison variables.
cohort identified in registry data using t-tests. The Multi- Data elements from MPOG used in this analysis
center Perioperative Outcomes Group (MPOG) provided included patient demographics (age, sex, BMI, ASA sta-
summary statistics on 22,109 adult patients with ASA 3 tus), clinical characteristics (Elixhauser comorbidities),
and 4 physical status, undergoing surgeries ≥ 180 min, procedural characteristics (procedure codes, blood pres-
with arterial line monitoring, treated between January sure observations, vasopressor use, estimated blood loss),
1, 2017 and December 31, 2017, at the same 11 hospitals and patient outcomes (AKI).
that participated in the HPI effectiveness study (Shah The main outcome of the post hoc analysis was the
et al., 2020). This information was used as a historical duration of hypotension in minutes (defined as MAP
control to define the retrospective amount of IOH, which < 65 mmHg for at least 1 min). The secondary outcome
was compared to that found in this prospective HPI mul- was AKI (using the Kidney Disease–Improving Global
ticenter study. All trial analyses were completed with SAS Outcomes definition of Stage 1 or greater, as an increase
version 9.4. of serum creatinine more than 0.3 mg/dl above baseline
within 48 h of anesthesia end time or more than 50% ele-
Post‑hoc analysis with propensity score‑weighted vation within 7 postoperative days) (Disease, 2012).
comparison group A statistical analysis plan for the post hoc analy-
To supplement the trial analysis that was designed a sis, specifying the outcomes and methods, was drafted
priori, we conducted a post hoc analysis that compared after the completion of the trial but before the post hoc
the duration of hypotension and the secondary outcome analyses began (Appendix 2). Descriptive statistics for
(AKI) among a subset of patients in the trial treatment continuous data were reported as mean ± standard devia-
group with a propensity-score weighted contemporane- tion or median (interquartile range) depending on the
ous control group, using data reported from MPOG for distribution of the data. Categorical data is presented
hospitals that participated in the trial. Trial subjects, as frequency counts and proportions. Weighted and
including both pilot and non-pilot subjects, from 10 of unweighted standardized mean differences were calcu-
the 11 sites (“Trial”) were compared with a contempora- lated and reported to compare trial participants to the
neous cohort of patients who had surgery in the same 10 comparison group.
Bao et al. Perioperative Medicine (2024) 13:13 Page 5 of 12

The post hoc analysis evaluated the association Austria) and RStudio (RStudio PBC, Boston, MA, USA),
between the prediction software and the incidence of with two-sided p values < 0.05 considered statistically
intraoperative hypotension, as defined above. To evaluate significant.
the difference in hypotension duration conditional on the
use of the prediction software, a generalized linear model Trial sample size estimate
was conducted regressing the duration of hypotension on Recent analyses demonstrated a mean duration of hypo-
the fixed effects for software presence or absence. Given tension of 29.27 min with a standard deviation 43.44
the skewed distribution for the duration of hypotension, (Shah et al., 2020). We anticipated that the use of the
a log link was specified to accommodate the distribution predictive algorithm would reduce that duration by
under study. Because it was anticipated that patients with 25%, based on based on an advisory panel expert opin-
longer surgical cases may have an increased period at ion and review of recent literature (van Waes et al., 2016;
risk of developing hypotension, the model was adjusted Maheshwari et al., 2018; Stapelfeldt et al., 2017). The ratio
a priori for the duration of intraoperative blood pressure of the standard deviation to the mean in the previous
measurement (i.e., time at risk). data was 1.44; however, the ratio from other publications
It was also anticipated that patients may have a differ- on hypotension and data gathered by the sponsor varied
ent probability of participating in the trial, therefore the between 0.88 to 1.76. To protect against the uncertainty
analysis employed the use of propensity score analyses. of the ratio underpowering the study, additional compu-
Specifically, individuals who elected to participate in tations were done to make the estimate more conserva-
the single-arm trial might possess characteristics that tive with a standard deviation to mean ratio of 1.65. The
differentiate them from eligible individuals who either minimum recommended required sample size, using Pass
declined to participate or were not offered participation. 14, is 380 completed subjects for 90% power for a one-
To address this selection mechanism, a logistic regression sided alpha = 0.025 test. Assuming 10% attrition for a less
model was first developed that predicts trial participation than 3-h surgery and a 5% loss to follow-up, the recruited
(i.e., yes vs no) conditional on demographic and disease sample size was estimated as a minimum of 380/0.85 ≈
characteristics. The predicted probability of participa- 448 for 90% power in the non-pilot cohort. Therefore, the
tion was then used as an inverse probability of treatment study sample size was capped at 485, including up to 33
weight (IPTW) in a second and final model (the primary pilot subjects and up to 452 non-pilot subjects, for a min-
analysis) that examines each outcome conditional on imum of 90% power.
prediction software use (i.e., yes or no) and duration of
blood pressure measurement. Variables in this IPTW Results
included age, sex, race, ethnicity, ASA physical status, Single‑arm trial with historical comparison group
Vanwalraven Elixhauser Comorbidity Index, procedure A total of 778 patients were screened for trial eligibility
timing (afternoon or morning), and procedural service. (Supplementary Figure S1). Among them, 293 failed to
Several versions of the inverse-probability of treatment meet inclusion criteria. Four hundred eighty-five subjects
weights were considered but non-truncated and non- have consented to the study, 425 of whom ultimately had
stabilized weights were chosen based on the distribution a surgery length of 3 h or longer (19 in the pilot cohort
of estimated propensity scores. Results are presented as and 406 in the non-pilot cohort). The analysis focused on
exponentiated coefficients that yield a percent difference the 406 subjects in the non-pilot cohort and 293 of those
(i.e., a ratio of geometric means) in the duration of hypo- who had at least 1 min of MAP below 65 mmHg. Table 1
tension between the trial and comparison groups and shows the primary and secondary endpoints from the
their associated 95% confidence intervals (CI). single-arm trial. During the study period, participants (n
The secondary outcome was evaluated using a simi- = 406) experienced a mean of 9 min (SD 13) of MAP <
lar approach but with a generalized linear model that 65 mmHg, as reported via the EV 1000 monitors, and a
included a binomial distribution and logit link function. mean area under MAP < 65 mmHg of 47 mmHg × min-
Results of the secondary outcome are thus presented as utes (SD 85). A historical comparison group from the
an odds ratio and 95% confidence interval (CI). A sensi- same set of hospitals (n = 22,109) experienced a mean of
tivity analysis was performed for both the primary and 25 min (SD 41) of MAP < 65 mmHg, based on data from
secondary outcomes using multiple imputation with the MPOG registry, representing 65% fewer minutes of
chained equations (m = 40 imputations) which were hypotension than trial participants (p < 0.0001). Subjects
derived from the preoperative clinical characteristics with at least one episode of hypotension (n = 293) had
used in the propensity model. a mean of 12 ± 14 min of MAP below 65 mmHg com-
All post hoc analyses were performed using R version pared with the MPOG historical control mean of 28 ± 43
4.1.2 (R Foundation for Statistical Computing, Vienna, min, a 58% reduction (p < 0.001). Trial sites reported a
Bao et al. Perioperative Medicine (2024) 13:13 Page 6 of 12

Table 1 Hypotension outcomes from the single-arm trial

Effectiveness including subjects with no Effectiveness among subjects with at
episodes of MAP < 65 mmHg least 1 min of MAP < 65 mmHg
Trial participants Historical comparison Trial participants Historical
(n = 406) cohort (n = 22,109) (n = 293) comparison cohort
(n = 19,446)

Mean (SD) Mean (SD) Mean (SD) Mean (SD)

Trial primary outcome
Duration of intraoperative hypotension (minutes 9 (13)* 25 (41) 12 (14)* 28 (43)
of MAP < 65 mmHg)
Trial secondary outcome
Area under MAP of 65 mmHg (mmH × minute) 47 (85) na 65 (94) na
*p < 0.0001. MAP mean arterial pressure, na not available, SD standard deviation

total of 21 postoperative safety events, including 17 inci- associated with a 35% reduction in the duration of hypo-
dents of AKI, 3 instances of myocardial injury, and 1 non- tension. There was no statistically significant difference in
fatal cardiac arrest. No strokes or in-hospital deaths were AKI (p = 0.637) between the two groups; 13.8% of trial
observed. participants and 15.8% of comparison patients had AKI.
All inferences were consistent across a series of sensi-
Post hoc analysis with propensity score‑weighted tivity analyses that used different modeling techniques,
comparison group including propensity adjustment, multiple imputation
The post hoc analysis focused on 457 subjects (pilot and propensity adjustment, and a post hoc sensitivity analysis
non-pilot) from 10 of the 11 sites with the intention to adjusted for patient sex (Table 4).
treat the analysis for which data were available. MPOG
identified in their registry 177,519 surgical cases from Discussion
10 trial sites that occurred during the trial recruitment The goal of predictive technology is to warn clinicians
period or within approximately 7 months thereafter. and prevent untoward events by timely intervention. We
These were then limited to the 16,253 cases that matched report that the use of the hypotension prediction algo-
the trial inclusion/exclusion criteria as closely as pos- rithm was associated with a 35% reduction in the dura-
sible: noncardiac inpatient surgeries that lasted at least tion of intraoperative hypotension versus comparison
3 hours and had hemodynamic monitoring through an patients in a propensity-weighed model. Our results align
arterial line (Supplementary Figure S2). Of those, 457 with several single-center trials that have tested this soft-
were participants enrolled in the trial, and the remaining ware device. In a small, randomized controlled trial in the
15,796 were designated as the comparison group. Table 2 Netherlands, Wijnberge et al. (2020) observed a statisti-
shows the patient characteristics and surgical charac- cally significant reduction in time-weighted average MAP
teristics and the standardized mean difference between < 65 mmHg (Wijnberge et al., 2020). Their secondary
groups. Figure 2 shows a balance plot for the group char- outcome (median minutes of MAP < 65 mmHg) was 8.0
acteristics, unweighted and weighted; it indicates that all min in the intervention group vs 32.7 min in the control
but one of the weighted standardized mean differences group. This is similar to the median of 9 min of hypoten-
between the trial and comparison groups are less than sion we observed in the post hoc analysis of our multi-
0.1, suggesting that the groups are comparable on meas- center trial group; however, our U.S. comparison group
ured characteristics. had a much lower duration of hypotension (median 15
Patients in the study group experienced fewer min- min) than this European comparison group. A trial in
utes of intraoperative hypotension than the comparison Greece showed a 28% reduction in time-weighted aver-
group [median 9 (3, 20) vs. 15 (5, 39) min, p < 0.001], as age MAP < 65 mmHg in the intervention group, although
determined using EHR data from the MPOG registry they also observed an increase in hypertension and
(Table 3). In the inverse probability treatment weigh- increased use of phenylephrine in the intervention group
ing propensity model, patients in the trial had reduced (Tsoumpa et al., 2021). Five other randomized trials
total time spent in hypotension [exponentiated coeffi- observed that the use of the predictive algorithm reduced
cient − 0.35 (95%CI − 0.43, − 0.27); p < 0.001]. The use intraoperative hypotension (Grundmann et al., 2021;
of predictive software in hemodynamic management was Schneck et al., 2020; Murabito et al., 2022; Šribar et al.,
Bao et al. Perioperative Medicine (2024) 13:13 Page 7 of 12

Table 2 Patient and surgical characteristics in the single-arm trial and contemporaneous comparison group
Contemporaneous Trial Standardized
comparison N = 457 mean
N = 15,796 difference

Age, years 64.0 [54.0, 72.0] 65.0 [56.0, 72.0] 0.107

Male ­Sexa 8838 (56.0) 237 (51.9) 0.083
Race 0.172
White 12192 (77.2) 377 (82.5)
Black 1417 (9.0) 37 (8.1)
Asian or Pacific Islander 698 (4.4) 18 (3.9)
Other 131 (0.8) 4 (0.9)
Unknown 1358 (8.6) 21 (4.6)
Hispanic or Latino ethnicity 314 (2.0) 6 (1.3) 0.053
ASA Physical Status Class IV 2186 (13.8) 40 (8.8) 0.161
Vanwalraven Elixhauser Comorbidity Index 11.0 [4.0, 19.0] 11.0 [3.0, 17.0] 0.094
AIDS/HIVb 47 (0.3) 1 (0.2) 0.017
Alcohol ­abuseb 294 (1.9) 4 (0.9) 0.085
Blood loss a­ nemiab 378 (2.4) 7 (1.5) 0.063
Cardiac ­arrhythmiasb 5451 (34.5) 108 (23.6) 0.244
Chronic pulmonary ­diseaseb 3606 (22.8) 87 (19.0) 0.095
Congestive heart ­failurec 1744 (11.0) 33 (7.2) 0.134
 ­Coagulopathyd 1900 (12.0) 32 (7.0) 0.173
Deficiency ­anemiad 689 (4.4) 15 (3.3) 0.058
 ­Depressiond 2964 (18.8) 86 (18.8) 0.010
Diabetes ­complicatedc 1382 (8.7) 36 (7.9) 0.033
Diabetes ­uncomplicatedc 2703 (17.1) 89 (19.5) 0.061
Drug ­abused 727 (4.6) 11 (2.4) 0.120
Fluid electrolyte ­disordersd 4978 (31.5) 116 (25.4) 0.138
Hypertension, ­complicatedd 3008 (19.0) 74 (16.2) 0.077
Hypertension, ­uncomplicatedd 8132 (51.5) 242 (53.0) 0.030
 ­Hypothyroidismd 2388 (15.1) 66 (14.4) 0.022
Liver ­diseased 1696 (10.7) 65 (14.2) 0.106
 ­Lymphomad 225 (1.4) 8 (1.8) 0.028
Metastatic ­cancerd 3183 (20.2) 121 (26.5) 0.150
 ­Obesityd 3631 (23.0) 117 (25.6) 0.061
Other neurologic ­disordersd 1953 (12.4) 24 (5.3) 0.254
 ­Paralysisd 602 (3.8) 7 (1.5) 0.142
Peptic ulcer disease excluding ­bleedingd 258 (1.6) 7 (1.5) 0.013
­ isordersd
Peripheral vascular d 2709 (17.1) 58 (12.7) 0.127
 ­Psychosesd 165 (1.0) 4 (0.9) 0.020
Pulmonary circulation ­disordersd 959 (6.1) 17 (3.7) 0.110
Renal ­failured 2777 (17.6) 71 (15.5) 0.057
Rheumatoid arthritis/collagen vascular ­diseasesd 654 (4.1) 15 (3.3) 0.047
Solid tumor without ­metastasisd 6578 (41.6) 209 (45.7) 0.083
Valvular ­diseased 1284 (8.1) 18 (3.9) 0.178
Weight ­lossd 2291 (14.5) 58 (12.7) 0.055
Procedure started in ­afternoond 5204 (32.9) 133 (29.1) 0.105
Procedural service 0.856
General 1971 (12.5) 124 (27.1)
Orthopedics 1955 (12.4) 61 (13.3)
Urology 1136 (7.2) 56 (12.3)
Neurosurgery 4168 (26.4) 47 (10.3)
Bao et al. Perioperative Medicine (2024) 13:13 Page 8 of 12

Table 2 (continued)
Contemporaneous Trial Standardized
comparison N = 457 mean
N = 15,796 difference

Vascular 1483 (9.4) 33 (7.2)

Transplant 877 (5.6) 23 (5.0)
Otolaryngology 1129 (7.1) 17 (3.7)
Obstetrics and gynecology 353 (2.2) 8 (1.8)
Oral/maxillofacial 95 (0.6) 5 (1.1)
Plastics 181 (1.1) 4 (0.9)
Cardiac 93 (0.6) 2 (0.4)
Colorectal 41 (0.3) 1 (0.2)
Surgery-oncology 25 (0.2) 1 (0.2)
Trauma 115 (0.7) 1 (0.2)
Thoracic 1192 (7.5) 1 (0.2)
Radiology 74 (0.5) 0 (0.0)
Cardiothoracic 185 (1.2) 0 (0.0)
Pain management 20 (0.1) 0 (0.0)
Surgical service-other 673 (4.3) 70 (15.3)
Other 30 (0.2) 3 (0.7)
ASA American Society of Anesthesiologists: HIV human immunodeficiency virus: AIDS acquired immunodeficiency syndrome
Data is presented as median [quartile 1, quartile 3] or n (%) depending on the variable type
a
Missing for 1 patient in the comparison group
b
Missing for 435 patients in the comparison group and 12 patients in the trial
c
Missing for 437 patients in the comparison group and 12 patients in the trial
d
Missing for 441 patients in the comparison group and 12 patients in the trial
d
Missing for 1 patient in the trial

Fig. 2 Balance Plot

Bao et al. Perioperative Medicine (2024) 13:13 Page 9 of 12

Table 3 Comparison of intraoperative hypotension and acute kidney injury in the single-arm trial versus contemporaneous
comparison group
Contemporaneous Trial Crude ­modelb Inverse probability of treatment
comparison N = 457 weighing propensity model
N = 15,796
Effect ­Estimatec P-Value Effect ­estimatec P value
(95% CI) (95% CI)

Duration of Hypotension 15 [5, 39] 9 [3, 20] − 0.31 (− 0.39 to − 0.22) < 0.001 − 0.35 (− 0.43 to − 0.27) < 0.001
(MAP < 65)a
Acute kidney injury 1898/12,421 (15.3%) 45/325 (13.8%) 0.93 (0.67 to 1.27) 0.674 0.91 (0.63 to 1.33) 0.637
CI confidence interval: MAP mean arterial blood pressure)
Data is presented as median [quartile 1, quartile 3] in minutes, or n (%) depending on descriptive statistics
a
Data is only available for 15,749 observations
b
All models are adjusting for time in which blood pressure is measured (i.e., time at risk)
c
Effect estimates for hypotension are reported as exponentiated beta coefficients, whereas effect estimates for acute kidney injury are reported as odds ratios

Table 4 Model effect estimates, sensitivity analyses

Modela Effect ­estimateb P value
(95% CI)

Duration of hypotension (MAP < 65)

Crude − 0.31 (− 0.39 to − 0.22) < 0.001
Propensity adjusted − 0.33 (− 0.41 to − 0.24) < 0.001
Inverse probability of treatment weighting − 0.35 (− 0.43 to − 0.27) < 0.001
Multiple imputation propensity adjustment − 0.33 (− 0.41 to − 0.25) < 0.001
Post hoc sensitivity–adjusted for sex − 0.35 (− 0.32 to − 0.27) < 0.001
Acute kidney injury
Crude 0.93 (0.67 to 1.27) 0.674
Propensity adjusted 0.83 (0.60 to 1.14) 0.270
Inverse probability of treatment weighting 0.91 (0.63 to 1.33) 0.637
Multiple imputation propensity adjustment 0.88 (0.65 to 1.20) 0.432
Post hoc sensitivity–adjusted for sex 0.90 (0.61 to 1.31) 0.571
CI confidence interval: MAP mean arterial blood pressure
a
All models are adjusting for time in which blood pressure is measured (i.e., time at risk)
b
Effect estimates for hypotension are reported as exponentiated beta coefficients (i.e., ratio of expected geometric means), whereas effect estimates for acute kidney
injury are reported as odds ratios

2023; Lorente et al., 2023), although they found no differ- followed the study protocol. In addition, the comparison
ence in lab values, clinical outcomes (Šribar et al., 2023), group had a low incidence of hypotension compared to
or tissue oxygenation (Lorente et al., 2023). An observa- the European trials (about one-third of the time-weighted
tional study of the software device found that those in average in the Wijnberge et al trial), possibly indicating
the HPI group had less hypotension, fewer postoperative the practice difference between the USA and Europe.
complications, and lower length of stay (Solares et al., Although the use of the predictive algorithm was asso-
2023), and a second observational study saw shorter ICU ciated with a reduction in the duration of intraoperative
ventilation time among the HPI group, although no dif- hypotension, we did not observe a statistically signifi-
ference in AKI (Reddy et al., 2023). cant reduction in AKI, our secondary outcome for the
Of the known trials of this predictive algorithm, only post hoc analysis. The incidence of AKI was 13.8% in the
one U.S.-based pilot study showed no difference in hypo- trial participants versus 15.3% in comparison patients.
tension in the intervention and control groups, with This study was not powered to detect a reduction in AKI;
both groups having a time-weighted average MAP < 65 rather, AKI was one component of the composite safety
mmHg of 0.14 mmHg (Maheshwari et al., 2020). A sub- outcome in the single-arm trial, and it was a secondary
group analysis by the authors demonstrated that the outcome for the post hoc comparison group analysis.
time-weighted average MAP < 65 mmHg reduced to 0.06 The effect of hypotension on AKI could be influenced
mmHg in the subset of alerts where anesthesia providers by patient baseline comorbidities and procedure risks.
Bao et al. Perioperative Medicine (2024) 13:13 Page 10 of 12

Mathis et al. (2020) reported no association of increased in methodology to calculate hypotension time. These
risk of AKI across all blood pressure ranges in patients limitations were the impetus for the post hoc analysis.
with low risk and a strong association in patients of the The design of the post hoc analysis, which compares
highest risk (Mathis et al., 2020). The acute profound trial participants to a propensity-weighted compari-
intraoperative hypotension could be hard to prevent and son group, is able to control for observable differences
result in more kidney injury. Our trial did allow the free- between groups. The weighted models may not fully
dom to anesthesia providers to ignore the alerts from control for differences between the trial participants
devices. Although we achieved a 35% reduction in hypo- and comparison patients on variables that are not
tension time, it may not be enough to convey kidney pro- observed or measured in the registry data. Also, as
tection. Also, operations only account for a small portion noted above, the trial was not designed or powered to
of patients’ hospital stays, and hypotension could occur assess AKI, which we used as a secondary outcome in
while patients are in postoperative care units, intensive our post hoc analysis.
care units, and floors, which would not be prevented by Despite the limitations, this analysis is a valuable addi-
this trial. tion to the literature on the use of predictive algorithms
It is worth noting that the measures of hypotension to guide hemodynamic monitoring and prevention of
duration in the prospective single-arm trial (in Table 1) intraoperative hypotension. It is the first multicenter
and the post hoc analysis with registry data (in Table 3) study of this predictive algorithm with the largest sample
are not identical. Data on the duration of hypotension size and adds to the existing single-center trials. Addi-
for the trial participants were extracted directly from the tionally, while the post hoc design cannot provide as
EV1000 monitor every 20 s, while the post hoc analysis strong a causal relationship as a randomized control trial,
outcome was calculated using blood pressure data from the observational design with propensity-score weighted
the anesthesia record at 1 min intervals. The EV 1000 models is a rigorous method for estimating impacts
monitor was attached to patients after the arterial line in situations when a randomized trial is not possible for
was placed and disconnected at the end of operations, ethical, practical, or financial reasons. Our IPTW model
which may not count all data from the anesthesia record provided a well-balanced match to compare to trial par-
and could miss volatile blood pressure swing at induc- ticipants. This analysis demonstrates that real-world data
tion and emergence phases. Importantly, however, in can be used in conjunction with trial data to advance the
the post hoc analysis that compares trial participants to evidence base.
cotemporaneous control patients, the hypotension data There is now a large body of observational evidence to
source and calculation method are the same for both show that intraoperative hypotension increases patient
groups, which makes the comparison valid. Additionally, risks for adverse outcomes related to perfusion, and there
in the prospective single-arm trial, 17 cases of AKI were is a consensus statement recommending that anesthesia
reported by sites as adverse events by using the AKIN providers maintaining systolic arterial pressure above
definition, whereas in the post hoc analysis, 45 instances 100mmHg and MAP above 60 to 70 mmHg to attempt
of AKI were identified with KDIGO diagnosis criteria. to reduce patient risk (Sessler et al., 2019). Neverthe-
It should be recognized that as a safety measure, kidney less, prevention and management of hypotension should
function was followed until postoperative day 3 in the be targeted to the underlying physiological changes of
prospective trial, while the registry data used for post hoc volume status, cardiac contractility, and vascular tone.
analysis reported kidney function until 7 days after oper- Aggressive or inappropriate volume overload or over-
ation, which may explain the discrepancy. use of vasopressors without accounting for hypovolemia
This study has several limitations. The trial group was could lead to worsening surgical outcomes. A recent mul-
subject to the Hawthorne effect; providers, aware of the ticenter study demonstrated an increased incidence of
trial, may have been more inclined towards aggressive AKI with decreased administration of crystalloid, shorter
correction of hypotension. In the initial analysis, the duration of hypotension, and higher usage of vasopres-
trial outcomes were compared to a historical compari- sor (Chiu et al., 2022; Shin et al., 2018). EV 1000 monitor
son cohort; however, the data source differed between could potentially provide a quick insight into the patient’s
groups. The blood pressure data for trial participants hemodynamic status. More research is needed on the
was pulled from the EV 1000 monitors, whereas for appropriate treatment for intraoperative hypotension
the historical comparison cohort, it came from a clini- in order to maintain hemodynamic stability most effec-
cal registry. Additionally, because we did not receive tively while minimizing overtreatment (Chiu et al., 2022;
patient-level data for the comparison cohort, we were Shin et al., 2018). Trials are also needed to more rigor-
unable to control for differences in the patient and pro- ously determine whether the use of predictive algorithms
cedure between the groups. There is also a difference to prevent hypotension can reduce organ system damage
Bao et al. Perioperative Medicine (2024) 13:13 Page 11 of 12

and other complications, such as AKI, myocardial injury, restrictions apply to the availability of these data, which were used under
license for the current study, and so are not publicly available. Data are how-
postoperative delirium, and mortality. ever available from the authors upon reasonable request and with permission
of the Multicenter Perioperative Outcomes Group.

Conclusion
The use of prediction software for blood pressure man- Declarations
agement was associated with a clinically meaningful Ethics approval and consent to participate
reduction in the duration of intraoperative hypotension. The trial was approved by a central Institutional Review Board (IRB; Western
Further studies must investigate whether predictive IRB approval #1-1131056-1) and 8 local IRBs. Written informed consent was
obtained from each subject in the prospective trial, but not from subjects who
algorithms to prevent hypotension can reduce adverse were retrospectively included in the comparison groups.
patient outcomes.
Consent for publication
Not applicable.
Abbreviations
AKI Acute kidney injury Competing interests
ASA American Society of Anesthesiologist XB, HC, CC, GM, LM, DP, MP, SR, MT, GW, MW declare that they have no com-
BMI Body mass index peting interests.
CI Confidence interval KD received grants or contracts in the past 36 months from Anesthesia Patient
EHR Electronic Health Record Safety Foundation regarding NORA, and lecture honoraria from Northwest
HPI Hypotension Prediction Index Anesthesia Seminars; she serves as Committee Chair for the ASA Committee
IOH Intraoperative hypotension on Practice Parameters.
IPTW Inverse probability of treatment weighted DD received grants or contracts in the past 36 months from NIH – NIA and
KDIGO Kidney disease: improving global outcomes Masimo Inc, and consulting fees from Masimo Inc.
MAP Mean arterial pressure SK received grants or contracts in the past 36 months from Edwards Lifes-
MPOG Multicenter Perioperative Outcomes Group ciences, PCORI, and Hemosonics; honoraria from ROTEM for lecture; and
SD Standard deviation reimbursement from Edwards Lifesciences for travel to a research meeting.
KM received grants or contracts and consulting fees in the past 36 months
from Edwards Lifesciences and Phillips Healthcare.
Supplementary Information NS received grants or contracts in the past 36 months from Edwards Lifes-
The online version contains supplementary material available at https://​doi.​ ciences, Blue Cross Blue Shield Michigan, National Institute of Aging, American
org/​10.​1186/​s13741-​024-​00369-9. Heart Association.

Author details
Additional file 1: Appendix 1. Statistical Analysis and Reporting Plan 1
Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital,
Additional file 2: Appendix 2. Statistical analysis plan Boston, MA, USA. 2 Department of Anesthesiology, University of Michigan
Medical School, Ann Arbor, MI, USA. 3 Department of Anesthesiology, Henry
Additional file 3: Supplementary Figure S1. HPI Trial Diagram
Ford Health System, Detroit, MI, USA. 4 Department of Anesthesiology
Additional file 4: Supplementary Figure S2. Data Flow Diagram and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA,
USA. 5 Department of Anesthesiology and Perioperative Medicine, Oregon
Health & Science University, Portland, OR, USA. 6 Department of Anesthe-
Acknowledgements sia, Stanford University, Stanford, CA, USA. 7 Department of Anesthesiology
Kathryn Cody, Ph.D. and Ariel Muller, MS (Massachusetts General Hospital, and Pain Medicine, University of Washington School of Medicine, Seattle, WA,
Boston, MA) contributed to the statistical analysis and model building. Anna USA. 8 Department of Anesthesiology, Indiana University School of Medicine,
L. Christensen, Ph.D. (Principal Researcher, Mathematica, Washington, DC) Indianapolis, IN, USA. 9 Department of Anesthesiology, Duke University School
assisted with drafting the manuscript. of Medicine, Durham, NC, USA. 10 Department of Anesthesiology, University
of Colorado Anschutz Medical Campus, Aurora, CO, USA. 11 Department
Authors’ contributions of Anesthesiology, College of Physicians & Surgeons of Columbia University,
XB, SK, DP, MW, GM, SR, DD, MP, KD, LM, MT, CC, GW, and KM were each trial New York, NY, USA. 12 Department of General Anesthesiology, Cleveland Clinic,
site-PIs or co-PIs who made substantial contributions to the conception, Cleveland, OH, USA.
acquisition, and interpretation of data. NS provided comparison group data
and made substantial contributions to the conception, acquisition, and inter- Received: 6 August 2023 Accepted: 25 February 2024
pretation of data. HC made substantial contributions to the conception and
analysis of data. All authors approved the submitted version and agreed to be
accountable for their own contributions.

Funding
The study sponsor is Edwards Lifesciences LLC, One Edwards Way, Irvine, CA
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