A Pilot Trial of Continuous Portable Postoperative Hemodynamic And Saturation Monitoring On Hospital Wards
Phase: NA
Conditions: Hemodynamic Instability, Respiratory Complications of Care
Sponsor: Wake Forest University Health Sciences

 
 
 
 
Official Title: A Pilot Trial of Continuous Portable Postoperative Hemodynamic And 
Saturation Monitoring On Hospital Wards 
 
NCT04574908 
IRB-Approved Date: 7/8/2021 

 
 
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Study Title:  A Pilot Trial of Continuous Portable Postoperative Hemodynamic And 
Saturation Monitoring On Hospital Wards 
 
 
Principal Investigator, Co-investigator(s):  Ashish K. Khanna, MD., FCCP.,FCCM, Associate Professor, Section Head 
for Research, Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest Baptist Medical Center. 
 
Sponsor or funding source: CTSI KL2 Award  
 
 
Background, Rationale and Context 
 
Postoperative death within 30 days of surgery is the third most common cause of mortality in this country.(1) 
The general care floor or hospital ward is traditionally perceived as a place for recovery of postoperative patients 
who are clinically stable and will transition quickly to leave the hospital. However, about half of all adverse 
events in hospitalized patients occur on the hospital ward (2-4). Cardiac and respiratory triggers seem to be the 
most common starting points for these events.(5) A majority of these acute cardiorespiratory events do not occur 
suddenly. Up to 60% of patients have at least one or more abnormal vital signs starting about 4 hours before an 
eventual cardiac or respiratory arrest.(4)  Early detection of this change in patient physiology therefore becomes 
critical in effective upstream preventative and therapeutic measures which can translate into improved 
downstream clinical outcomes. Whereas most patients are still being monitored on an intermittent ‘spot check’ 
basis on hospital wards, the evolving role of continuous portable monitoring systems is of obvious benefit in 
these clinical settings.  
At Wake Forest Baptist Medical Center, continuous monitoring of vital signs is as yet not a gold standard of care 
and is limited to certain units. Most patient assessments are still performed on an intermittent basis with every 4 
hourly vital signs checks. As an institution we are leading the way in adoption of portable monitoring technology 
and have continuous portable monitoring (ViSi device, Sotera Wireless, San Diego, CA) that has been installed 
in a phased manner for the last 4 years. However, the use of this technology has been incomplete and inconsistent, 
since there is much question to whether it leads to improved patient outcomes. There is, therefore, availability and 
familiarity with technology, and also perfect equipoise to conduct the proposed trial. This pilot data will add 
much needed scientific rigor that is essential for changing and implementing practice guidelines locally and 
nationally, to help adopt or refute appropriate continuous patient monitoring. This will also form the basis for a 
much larger multi-center interventional trial of continuous monitoring, which would be the next step to add much 
needed evidence in this area of work.  
 
Preliminary Studies A recent analysis, led by Dr. Daniel I. Sessler (co-mentor) showed that ward hypoxemia is 
common, prolonged and profound in both severity and duration. 21% of postoperative non-cardiac inpatients were 
found to have ≥10 minutes SpO2 < 90% per hour in patients with clinician-blinded monitoring11. More than 90% 
of desaturation episodes (<90% for a continuous hour) were missed using routine measurements at 4-hour 
intervals.11Patients at highest risk for hypoxemia after surgery, may be those with obstructive sleep apnea and 
those on narcotic medication for analgesia or a combination of these. The STOP-BANG scoring system is a 
validated and easy to use mechanism for screening for obstructive sleep apnea (OSA).12 A higher STOP-BANG 
score predicts for worsening OSA status and patients with OSA desaturate episodically as a part of the defining 
criteria of the problem. We monitored patients on the regular ward (with continuous blinded pulse oximetry) for 
at least 48 postoperative hours, but rather surprisingly found no association between an increasing STOP-BANG 
score and postoperative hypoxemia.13 There was also no relationship between the type of narcotic used in a 
patient controlled analgesia system (IV hydromorphone and morphine compared with IV fentanyl) and 
postoperative hypoxemia.14These results highlighted the fact that respiratory depression in the postoperative period 

 
 
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remains difficult to predict with commonly available tools.6,15 Several other key preliminary studies have already 
been published in the Lancet,9NEJM,10 JAMA,16 and Anesthesiology.8,17,18 These studies show that hypotension 
on surgical wards is common and prolonged; that both intraoperative and ward hypotension are strongly associated 
with myocardial injury and death; that postoperative myocardial infarctions are far more common that generally 
appreciated and have a 10% 30-day mortality. Dr. Khanna was previously involved in a trial of portable 
continuous monitoring that showed at least 10% of all hospital ward patients had 15 continuous minutes or more 
of mean arterial pressures less than 65mmHg over a 48-hour monitoring period. Importantly, nurse initiated spot 
checks missed detection of hypotension in 50% of these patients. 19 A recent analysis of the PeriOperative ISchemic 
Evaluation-2 Trial (POISE-2) data showed that exposure to systolic blood pressure less than 90mmHg (as detected 
using routine nursing evaluation), occurred in 42% of postoperative ward patients and was associated with a nearly 
3-fold increase in the odds of mortality.18 Intraoperative tachycardia is also common to the tune of 71% for a 
HR>90/min.20 Dr. Khanna recently finished PRediction of Opioid-induced respiratory Depression In patients 
monitored by capnoGraphY (PRODIGY), a prospective, observational study of continuous bedside capnography 
and oximetry conducted in the United States, Europe, and Asia.21 Hospitalized in patients receiving opioids were 
included. Monitor alarms and data were blinded. Respiratory compromise episodes were defined by respiratory 
rate ≤8 bpm for ≥3 minutes; oxygen saturation ≤85% for ≥3 minutes; end-tidal carbon dioxide ≤15 or ≥60 mmHg 
for ≥3 minutes; apnea episode lasting >30 seconds; or any respiratory Opioid-Related Adverse Events 
(rORADE). One or more respiratory compromise episodes were detected in 615 (46%) of 1,336 patients over 24 
hr (manuscript accepted for publication in Anesthesia & Analgesia). Separate work has shown that half of all 
closed claims for postoperative respiratory events were lethal and a quarter caused serious neurologic injury. 
Almost all these events were deemed preventable with a better monitoring and response system.6,22 
It is thus apparent that postoperative cardio-respiratory events are common and largely unpredictable. It seems 
highly likely that only continuous hemodynamic/saturation/ventilation monitoring will detect and prevent cardio-
respiratory compromise.6,23-25 
 
Significance for Patient Safety Currently, there are no standards and limited scientific evidence for patient 
monitoring on surgical floors. 26 Nationally, standard of care for patient monitoring on hospital wards is 
intermittent vital signs checks that happen anywhere from once every 4-6 hours. Hospital inpatients represent a 
large constituency in the health care system—the National Center for Health Statistics estimated a total of 34.7 
million discharges in 2005. Accordingly, much effort has historically been expended to keep these patients safe 
during their stay. In its 2001 report the Institute of Medicine identified failure to rescue—as hospital deaths 
following adverse occurrences such as post-surgical complications—as a primary patient safety target. The 
Anesthesia Patient Safety Foundation (APSF) has recently focused significant attention at education and 
awareness to patient deterioration in the peri surgical period and themed their annual meeting in 2019 as 
“Perioperative Deterioration: Early Recognition, Rapid Intervention, and the End of Failure to Rescue” 
Significance for Bioinformatics, Implementation Science & Innovation for the Future Continuous 
postoperative monitoring and associated nursing alerts may help detect cardiorespiratory compromise earlier, and 
in so doing, result in more rapid initiation of correct treatment responses and hospital rapid response systems. 
These will also generate many thousands of data points which will be connected to patient level data in the 
electronic medical record. Pilot data from this trial will thus be a rich pool of bioinformatics variables that would 
be used in the future to develop analytics and machine learning based algorithms to predict who would be likely to 
experience a cardiac or respiratory decompensation on the floor. This pilot data would also be critically important 
to the growth of implementation science and the utilization/improvement of portable continuous monitoring on 
inpatient units both within and outside this hospital network. The technology used in this trial is futuristic and the 
trial design is innovative (see under methods) hence the results of this trial will determine the need for future 
innovations in design & technology that would track our hospitalized patients and their continuum of vital signs 
during their entire hospital stay and possibly even after their discharge home. 

 
 
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Significance for Wake Forest Baptist Health At Wake Forest Baptist Medical Center, continuous monitoring 
of vital signs is as yet not a gold standard of care and is limited to certain units. Most patient assessments are still 
performed on an intermittent basis. As an institution we are leading the way in adoption of portable monitoring 
technology (ViSi device, Sotera Wireless, San Diego, CA) that has been installed in a phased manner for the last 
4 years. However, the use of this technology has been incomplete and inconsistent, since there is much question to 
whether it leads to improved patient outcomes. There is, therefore, availability and familiarity with technology, 
and also perfect equipoise to conduct the proposed trial. This pilot data will add much needed scientific rigor that 
is essential for changing and implementing practice guidelines locally and nationally, to help adopt or refute 
appropriate continuous patient monitoring. 
 
Objectives 
Our primary objective is to show that continuous portable hemodynamic and respiratory monitoring on hospital 
wards allows clinicians to intervene early and effectively, thus reducing patient exposure to hypotension, 
tachycardia, and hypoxemia. Continuous monitoring systems on hospital wards should lead to increased nursing 
interventions, however the danger is false alarms and resultant alarm fatigue will negate any proposed benefit on 
patient safety outcomes. Therefore, we will access the highest level of nursing response (graded on an ordinal 
scale) to unblinded (available to healthcare providers) monitor generated alarms in response to hypotension, 
tachycardia or hypoxemia. Myocardial injury after non-cardiac surgery (MINS) is defined by troponin elevation 
apparently from cardiac ischemia with or without signs and symptoms. It is a leading cause of postoperative 
mortality, with about 20% of all deaths being secondary to MINS.(6) About 80% of postoperative myocardial 
injury is clinically silent, detected only by troponin screening. MINS is strongly associated with both intraoperative 
(7, 8) and postoperative hypotension.(9, 10) However, nearly all MINS occurs during the initial three postoperative 
days suggesting that postoperative hypotension may be a major cause. As an exploratory outcome we will 
investigate whether the availability of continuous monitoring and interventions to reduce hypotension would 
decrease MINS. Assuming positive results, data from this pilot (N= 500 exposed to each of unblinded and blinded 
monitoring) trial will form the basis for a large randomized trial of ward monitoring assessing “hard” outcomes 
such as myocardial injury, respiratory failure, and death. In this context, unblinded monitoring will be continuous 
vital signs available at all times to healthcare providers, whereas blinded monitoring would be silenced monitoring 
with bedside providers having no access to continuous vital signs or associated alarms.  Standard of care 
monitoring (every 4 hours vital signs checks) will be used as the comparator and will be available in blinded arm. 
Fail-safe alarms set at extreme limits will also be available in the blinded arm.  
Specific Aim 1, primary: Determine whether continuous unblinded (vs. blinded) monitoring and nursing alerts 
reduce the duration of hypotension, tachycardia, or hypoxemia over the first 48 hours after surgery, without 
substantially increasing the duration of any of the 3 outcomes (i.e., noninferior on all, superior on at least one) 
Hypothesis 1: Continuous unblinded postoperative blood pressure, heart rate, and saturation monitoring with 
associated nursing alerts and management strategies reduces the duration of hypotension (MAP <65 mmHg) and/or 
tachycardia (>90 beats/min) and/or desaturation (SpO2<90%). Specific Aim 2, secondary: Assess the effect of 
unblinded versus blinded continuous postoperative monitoring on the fraction of patients in which a clinical 
intervention is triggered due to hypotension (MAP <65 mmHg), tachycardia (>90 beats/min) or desaturation 
(SpO2<90%). Clinical nursing intervention responses over the duration of the trial will be categorized as (1) none, 
(2) independent nursing intervention, (3) notification of physician team, or (4) activation of the hospital Emergency 
or Rapid Response System. These will also serve as surrogate markers of alarm fatigue for the bedside nurses. We 
will have at least two independent evaluators adjudicate monitor data and electronic medical records during the 
alarm period to define which of hypotension, tachycardia or hypoxemia was the primary trigger for each response. 
The main secondary outcome will be summarized for a patient as the worst clinical nursing intervention response 
among hypotension, tachycardia and desaturation, on the above ordinal scale.     Hypothesis 2: Increasing bedside 
clinical nursing interventions (ranging from no response, to activation of the hospital rapid response team) are more 
common in patients randomized to unblinded monitoring and associated nursing alerts.  Specific Aim 3, 
exploratory: Assess the effect of unblinded versus blinded continuous postoperative monitoring on the incidence 

 
 
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of myocardial injury after non-cardiac surgery (MINS). Hypothesis 3: MINS is less common when continuous 
hemodynamic monitoring is available to clinicians.   
 
Methods and Measures 
Participant selection: We will include surgical inpatients (transferred to pre-designated wards) ≥65 years or 
≥45 years with at least one cardiovascular risk factor (e.g. hypertension, diabetes) having noncardiac surgery 
who require a general or regional anesthesia and at least a 48 hours hospital stay after surgery. The proposed trial 
will receive approval by the Wake Forest Institutional Review Board. The risks of the proposed study are 
minimal since no patient will be denied routine monitoring and treatment as per institutional guidelines. 
Protocol: Two wards at Wake Forest Baptist will be enrolled in a prospective ward- cluster randomized (to one 
of the two sequences) alternating cohort study,27,28 where the wards alternate monitoring policies in 4-week 
blocks over the course of a calendar year, as outlined in Table 1. These two wards will be randomized to one of 
the two sequences displayed in Table 1 by a coin flip. Entire wards will be allocated to continuous ward 
monitoring with alarms silenced and screens covered (blinded), or to continuous monitoring accessible to 
clinicians (unblinded) with pre-specified alerts at MAP <65 mmHg, heart rate >90 b/m, and SpO2 <90%. Of 
note, to ensure patient safety and no risk in either arm, factory alarm limits (see table under human subjects 
protection) at extremes of physiological vital signs will stay on in the blinded/silenced arm, and both arms will 
have every 4 hourly checks by nursing teams. The ViSi mobile is a portable wrist mounted (Sotera wireless, San 
Diego, CA) continuous ambulatory monitoring system functions throughout Wake Forest Baptist Health, and 
health care providers are very familiar with its use and interpretation of data. We will educate & collaborate with 
all of the relevant nursing teams, surgeons, resident doctors, and the Emergency Medical Response Team, 
regarding the trial protocol and expected responses. Attractive features of this study design include its ability to 
(i) be easily implemented within wards, as ward personnel won’t have to keep track of subsets assigned to 
blinded and unblinded, (ii) protect against the Hawthorne effect, as each ward will be similarly exposed to 
unblinded monitoring,29(iii) account for within-ward trends over time, e.g., personnel or procedure changes, as 
each ward will have similar amounts of exposure to unblinded monitoring, equally distributed over the course of 
a calendar year, and finally (iv) prevent contamination within ward as each patient will be only surrounded by 
patients with the same type of monitoring. 
 
Table 1: Alternating cohort study design; U=unblinded, B=blinded to 
monitoring 
Wee
ks 
1-4 
Wee
ks 
5-8 
Wee
ks 
9-12 
Wee
ks 
13-
17 
Wee
ks 
18-
21 
Wee
ks 
22-
25 
Wee
ks 
26-
29 
Wee
ks 
30-
33 
Wee
ks 
34-
37 
Wee
ks 
38-
41 
Wee
ks 
42-
44 
Wee
ks 
45-
48 
Wee
ks 
49-
52 
Ward 
1 
U 
B 
U 
B 
U 
B 
U 
B 
U 
B 
U 
B 
U 
Ward 
2 
B 
U 
B 
U 
B 
U 
B 
U 
B 
U 
B 
U 
B 
 
Measurements: ViSi continuous monitoring will start on ward admission and continue until the 3rd 
postoperative morning or 48 continuous hours (whichever comes earlier) while patients remain hospitalized. The 
ViSi monitoring system is wrist-mounted and battery powered; it communicates via secure Wi-Fi. Values and 
alerts (in unblinded patients) will display on individual monitors and on each nursing station. For blinded 
patients, nursing station screens will be turned off, and alarms disabled, except for fail-safe alarms at extreme 
limits and technical alerts. (specific aim 1) To ensure patient safety, all patients will also have routine 
intermittent nurse monitoring and any clinically appropriate interventions. Details of interventions in response 
to unblinded alarms will be obtained from the electronic medical record and grouped on the pre-specified 

 
 
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ordinal scale.(specific aim 2)  Blood for troponin I will be obtained on the first three postoperative mornings; 
concentrations ≥0.03 ng/ml increase mortality by a factor-of-nine and will be considered MINS if there is no 
evidence of a non-ischemic etiology.17(specific aim 3) 
 
Setting 
This study is taking place at Wake Forest Baptist Health-Winston Salem campus on post-surgical wards.   
 
Subject selection criteria 
 
We will include surgical inpatients (transferred to pre-designated wards) ≥65 years or ≥45 years with at least one 
cardiovascular risk factor (e.g. hypertension, diabetes) having noncardiac surgery who require a general or regional 
anesthesia and at least a 48 hours hospital stay after surgery. The proposed trial will receive approval by the Wake 
Forest Institutional Review Board.  
 
• Inclusion Criteria 
>/= 65 years of age  
>/= 45 years of age with at least 1 cardiovascular risk (hypertension, diabetes) 
Requiring a general or regional anesthetic as part of their surgical procedure. 
Requiring (or anticipated to require) at least a 48 hour hospital stay after surgery. 
• Exclusion Criteria 
< 48 hour hospital stay 
Receiving local anesthetic for their surgical procedure 
<65 years of age without a single cardiovascular risk factor or <45 years of age 
• Sample Size 
The wards we plan to partner with at Wake Forest Baptist have approximately 2-4 new patient 
admissions per day. Given 365 days in a year, each ward expects to see about 365*3 = 1,095 patients 
per ward per year. We will exclude patients whose admissions occur at the end of a 4-week period and 
spill over into the subsequent 4-week period to avoid analyzing patients exposed to both blinded and 
unblinded monitoring. Assuming some level of ward transfer, spillover exclusions to subsequent 4-week 
periods, cost of monitoring, and patient refusal to wear the monitoring device, and use of age and risk 
based inclusion criteria cited earlier, we anticipate about n=500 participants in each ward over the 
course of the calendar year. 
 
Interventions and Interactions 
Two wards at Wake Forest Baptist will be enrolled in a prospective ward- cluster randomized (to one of the two 
sequences) alternating cohort study,27,28 where the wards alternate monitoring policies in 4-week blocks over the 
course of a calendar year, as outlined in Table 1. These two wards will be randomized to one of the two sequences 
displayed in Table 1 by a coin flip. Entire wards will be allocated to continuous ward monitoring with alarms 
silenced and screens covered (blinded), or to continuous monitoring accessible to clinicians (unblinded) with pre-
specified alerts at MAP <65 mmHg, heart rate >110 b/m, and SpO2 <90%. Of note, to ensure patient safety and no 
risk in either arm, factory alarm limits (see table under human subjects protection) at extremes of physiological 
vital signs will stay on in the blinded/silenced arm, and both arms will have every 4 hourly checks by nursing 
teams. 
The 2 wards will alternate every 4 weeks (first Wednesday of each month changeover) as to blinded/unblinded 
allocations. 
 
Outcome Measure(s) 
 
• 
Specific Aim 1, primary: Determine whether continuous unblinded (vs. blinded) monitoring and nursing 
alerts reduce the duration of hypotension, tachycardia, or hypoxemia over the first 48 hours after surgery, 

 
 
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without substantially increasing the duration of any of the 3 outcomes (i.e., noninferior on all, superior on at 
least one)  
Hypothesis 1: Continuous unblinded postoperative blood pressure, heart rate, and saturation monitoring 
with associated nursing alerts and management strategies reduces the duration of hypotension (MAP <65 
mmHg) and/or tachycardia (>110 beats/min) and/or desaturation (SpO2<90%). Specific Aim 2, secondary: 
Assess the effect of unblinded versus blinded continuous postoperative monitoring on the fraction of 
patients in which a clinical intervention is triggered due to hypotension (MAP <65 mmHg), tachycardia 
(>110 beats/min) or desaturation (SpO2<90%). Clinical nursing intervention responses over the duration of 
the trial will be categorized as (1) none, (2) independent nursing intervention, (3) notification of physician 
team, or (4) activation of the hospital Emergency or Rapid Response System. These will also serve as 
surrogate markers of alarm fatigue for the bedside nurses. We will have at least two independent evaluators 
adjudicate monitor data and electronic medical records during the alarm period to define which of 
hypotension, tachycardia or hypoxemia was the primary trigger for each response. The main secondary 
outcome will be summarized for a patient as the worst clinical nursing intervention response among 
hypotension, tachycardia and desaturation, on the above ordinal scale.      
Hypothesis 2: Increasing bedside clinical nursing interventions (ranging from no response, to activation of 
the hospital rapid response team) are more common in patients randomized to unblinded continuous 
monitoring and associated nursing alerts.  Specific Aim 3, exploratory: Assess the effect of unblinded 
versus blinded continuous postoperative monitoring on the incidence of myocardial injury after non-cardiac 
surgery (MINS). Blood for troponin I will be obtained on the first three postoperative mornings; 
concentrations ≥0.03 ng/ml increase mortality by a factor-of-nine and will be considered MINS if there is 
no evidence of a non-ischemic etiology.(11)  
Hypothesis 3: MINS is less common when continuous hemodynamic monitoring is available to clinicians 
and appropriate interventions are made in response to hypotension detected by the same. 
 
Ancillary outcomes: At the end of the study period and prior to discharge from the hospital, all included 
patients will be provided a research information document. This will include (via a link to a REDCap 
anonymous survey) a post study satisfaction questionnaire that will collect useful data on the patient’s 
perception of continuous monitoring and the comfort/discomfort with the devices used in each arm. This 
data will only be used with descriptive statistics and will be used to gain useful insight into the need for 
surveillance monitoring on hospital wards.  
The following questions will be included in the post study survey questionnaire:  
On a scale of 1-5 ( 1 = disagree 2 = somewhat disagree 3= neutral 4= somewhat agree and 5=agree), please 
rate your experience with vital signs checks during your hospital stay  
1. 
Were continuous vital signs monitoring using a monitoring device important to you?  
2. 
Was intermittent nursing checks (provider in the room) to check on your vital signs important to 
you?  
3. 
Was the type of devices that were used to monitor your vital signs important to you? 
4. 
Were you inconvenienced with the portable monitoring device on your wrist? 
5. 
Were you inconvenienced with the intermittent nursing checks (provider in the room) to check on 
your vital signs? 
6. 
Did alarms inconvenience you?  
7. 
Would you feel safer with a continuous monitoring device strapped to you all the time while you 
recover in the hospital?  
8. 
Is the size of the continuous monitoring device important for you?  
9. 
Is the ability to ambulate/walk around freely while being monitored important for you?  
10. 
Would it be a good idea to continue to monitor your vital signs remotely even after you go home?  
 
        Analytical Plan 
Both ward and individual level data will be collected for statistical analysis. The two wards will be 
compared on baseline characteristics using descriptive statistics. Variables with an absolute standardized 

 
 
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difference > 0.10 will be considered imbalanced and will be adjusted for in all analyses. Analyses will be 
done under the modified intention-to-treat principle, where enrolled patients will be included in all 
analyses as long as they received at least some of blinded or unblinded ward monitoring. Missing data as 
well as the reason for missing will be summarized. Our modeling framework (generalized linear mixed 
effects modeling) makes the same assumptions about missing data as multiple imputation. 
Data Storage Sotera is responsible for the ViSi monitoring data, which will be stored in the Sotera cloud-
based database. This data set will contain device IDs, along with dates, to be merged to EPIC charts 
collected here at Wake Forest School of Medicine. We have easily piloted this data collection approach 
from the period February 2015 to April 2018, and these merged data now live in a SQL databased here at 
Wake. Dr. Amit Saha, PhD., Assistant Professor of Anesthesiology and member of the Wake Forest 
Center for Biomedical Informatics will provide expertise on data collection and storage. 
Sample size and power: As is standard in the clustered study design literature, 30we will perform a power 
calculation that (i) assumes individual-level randomization and then (ii) adjusts for cluster-level correlation, 
as study participants cannot be viewed as statistically independent within a cluster and are not actually 
individually randomized. Presumably, for Aim 1, the true incidence of hypotension and tachycardia, 
based on unblinded continuous monitoring, will be much higher than that measured via blinded routine 
monitoring. We have observed that median [quartiles] minutes under MAP of 65 mmHg of 6 [0, 19] or 
higher for noncardiac patients who suffer AKI and MI. In our power calculation to follow, we assume 
that the unblinded patients will have approximately mean 7.3 minutes exposed to MAP <65 mmHg with 
standard deviation of 13, whereas blinded patients will have mean 13 minutes exposed to MAP <65 
mmHg with a standard deviation of 13. 
In a two-group individually randomized study, a two-sample two-sided t-test with type 1 error set to 0.05 
would have 100% power to reject the null hypothesis that the exposed time to MAP <65 mmHg was the 
same in unblinded versus blinded under the alternative hypothesis listed above. With our anticipated effect 
size, we would have 80% power in an individually randomized study for sample sizes as low as 89 per 
group. Given the clustered nature of our study design, we must adjust our calculations by the design 
effect, Deff = 1+(m-1)*ICC, where m is the number of patients per ward in a given month and ICC ∈ [0, 1] 
is the correlation of patients within a ward. The figure below displays how sample size to achieve 80% 
statistical power for our anticipated effect size will inflate as a function of increasing ICC. 
 
 
 
The wards we plan to partner with at Wake Forest Baptist 
have approximately 2-4 new patient admissions per day. 
Given 365 days in a year, each ward expects to see 
about 365*3 = 1,095 patients per ward per year. We will 
exclude patients whose admissions occur at the end of a 
4-week period and spill over into the subsequent 4-week 
period to avoid analyzing patients exposed to both 
blinded and unblinded monitoring. Assuming some level 
of ward transfer, spillover exclusions to subsequent 4-
week periods, cost of monitoring, and patient refusal to 
participate in the study, and use of age and risk based 
inclusion criteria cited earlier, we anticipate about n=500 
participants in each ward over the course of the calendar 
year. As seen in Table 1, these 500 participants per ward 
will be somewhat evenly split into m=13 distinct groups 
* n=89 if no correlation within ward 
Sample size per ward over one year 
100 
200 
300 
400 
500 

 
 
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of approximately 500/13 
= 39 patients. Our study design is similar to a cluster 
randomized study that compares 13 groups of 39 patients 
 
0.00 
0.02 
0.04 
0.06 
0.08 
0.10
 
0.12 
 
Correlation within ward 
randomized to unblinded monitoring to 13 groups of 39 
patients randomized to blinded monitoring. As shown in 
the above figure, we will have sufficient power as long as 
(i) ICC remains 
0 

 
 
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10 
below 0.12, which is a reasonable assumption,26 and we can recruit upwards of n=500 per 
ward over the course of a year. If we plan to only recruit n=300 per ward, ICC could be up to 
0.10. 
Statistical Analysis Plan 
Aim 1. We will assess the effect of unblinded continuous monitoring and the associated alerts 
on the cumulative duration (min/hour) of each of hypotension, tachycardia, and desaturation 
using negative binomial regression, within a generalized linear mixed effects modeling 
framework (to adjust for correlation of participants within ward with a random effect for 
ward). Individuals exposed to unblinded versus blinded monitoring will be compared on the 
number of minutes less than each threshold (i.e., a count outcome), considering the total 
number of minutes observed for the patient as an offset.  Treatment effects will be reported as 
the estimated incidence rate ratio of unblinded to blinded and confidence interval separately for 
hypotension, tachycardia, and hypoxia. A rate ratio less than 1 will indicate a favorable effect 
of unblinded monitoring on the outcome, i.e., participants are less likely to be exposed to 
harmful conditions, e.g., MAP<65, in the presence of unblinded monitoring.  
Aim 2. We will assess the effect of continuous monitoring and associated alerts on the ordinal 
clinical intervention outcome which measures the single most extreme/elevated clinical 
intervention incurred by a patient for any of the 3 outcome variables of interest (hypotension, 
tachycardia, hypoxia) during the study period, summarized on an ordinal scale as (1) none, (2) 
independent nursing intervention, (3) notification of physician team, or (4) activation of the 
hospital Emergency or Rapid Response system using ordinal logistic regression model (with a 
random effect for ward) and expressing the treatment effect as the odds ratio and confidence 
interval for having a more extreme/elevated clinical intervention in the unblinded versus 
blinded monitoring. As in Aim 1, an odds ratio less than 1 will indicate a favorable effect of 
unblinded monitoring. Aim 3. We will assess the treatment effect on MINS (yes/no) during the 
study period using logistic regression with a random effect for ward. Results for Aims 2 and 3 
are exploratory and will be used mainly for hypothesis generation for future studies. In this 
pilot study we will use a significance level of 0.05 for each outcome variable of interest, 
making no correction for assessing multiple outcome variables. As in previous Aims, an odds 
ratio less than 1 will indicate a favorable effect of unblinded monitoring 
Results will be analyzed initially using descriptive statistics.  Comparison between groups will 
be done using chi square tests for proportions, and t-tests or ANOVA procedures for continuous 
variables.  Regression analysis will be performed to identify independent outcome predictors.  
Other inferential statistical analysis will be conducted as appropriate. 
 
Addition of Interim Analysis 
Our initial sample size calculations were powered to detect an effect size of a 5.7-minute 
difference between treatment groups in terms of time exposed to MAP < 65mmHG (assuming an 
equal standard deviation of 13 minutes exposed for each group). We calculated our sample size 
projections to have 80% power with a 5% type-I error rate. In our calculations, we recognized 
there currently exists a degree of uncertainty regarding intra-ward correlation (ICC), the degree 
of which has implications on our necessary sample size. As ICC increases, our required sample 
size to achieve 80% power increases. To address this uncertainty, we propose conducting an 
interim analysis at 6-months to assess the estimated ICC of our population, from which we can 

 
 
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11 
adjust our period of accrual accordingly to ensure adequate power without unnecessary (i.e. 
prolonged) recruitment. In this interim analysis, we will not evaluate our primary hypothesis 
assessing a difference between groups with respect to our primary outcomes. Therefore, we do 
not propose amending our primary statistical analysis plan to account for multiple looks.  
At 6 months, we expect to have accrued approximately 250 patients. The decision rules based on 
our interim assessment of ICC are as follows:  
- 
If the ICC is sufficiently low enough to have achieved ≥80% power given our existing 
sample size at the time of the interim analysis, we will conclude accrual at the end of the current 
(ongoing) 4-week phase of the study. Given the timeline of the study, this would mean our 
interim analysis of ICC would be conducted at week 26 of the study, and thus the study would 
conclude after week 29 (the 4th week of the study phase accruing over weeks 26-29).  
- 
If the estimated ICC is higher than what would yield ≥80% power at the time of the interim 
assessment, but less than our maximum assumed possible ICC of 0.12 requiring 500 patients, we 
will re-estimate our required sample size assuming the estimated ICC from the first 6 months.  
Based on our new estimate for required sample size, we will adjust our timeframe for accrual 
accordingly such to complete the study after the month in which we expect to meet our necessary 
sample size.  
- 
If the estimated ICC > 0.12, thus requiring > 52 weeks of accrual, we will estimate the 
amount of additional time necessary to reach our required sample size, beyond our initially 
proposed 52 weeks. Our decisions to continue or stop the study due to futility will be made based 
on funds and time available. 
 
Approach To Potential Limitations 
(i)Although the ViSi monitor is lightweight and battery powered, patients may refuse to be 
tethered to wear the system for 48 hours. We are currently using this monitor, with good 
patient cooperation; specifically, we have been able to obtain reliable near-continuous 
recordings in postoperative patients over several postoperative days. The ViSi Mobile 
technology is cleared by the FDA and is accurate within ±8 mmHg (SD) against a radial 
arterial catheter.  
(ii) Continuous monitoring may detect more hemodynamic and respiratory critical events than 
routine nurse monitoring at four-hour intervals. This per se may not prompt nurses and 
clinicians to intervene — much less that the interventions will prove effective. We will provide 
a broad framework of suggested interventions, none of which would be binding. We will also 
evaluate the frequency and nature of interventions. Since, alarm fatigue from the continuously 
generated alarms (some of which may be false) may be common, we propose to categorize 
nursing responses on an incremental scale from 1-4. From these data, it will be apparent 
whether nurses responded quickly to the alarms, and with reasonable interventions either 
themselves or from the physician alerted, or via rapid response team intervention. This data 
will also over the time course of the study tell us an estimate of alarm fatigue.  
(iii) In addition, our primary outcome characterizes important mechanisms by which 
hemodynamic perturbations and desaturation might contribute to myocardial injury after non-
cardiac surgery (MINS) and serious respiratory complications. This study will be underpowered 
for an exploratory outcome of MINS, but the pilot data will be used to adequately power the 
proposed R01 which will be a much larger trial. 
 

 
 
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Human Subjects Protection 
 
Subject Recruitment Methods 
With collaboration with nursing management, 2 postsurgical units will be identified who 
currently have the capabilities to utilize ViSi monitoring.  The surgical population that these 2 
units receive from the operative area will likely include a majority of general surgery, 
gynecological, urological, orthopedic, spine and plastic surgery. Surgical leaders with each of 
these specialties have been approached and will be re-approached prior to the study to ascertain 
their willingness to participate. In case, a specific surgical team feels that a certain patient should 
not be included in the proposed study that patient will be withdrawn and likely moved to another 
postsurgical ward in the hospital.  
 
Informed Consent 
A waiver of the requirements for signed informed consent and a waiver of HIPPA authorization 
is being requested.  This research presents no more than minimal risk of harm to subjects and 
involves no procedures which written consent is normally required outside of the research 
context.  This device is currently not utilized routinely on all hospital units at this time.  The risks 
of the proposed study are minimal since no patient will be denied routine monitoring and 
treatment as per institutional guidelines. We will however provide every patient with a research 
information sheet before they leave the hospital as part of their after visit summary. This sheet 
will provide all necessary details about the data that has been collected and how it will likely be 
used for research. Every patient will be given the opportunity to opt out of their data being used 
for the study. This document will include (via a link to a REDCap anonymous survey) a post 
study satisfaction questionnaire that will collect useful data on the patient’s perception of 
continuous monitoring and the comfort/discomfort with the devices used in each arm.   (See 
questions and details under ancillary outcomes – under specific outcomes)  
 
Safety considerations 
As previously specified, this study poses minimal risk in either of the randomized clusters. Both 
the randomized clusters will continue to receive at least every four hourly vital signs checks, 
which is current standard of care across the nation. Both arms (including the blinded arm) will 
always have factory alarm limits (as specified in the table below) always switched on, so no 
critical event is missed on any patient (no matter what cluster that patient is part of). Therefore 
though one cluster of patients will have continuous monitoring silenced and blinded, extreme 
alarms limits will always be available and standard of care intermittent monitoring will also 
always be available on these patients.  

 
 
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Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that could 
directly identify subjects, and maintaining all study information in a secure manner.  To help 
ensure subject privacy and confidentiality, only a unique study identifier will appear on the data 
collection form.  Any collected patient identifying information corresponding to the unique study 
identifier will be maintained on a linkage file, store separately from the data.  The linkage file 
will be kept secure, with access limited to designated study personnel.  Following data collection 
subject identifying information will be destroyed following data analysis, consistent with data 
validation and study design, producing an anonymous analytical data set.  Data access will be 
limited to study staff.  Data and records will be kept locked and secured, with any computer data 
password protected.  No reference to any individual participant will appear in reports, 
presentations, or publications that may arise from the study. 
 
 
Data and Safety Monitoring 

 
 
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The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study 
staff. 
 
Mentorship and role of other key investigators:  Dr. Khanna will oversee all aspects of the 
study including IRB approval, pre-study education and orientation of nursing and research 
teams, patient recruitment, enrollment, monitoring, and data analysis. Dr. Khanna will 
collaborate with the monitoring device manufacturers (Sotera wireless) to ensure quality of 
data collection. Dr. Walter Ambrosius (professor and chair biostatics and public health 
sciences) initially supervised the creation of trial statistical methodology and will mentor Dr. 
Khanna during data analysis and for the construct of a robust plan for analysis on a follow up 
grant mechanism. Drs. Eric Kirkendall (chief for the center for healthcare innovation), Dr. Brian 
Wells (director for the center for biomedical informatics), and Dr. Daniel Sessler (professor & 
chair, department of outcomes research at Cleveland Clinic) will guide Dr. Khanna in development of a 
best mechanistic process for data collection, and interpretation/presentation of the results, and 
will provide direct mentorship for the proposed R01. Given their expertise in clinical 
informatics and innovation, Drs. Kirkendall and Wells, are well positioned to assist Dr. 
Khanna with testing of the data set, (including future device/technology innovations and 
utilization for predictive analytics) as well as troubleshooting any issues that may arise with 
the current implementation of this monitoring technology. The entire mentoring team will also 
participate and guide Dr. Khanna in data analysis, interpretation, dissemination (abstract and 
manuscript review), and NIH R01 application preparedness. 
In addition, this study is appropriately supported by the nursing leadership at WFBMC, 
including the CNO Dr. Deb Harding, Director of Nursing Research, Dr. Carolyn Huffman, 
Nursing Informatics, Ann Faris & Robin Hack, amongst others. Physician leaders include Dr. 
Robert Weller, Professor of Anesthesiology, who has championed use of the ViSi device 
across WFBMC for the last 4 years, and the chairs of the CIIRRC group Dr(s). Chad Miller 
and Clark Files. Furthermore, additional support with data analysis is also being provided by 
Dr. Joseph Rigdon from the School of Public Health Sciences. Research support is also 
provided by the department of Anesthesiology, including data handling support by Dr. Amit 
Saha (departmental data scientist)  and by two senior research nurses along with 6-8 research 
assistants, each of whom will be appropriately trained prior to be being introduced into the 
trial.  
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB and sponsor or appropriate government agency if appropriate. 
 
SUBSTUDY 
In an effort to determine the nursing perceptions of the benefits and failures of continuous 
hemodynamic monitoring systems as well as the value of these devices in the care of their 
patients, we propose a sub-study to evaluate on both of the stated research units (9 Ardmore East 
and 10 Reynolds Tower) and the non-research units who have continuous hemodynamic 
monitoring utilizing the ViSi monitoring system.  These surveys are identical, will be 
anonymous and unidentifiable, and will be distributed manually by research staff at various 

 
 
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timepoints in an effort to capture the most responses.  Information to be collected include the 
following types of information:  the importance of continuous monitoring important to nursing 
practice and to the safety of their patients, perceptions of increased workload based on the alerts 
received, accuracy in alerting to patient deterioration, appropriateness of the alarm limits, alarms 
that cause the most concern when received, and how the nurse perceives the ease of use and 
confidence in the ViSi monitoring system.  We are capturing the role of the nursing staff on that 
unit, unit worked on and number of years in practice. 
We feel the information received on the conduct of this survey will provide feedback to the 
clinical research team and the clinical practice team practitioners with much needed information 
in order to see and identify barriers to the implementation of safe and effective continuous 
monitoring systems throughout the hospital. This is specifically important because the successful 
use of a continuous monitoring system and associated alarms is dependent on the actual response 
to alarms with actions that prevent harm from happening or further escalating.   
We are asking for a waiver of informed consent for this survey distribution.  A waiver of signed 
consent is being asked.  The survey questions are evaluating nurses experiences pertaining to 
their positions. Information concerning the purpose of the surveys and assurance of 
confidentiality and no retaliation for responses. No signature would be obtained as the only 
record linking the subject and the research would be the informed consent form and the principal 
risk would be potential harm resulting from a breach of confidentiality. 
 
 
 
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