Validation of Heart Rate Recovery as a Peri-operative Risk Measure (VERVE)
Conditions: Peri-operative Injury
Sponsor: University of Glasgow

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol 
 
Title: Validation of heart rate recovery as a peri-operative 
risk measure 
 
Version: 2.2 
 
Date: 29/10/2021 
 
Funding: NIAA/VASGBI Trainee Research Development 
Grant 
 
REC Reference: 21/WA/0207 
NCT NCT05561608 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
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Names and appointments of collaborators 
 
Chief Investigator: 
Dr. Ben Shelley 
Consultant in Cardiothoracic Anaesthesia and Intensive 
Care/Hon. Clinical Associate Professor 
National Waiting Times Centre Board, 
Agamemnon Street, 
G81 4DY 
0141 951 5600 
Benjamin.Shelley@glasgow.ac.uk 
 
Principal Investigator:  
Dr. Cara Hughes 
 
Clinical Research Fellow  
 
Academic Unit of Anaesthesia, Pain and Critical Care Medicine, 
University of Glasgow 
 
New Lister Building, 
10-16 Alexandra Parade,  
Glasgow, 
G31 2ER  
07810 292659 
 
Cara.hughes@glasgow.ac.uk 
 
Co-investigator: 
Dr. Gareth Ackland 
 
Consultant Anaesthetist/Professor of Anaesthesia and Critical 
Care 
Barts and the London Hospitals/Queen Mary’s University, 
Mile End Road, 
E1 4NS 
g.ackland@qmul.ac.uk 
 
Co-investigator:  
Dr. Andrew Clark 
 
Consultant Anaesthetist 
 
University Hospital Crosshouse, 
 
Kilmarnock Road, 
 
KA2 0BE 
 
01292 827172 
 
Andrew.clark@aapct.scot.nhs.uk 
 
Co-investigator: 
Dr. Phil McCall 
 
Consultant Anaesthestist 
National Waiting Times Centre Board, 
Agamemnon Street, 
G81 4DY 
0141 951 5600 
Philip.mccall@glasgow.ac.uk 
 
Co-investigator: 
Dr. Tina McLennan 
 
Consultant Anaesthetist/Intensivist 
 
University Hospital Hairmyres, 
 
218 Eaglesham Road, 
 
East Kilbride, 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
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G75 8RG 
 
01355 585724 
 
Tina.mclennan@lanarkshire.scot.nhs.uk 
 
Co-investigator: 
Dr. Indran Raju 
 
Consultant Anaesthetist 
 
Queen Elizabeth University Hospital, 
 
1345 Govan Road, 
 
Glasgow,  
 
G51 4TF 
 
0141 452 3430 
 
Indran.raju@ggc.scot.nhs.uk 
 
Co-investigator: 
Dr. Martin Shaw 
 
Medical Physicist and Statistician 
Academic Unit of Anaesthesia, Pain and Critical Care Medicine, 
University of Glasgow 
 
New Lister Building, 
10-16 Alexandra Parade,  
Glasgow, 
G31 2ER  
0141 330 2000 
 
Martin.shaw@ggc.scot.nhs.uk 
 
Co-investigator: 
Dr. Stuart Watkins 
 
Consultant Interventional Cardiologist 
National Waiting Times Centre Board, 
Agamemnon Street, 
G81 4DY 
0141 951 5000 
Stuart.watkins@glasgow.ac.uk 
 
Co-investigator: 
Dr. Malcolm Watson 
 
Consultant Anaesthetist 
 
Queen Elizabeth University Hospital, 
 
1345 Govan Road, 
 
Glasgow,  
 
G51 4TF 
 
0141 452 3430 
 
mwatson@doctors.org.uk 
 
 
 
 
 
 
 
 
 
 
 

Study Protocol: VERVE 
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Contents 
Lay summary ........................................................................................................................................... 6 
1.  Background and rationale ............................................................................................................... 7 
1.1 
Introduction ............................................................................................................................ 7 
1.2 
Pre-operative risk assessment ................................................................................................ 7 
1.3  
Exercise physiology and functional capacity ........................................................................... 8 
1.4 
Markers of vagal parasympathetic activity ............................................................................. 8 
1.5 
Heart rate recovery ................................................................................................................. 9 
1.6 
Previous HRR work .................................................................................................................. 9 
1.7 
Validation of clinical tests ..................................................................................................... 10 
1.8 
Rationale ............................................................................................................................... 10 
1.9 
Aim and Hypotheses ............................................................................................................. 11 
2.  Study Plan ..................................................................................................................................... 11 
2.1 
Study Design.......................................................................................................................... 11 
2.2 
Study Setting ......................................................................................................................... 11 
2.3 
Study Summary ..................................................................................................................... 11 
3.  Objectives and outcomes measures ............................................................................................. 12 
3.1  
Primary outcome measures .................................................................................................. 12 
3.1.1  
Rationale for primary outcome ..................................................................................... 12 
3.2  
Secondary outcome measures .............................................................................................. 12 
3.2.1 
Rationale for secondary outcomes ............................................................................... 13 
4.  Selection and withdrawal of study participants ........................................................................... 13 
4.1 
Inclusion criteria .................................................................................................................... 13 
4.2 
Exclusion criteria ................................................................................................................... 13 
4.2.1 
Rationale for inclusion/exclusion criteria ..................................................................... 13 
4.3  
Withdrawals and exclusions ................................................................................................. 14 
5. 
Study Conduct ............................................................................................................................... 15 
5.1 
Recruitment .......................................................................................................................... 15 
5.2 
Consent ................................................................................................................................. 15 
5.3 
Data collection ...................................................................................................................... 15 
5.3.1 
Baseline demographic data ........................................................................................... 15 
5.3.2 
Laboratory sampling ..................................................................................................... 16 
5.3.3 
Pre-operative questionnaires (Full details in Appendix 2) ............................................ 16 
5.3.4 
Pre-operative risk scores ............................................................................................... 16 
5.3.5 
Post-operative clinical data (Full details in Appendix 3) ............................................... 16 
5.3.6 
Post-operative questionnaires ...................................................................................... 17 

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5.4 
Exercise Protocol ................................................................................................................... 17 
5.4.1 
Orthostatic HRR............................................................................................................. 17 
5.4.2 
Step test ........................................................................................................................ 17 
5.5 
Medical Management and Safety Reporting ........................................................................ 17 
5.6 
Covid-19 Considerations ....................................................................................................... 18 
5.6.1 
Deliverability ................................................................................................................. 18 
5.6.2 
Scientific validity ........................................................................................................... 18 
6. 
Data Management ........................................................................................................................ 18 
6.1 
Data collection ...................................................................................................................... 18 
6.2 
Data storage .......................................................................................................................... 19 
6.3 
Archiving ............................................................................................................................... 19 
7. 
Statistical Considerations .............................................................................................................. 19 
7.1 
Power calculation .................................................................................................................. 19 
7.2  
Primary Outcome .................................................................................................................. 19 
7.3 
Secondary Outcomes ............................................................................................................ 19 
8. 
Study Organisation ........................................................................................................................ 20 
8.1 
Sponsor ................................................................................................................................. 20 
8.2 
Administration ...................................................................................................................... 20 
8.3 
Indemnity .............................................................................................................................. 20 
8.4 
Monitoring ............................................................................................................................ 20 
8.5 
Funding ................................................................................................................................. 20 
9. 
Ethics and regulatory approval ..................................................................................................... 20 
10. 
Protocol amendments .............................................................................................................. 20 
11. 
Dissemination ........................................................................................................................... 20 
12. 
Projected study timetable ......................................................................................................... 20 
Appendix 1 – ATS Contraindications to exercise testing ...................................................................... 21 
Appendix 2 – Pre-operative Questionnaires ......................................................................................... 22 
Appendix 3 – Secondary outcome definitions (alphabetical) ............................................................... 24 
References ............................................................................................................................................ 28 
 
 
 
 
 
 
 
 
 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
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Lay summary 
Introduction 
There are approximately 1.5 million major operations carried out in the NHS every year. As the 
population ages, and surgical technique becomes more advanced, more patients are undergoing 
operations which carry a high risk of complications. Currently, doctors predict this risk by asking 
patients about their history of medical problems and how these impact on how active they are able 
to be. Investigations such as a heart scan or breathing tests can give further information. If an 
operation is very high risk, a patient may undergo cardiopulmonary exercise testing (CPET) where the 
patient rides an exercise bike to maximum effort (exhaustion) whilst their heart and lung function is 
monitored. This gives the doctor specific numbers which can be discussed with the patient about the 
risk of complications after surgery. By using a portable heart rate monitor placed on the skin we aim 
to produce a new measure of a patient’s fitness for surgery which can be easily performed at clinic 
without needing to exercise to maximum effort (submaximal). This measure looks at how quickly heart 
rate slows again after submaximal exercise, called heart rate recovery (HRR). 
 
Aim 
To assess whether HRR is a valid measure of a patient’s risk of post-operative complications.  
 
Method 
With their consent, patients undergoing intermediate/high risk non-cardiac surgery will be asked 
routine questions and blood tests will be taken. Patients will then be asked to perform a HRR 
assessment. To do this, a small external device will be placed on the patient’s chest and their heart 
rate recorded. This will be done sitting at rest and performing a step test until approximately two-
thirds of their predicted maximum heart rate is reached. The patient will step on and off a low box for 
a further minute and then rest for five minutes. Additionally, some patients will undergo pre-operative 
CPET as part of their routine care. After the operation, blood tests indicating whether the patient’s 
heart has been under strain will be taken on days one and two and the presence of post-operative 
complications will be recorded. Patients will also complete questionnaires to describe the quality of 
their recovery and quality of life. Data regarding their length of hospital stay and, if applicable in rare 
cases, death will also be collected. This data will be analysed to see how well HRR predicts post-
operative complications and how well it agrees with the predictive measures doctors currently use.  
 
Expected outcome and implications 
HRR tests will predict post-operative complications in intermediate/high risk surgical patients and will 
prove a valid measure compared to current practice. HRR could be used as part of a doctor’s toolkit 
to predict the operative risk of surgical patients. Future studies will investigate whether HRR can be 
improved with exercise, so could be targeted to improve patients’ fitness for surgery. Patients 
identified as high risk could be offered interventions to reduce their risk and therefore improve patient 
outcomes after surgery. 
 
 
 
 
 
 
 
 
 
 
 

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1.  
Background and rationale 
1.1 
Introduction 
There are approximately 1.5 million major operations performed in the UK annually1, with the 
majority of these surgeries carrying an intermediate (1-5%) or high (>5%) mortality risk2, 3. The 
number of operations performed annually is increasing4 concurrent with an increase in 
population age5 and therefore the prevalence of co-morbidities. Despite this, surgical 
mortality is reducing. In 2017 all major NHS surgery was found to have a 30-day mortality of 
1.1%1. A planned sub-analysis of the ENIGMA-II study demonstrated that 15.7% of patients 
with increased peri-operative cardiovascular risk undergoing non-cardiac surgery developed 
a major post-operative complication. This was associated with a 1-year disability-free survival 
of 87.5% and a 1 year mortality of 7.4%6. As well as increasing the risk of mortality and further 
morbidity, post-operative complications have been shown to cause detriment to an 
individual’s quality of life7. Post-operative complications also affect wider society by adding a 
financial burden on limited NHS resources, and reducing the ability of patients and their 
families to contribute towards the economy8. One of the main ways to mitigate post-operative 
complications is via effective pre-operative risk stratification. 
 
1.2 
Pre-operative risk assessment 
Pre-operative risk assessment is primarily based on patients’ functional capacity. This 
encompasses an assessment of how co-morbidity and physiological fitness impacts on 
patients’ daily life and indicates the level of cardiopulmonary reserve available for undergoing 
the physiological insult of surgery. Current modalities for pre-operative risk stratification 
range from subjective assessments and validated physiological scoring systems such as the 
Surgical Outcome Risk Tool (SORT)9, to measurement of biomarkers such as brain natriuretic 
peptide (BNP), and to cardiopulmonary exercise testing (CPET), an objective measure of 
cardiopulmonary function. Subjective assessment of patients’ functional capacity conducted 
via pre-operative interview has been shown to be unreliable10. Validated scoring systems 
combine multiple risk indices to stratify post-operative risk. Activity scales such as the Duke 
Activity Index Score (DASI)11 however still rely on the patient’s subjective view of their ability 
to perform daily tasks, whilst physiology scores such as P-POSSUM12 do not include functional 
domains. Biomarkers are increasingly proposed as part of peri-operative risk stratification. 
Brain natriuretic peptide (BNP) is a hormone released by cardiac myocytes in response to 
stress. BNP and corresponding N-terminal proBNP (NT-proBNP) are recommended by the 
European Society of Cardiology for cardiac risk stratification in high risk patients2. The gold-
standard exercise test for measuring functional capacity is CPET. CPET comprises incremental 
workload increases during cycle ergometry until exhaustion and peak oxygen consumption 
(VO2peak) is reached. Analysis of measured variables including oxygen consumption at 
anaerobic threshold and VO2peak determine the patient’s risk threshold for post-operative 
morbidity and mortality13. Unfortunately, a proportion of patients are unable to perform 
effective CPET, for example due to arthritis or failure to reach maximal exertion. CPET is also 
resource-intensive and its availability varies extensively. Submaximal exercise tests are 
advocated as predictive tests because they are better tolerated for patients and are less 
resource-intensive than maximal exercise testing14. Defined cut-offs for risk however are 
limited, as measurements are effort-dependent i.e. HRR may be relative to the peak heart rate 
reached during the submaximal test. Different methods of HRR analysis can take this into 
account, and analysis of the whole HRR curve may give further information. Previous work by 
our group has identified novel objective submaximal heart rate recovery (HRR) analyses to 
account for effort by HRR and utilising the whole HRR curve profile. As an intermediary 
(enabling high risk patients to be triaged to formal CPET) or alternative objective measure of 
physiological fitness we suggest HRR measured after submaximal exertional effort as a simple, 
lower-cost alternative.  

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
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1.3  
Exercise physiology and functional capacity 
 During exercise, cardiac output increases linearly to meet the metabolic demands of 
contracting skeletal muscle. Heart rate (HR) increases and there is an associated rise in systolic 
blood pressure and stroke volume to increase oxygen delivery to working muscles in order to 
match oxygen consumption (VO2, the product of cardiac output and arterio-venous oxygen 
content difference). This HR increase occurs primarily due to initial withdrawal of vagal 
stimulation, with sympathetic activation at moderate work rates increasing as exercise 
intensity increases, although the extent of this autonomic “imbalance” is debated15. At 
exercise cessation, heart rate initially drops rapidly due to reactivation of the parasympathetic 
system followed by a slower reduction due to withdrawal of sympathetic stimulation. Vagal 
modulation therefore is a very important component in the attainment of oxygen delivery, 
consumption and recovery during exercise. 
 
Training (repetitive exercise at increasing intensities) improves the VO2max, the maximum rate 
at which oxygen is used during dynamic exercise. This is via adaptation of the cardiorespiratory 
and skeletomuscular system in a variety of ways including increased stroke volume and 
reduced resting heart rate, and improved skeletal muscle oxygen utilisation. Resting heart rate 
is indicative of vagal activity as the vagus reduces the intrinsic rate of cardiac pacemaker cells. 
It has long been assumed that vagal activity is a marker of aerobic fitness but recent evidence 
also suggests that cardiac vagal activity also determines the ability to exercise15. Therefore, 
measures of vagal tone can indicate both the aerobic capacity of an individual, but also their 
potential to respond to exercise and training.  
 
In Anaesthesia, the term functional capacity is used to describe the ability of the body to  
increase and maintain tissue oxygen delivery and consumption16 in response to the 
physiological stress and increased oxygen demand that surgery places on the body. Although 
the mechanisms are different to exercise, the surgical stress response results in an increase in 
VO2, primarily via entering a catabolic state which can continue for several days post-
operatively. Inability to compensate for this increased oxygen demand increases the risk of 
post-operative complications including delayed wound healing, impaired immune function 
and organ failure17. Therefore, an individual with a higher functional capacity is likely to be 
able to maintain oxygen delivery to the tissues under surgical stress better than an unfit 
individual. This forms the fundamental pretext underlining the majority of pre-operative 
assessment and risk stratification for patients. On this basis, a patient’s capacity to exercise is 
a surrogate marker for how their body will cope with the increased oxygen demand of surgery.  
It follows that vagal tone can be used as a measure of functional capacity in surgical patients.   
 
1.4 
Markers of vagal parasympathetic activity 
There are three relatively simple in-vivo methods to indicate vagal activity measured via 
electrocardiograph: heart rate variability (HRV), resting heart rate and heart rate recovery. 
Heart rate variability describes the oscillation between R-R intervals. There are many indices 
incorporated within HRV measurement but overall, high HRV indicates high vagal tone18. HRV 
however, is dependent on resting heart rate and respiration, and recent evidence suggests 
that it may not be a reliable measure19. A low resting heart rate indicates high vagal activity as 
the vagus inhibits activity of the cardiac pacemaker cells in the sino-atrial node which have an 
intrinsic rate of approximately 100-110bpm. There is also some evidence that in trained 
athletes, a low resting heart rate also reflects a reduced intrinsic pacemaker cell rate20. In 
patients with subclinical cardiac failure a higher resting heart rate is associated with increased 
post-operative mortality21, and in healthy individuals associated with an increased risk of 
developing cardiac failure over a 15 year period22. Although reflective of vagal tone, the 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
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parameters of resting heart rate which increase peri-operative risk have not been defined. 
Heart rate recovery presents a measure combining both heart rate evaluation and exercise 
testing. 
 
1.5 
Heart rate recovery 
HRR after exercise is mediated by rapid re-activation of the parasympathetic nervous system23 
and has been shown to be independent of resting heart rate and respiration24, but correlates 
with other markers of vagal tone25. Greater initial HRR is considered to indicate greater aerobic 
fitness (Figure 1). HRR has been described as a prognostic marker in heart failure26, after non-
cardiac surgery27, 28 and in healthy individuals29. The majority of studies investigating the 
prognostic application of HRR measure HRR1 (reduction in HR one minute after exercise 
cessation after maximal exercise). HRR1 ≤12bpm after symptom-limited maximal exercise is a 
strong predictor of mortality in patients with coronary artery disease30. A study by Ha et al27 
investigated HRR1 after six minute walk test (submaximal) and found that post-operative 
cardiopulmonary complications were increased in patients undergoing lung resection with 
HRR1<12bpm. HRR1 however is effort-dependent31, so may not be the most appropriate 
measure for submaximal exercise testing. HRR after two minutes (HRR2) ≤42bpm after 
exercise cessation predicted all-cause mortality in healthy individuals32.  Further analyses of 
submaximal HRR as a peri-operative risk measure are absent, so it is an area requiring further 
investigation. 
 
1.6 
Previous HRR work 
Previous volunteer studies by our group have developed novel methods for HRR assessment 
utilising all the data contained within the HRR curve, including non-linear mixed-effects 
modelling and determination of the area under the curve (Figure 1)33, and have demonstrated 
their reproducibility following submaximal exercise across differing workloads and exercise 
modalities.  
 
The exercise protocol for the submaximal test used in this investigation (detailed below) is 
based on these previous study findings. Specifically, this prior work reveals that in a healthy 
population, resting heart rate is approximately 40% predicted maximum heart rate (HRmax). 
Reproducibility across differing exercise modalities was demonstrated. Participants walked on 
a flat surface, performed a ramped protocol on an exercise bike, and repeatedly stepped on 
and off a low box. During the step test, participants reached a median (IQR) of 64%(62-72%) 
predicted HRmax. All of our previous work has examined HRR over a recovery time of six 
minutes. However, during the six minutes heart rate does not return to baseline, even when 
exercising at low levels (e.g. 20% predicted maximum power). In general, the heart rate curve 
plateaus after approximately four minutes after cessation of exercise (Figure 1).  
 
The natural next step of our group’s work therefore is the validation of effort-corrected 
submaximal HRR in a clinical population (Table 1).   

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
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0
100
200
300
0
50
100
150
Time (s)
Heart rate (bpm)
HRR1 = 55bpm
AUC = 22800
a)
0
100
200
300
0
50
100
150
Time (s)
Heart rate (bpm)
HRR1 = 17bpm
AUC = 30270
b)
 
Figure 1 Graphs demonstrating HRR curves after cessation of exercise. a) typical curve of fitter participant with high HRR1 
and smaller AUC, incorporating lower resting HR. b) typical curve of less fit participant for comparison. Red dashed line = 
baseline HR. Yellow line = non-linear mixed-effects modelling curve from which rate constant can be obtained. AUC can be 
effort-corrected by dividing AUC by effort ratio (cessation HR/age-corrected maximal HR).  
 
1.7 
Validation of clinical tests 
 In order for submaximal heart rate recovery to be used as a peri-operative risk measure, we 
need to demonstrate scientific validity. There are several types of validity which can be applied 
to a clinical test34. Face validity is where the theoretical basis behind the measurement is 
scientifically sound and so taken at “face-value” represents what it purports to measure. 
Criterion validity is where the test is compared to a “gold-standard” criterion. Concurrent 
validity is where both measurements are taken concurrently and the test has the ability to 
distinguish between different groups of patients, for example, between patients at high or low 
risk of complications. Predictive validity is observed when the measurement identifies patients 
who develop a specific outcome. Construct validity is comparison of the measure against 
“constructs” used in place of the gold-standard. Table 1 details the types of validity and their 
application in the validation of submaximal heart rate recovery as a peri-operative risk 
stratification tool. 
 
Table 1. Types of validity and how these will be applied to HRR measurement. Modified from Ferguson et al35. 
 
1.8 
Rationale 
Validity 
Measure 
Explanation 
Example as applied to HRR 
Criterion 
validity 
Test corresponds to a gold standard 
measure 
HRR is associated with cardiopulmonary 
exercise testing derived indices – anaerobic 
threshold (AT) and peak VO2 (VO2peak) 
Concurrent 
validity 
Test is able to distinguish between 
groups that theoretically it should be 
able to distinguish between 
High risk patients as determined by CPET13: 
• 
AT <10ml/kg/min 
 
• 
VO2peak < 20ml/kg/min 
• 
VE/VCO2 at AT >34 
Predictive 
validity 
Test is able to predict something it 
theoretically should be able to 
predict 
Identifies patients with poor post-operative 
outcomes e.g. myocardial injury 
Construct 
validity 
Extent to which the test corresponds 
to 
other 
measurements 
that 
theoretically support the concept (or 
construct) being measured 
Association observed between HRR and 
clinically used pre-operative risk predictors 
e.g. METs score, DASI, Clinical frailty score, 
Revised cardiac risk index, P-POSSUM and 
NT-ProBNP 

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VERVE: validation of heart rate recovery as a peri-operative risk measure 
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Effective pre-operative functional capacity testing is part of the evolving peri-operative care 
pathway which aims to involve patients and their families in integrated and shared decision 
making to improve patient experience and outcome, and also cost-effectiveness of the 
surgical pathway within the NHS. Heart rate recovery after submaximal exercise testing offers 
a widely available and economical additional way to identify high risk patients in order to 
discuss risk with patients and to allocate resources correctly e.g. elective post-operative 
critical care36. This is the first study seeking to validate submaximal HRR in an 
intermediate/high risk surgical population.    
 
1.9 
Aim and Hypotheses 
• 
To assess predictive, criterion and construct validity of submaximal heart rate recovery 
as a peri-operative risk measure in patients undergoing intermediate/high risk surgery 
• 
Heart rate recovery following submaximal exercise is a valid predictor of post-operative 
myocardial injury in patients undergoing intermediate/high risk surgery and when 
compared to current peri-operative risk measures, HRR fulfils both criterion and 
construct validity.  
 
2.  
Study Plan 
2.1 
Study Design 
Multi-centre prospective observational cohort study of 95 patients presenting for 
intermediate/high risk elective surgery. 
 
2.2 
Study Setting 
Multi-centre study led by the Golden Jubilee National Hospital (GJNH). The other collaborating 
centres are the Queen Elizabeth University Hospital (QEUH), University Hospital Hairmyres 
(UHH) and University Hospital Crosshouse (UHC). The centres comprise a mixture of tertiary 
referral centres and district general hospitals in the West of Scotland.  
 
2.3 
Study Summary 
Intermediate/high risk surgical patients will be identified at surgical multi-disciplinary 
meetings, clinics or at anaesthetic pre-assessment clinic. All patients will have baseline 
demographics, subjective functional capacity and risk scores recorded pre-operatively (Table 
1). NT-proBNP and troponin samples will be taken. A cohort of patients at UHH and UHC will 
undergo CPET testing as per their routine pre-operative care. A sub-study of the CPET patients 
will compare submaximal heart rate recovery with maximal heart rate recovery, and also 
patients’ perceptions of the two different tests.  
 
Submaximal HRR will be measured and recorded at pre-assessment clinic or on admission to 
hospital if prior to the day of surgery. Patients will undergo their operation as standard with 
clinicians blinded to the HRR result.  
 
The primary outcome is myocardial injury as defined by  a troponin level above the 99th centile 
upper reference limit and a 20% change (increase or decrease)37, therefore troponin levels will 
be measured at baseline and on post-operative days 1 and 2. Secondary outcomes will include 
quality of life questionnaires, clinical indicator outcomes and post-operative complications 
measured up to 1 year post-operatively (Table 2). 
 
 
 
 
 

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Table 2 Indication of timeline for both pre-operatitve measures and post-operative measures. METS = metabolic equivalents; 
DASI = Duke Activity Status Index; CFS = Clinical Frailty Score; RCRI = Revised Cardiac Risk Index; SORT = Surgical Outcome 
Risk Tool; POSSUM = Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity; QoR = quality 
of recovery score; DaOH = days alive and out of hospital; AKI = acute kidney injury; MAKE = major adverse kidney events; CVS 
= cardiovascular complications; MACE = major adverse cardiac events; PPC = post-operative pulmonary complications 
 
 
3.  
Objectives and outcomes measures 
3.1  
Primary outcome measures 
Post-operative myocardial injury as defined by the 4th Universal definition of Myocardial 
Infarction37, with troponins measured pre-operatively and on days one and two post-
operatively.  
 
3.1.1  Rationale for primary outcome 
Post-operative myocardial injury is a well-recognised and widely used outcome measure of 
the cardiovascular effects of surgery and anaesthesia. It is independently associated with an 
increased risk of post-operative death in the absence of myocardial infarction6. Troponin 
assays are a relatively cost-effective test to add to the peri-operative blood tests the majority 
of patients will undergo as part of their routine care. Recent studies have demonstrated that 
approximately 90% of troponin elevation occurs within the first two days post-operatively39, 
40. 
 
3.2  
Secondary outcome measures 
• 
Post-operative complications at day 7 based on and including StEP-COMPAC 
cardiovascular complications38, post-operative pulmonary complications41, infection42, 
cognitive dysfunction,  and acute kidney injury43. 
• 
Composite outcomes: major adverse cardiac events (MACE) and major adverse kidney 
events (MAKE) at days 7 and 30 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
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• 
Patient-centred outcomes44: quality of recovery scale 15 (QoR-15), EQ-5D-5L score, days 
alive and out of hospital (DAOH) at day 30 and after 1 year 
• 
Clinical indicators45: mortality at day 30 and after 1 year, admission to ICU at day 14, 
readmission to hospital at day 30 and length of hospital stay (with/without in-hospital 
mortality) 
• 
CPET sub-study: comparison of maximal and submaximal heart rate recovery, plus HRR 
versus CPET derived indices (AT, VO2peak, and VE/VCO2 at AT). We will also examine 
patients’ perceptions of both tests. 
 
3.2.1 
Rationale for secondary outcomes 
Poor functional capacity has been associated with post-operative morbidity10. StEP-COMPAC 
aims to standardise and clearly define a set group of outcomes to facilitate comparison 
between studies46. Therefore, all secondary outcomes reflect criteria within the current StEP-
COMPAC endpoints, with outcomes of relevance to clinicians but also to patients.  
 
4.  
Selection and withdrawal of study participants 
4.1 
Inclusion criteria 
1. Provision of informed consent 
2. Age >50 years 
3. Able to walk unaided 
4. Planned elective intermediate/high risk surgery as defined by European Society of 
Cardiology/European Society of Anaesthesiology (ESC/ESA) guidelines 3 (Table 3) 
 
Table 3 Reproduced from ESC/ESA non-cardiac surgery guidelines2 
  
 
4.2 
Exclusion criteria 
1. Pregnancy 
2. On-going participation in any investigational research which could undermine the scientific 
basis of the study 
3. Presence of any of the American Thoracic Society’s contraindications to exercise testing 
(Appendix 1) 
4. Previous intermediate/high risk surgery within three months prior to recruitment 
5. Previous participation in the VERVE study at any time 
6. Presence of cardiac pacemaker or implantable cardioverter-defibrillator. 
 
4.2.1 
Rationale for inclusion/exclusion criteria 
 Aging is a cardiovascular risk factor. Previous studies have identified patients over 65 years or 
age over 40-45 years with one peri-operative risk factor6, 10 as at increased risk of post-
operative cardiovascular events. Proportionally, the majority of patients undergoing high risk 
surgery are aged over 59 years1 so including patients over 50 years of age should allow for a 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
14 
cohort at increased risk of peri-operative myocardial injury whilst ensuring a degree of 
generalisability within non-cardiac surgery patients.  
 
Although incorporating orthostatic heart rate recovery47 into the protocol, our main 
intervention relies on patient’s being able to step well enough to generate a heart rate 
response of approximately 60% predicted maximum heart rate (HRmax). This criterion will also 
therefore exclude a proportion of patients whose mobility may be limited by musculoskeletal 
problems rather than impaired cardiovascular fitness. The presence of a cardiac pacemaker 
may alter the heart response to exercise and recovery; an implantable cardioverter-
defibrillator (ICD) may be stimulated if the patient heart rate exceeds that which is expected. 
 
The prevalence of post-operative myocardial injury after low risk surgery is low, and so may 
be a difficult signal to identify. Low risk surgery is often performed as day-case and so post-
operative monitoring is difficult in this cohort. In order to facilitate generalisability of the 
measure, patients undergoing intermediate/high risk surgery as defined by the ESC/ESA i.e. 
>1% risk of cardiovascular death or myocardial infarction will be recruited2. Identifying 
patients by surgical risk rather than individual patient risk should allow a wide variety and 
degree of co-morbidity.  
 
4.3  
Withdrawals and exclusions 
 A patient may request withdrawal from the study at any time without it affecting their clinical 
care. The patient will not have to give a reason for their decision to withdraw. 
 
 Participants will be made aware from the beginning of their participation in the study that 
they can freely withdraw (discontinue participation) from the study (or part of) at any time. 
The sample size calculation allows for participant withdrawal of approximately 5%, so it is not 
anticipated that it will be necessary to replace participants who withdraw. The situation will 
be monitored throughout the study by the Chief Investigator.  
 
Types of withdrawal will be collected on a “Change of Status Form” defined as: 
• 
The participant would like to withdraw from the study but is willing to be remotely 
followed up in accordance with the schedule of assessments (i.e. the participant has 
agreed that data from medical notes can be collected and used in the study analysis 
but they do not want to be contacted via telephone for questionnaires from that point 
onwards). 
• 
The participant would like to withdraw from the study and is not willing to be followed 
up in any way for the purposes of the study and for no further data to be collected 
(i.e. only data collected prior to the withdrawal can be used in the study analysis). 
• 
The participant wishes to withdraw completely from the study and all study follow up, 
and is not willing to have any of their data, including that already collected, to be used 
in any future analysis. 
 
The details of withdrawal (date, reason and type of withdrawal) will be clearly documented in 
the source data and on the “Change of Status Form”. 
 
 All patients will be consented pre-operatively, but can withdraw consent at any time. Patients 
undergoing some high risk procedures e.g. elective AAA repair may be admitted to Intensive 
Care post-operatively, and may be sedated for longer than one post-operative day. This will 
be explicitly clarified with the patient pre-operatively, and confirmed that troponin levels and 
post-operative complication data will still be collected and recorded if they are unconscious. 
However, the day 2 QoR-15 scale will not be performed. If sedation is required for longer, the 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
15 
patient-centred secondary outcomes may not be completed but we envisage this will be a 
minority of patients. All other post-operative complication and clinical indicator data will be 
collected from notes reviews.   
 
5. 
Study Conduct 
5.1 
Recruitment 
Each recruiting hospital and surgical specialty has its own referral pathway from surgical 
outpatient clinic and diagnosis through to pre-assessment and admission for surgery. 
Therefore each pathway will vary, but in general we will aim to identify patients as early as 
possible in their pathway either via surgical referral or pre-assessment clinic. Eligible patients 
will ideally speak with a member of the research team face to face and take the Participant 
Information Sheet home to consider and discuss with others. Due to the rapid turnaround of 
surgical referrals to surgery however, some patients may receive a cover letter and Patient 
Information sheet in the post with the paperwork about their procedure. This will allow for 
telephone discussion prior to consent. We will aim to consent and collect all pre-operative 
data, including performing the submaximal exercise test at pre-assessment clinic or on the 
ward if the patient is admitted prior to the day of surgery. Exercise testing will not be 
performed on the day of surgery. 
 
5.2 
Consent 
 Written informed consent will be obtained following a face-to-face discussion about the 
study. Prior to obtaining consent, patients will have received a Patient Information Sheet and 
allowed at least 24 hourscontemplation time before consenting to participate and 
performance of the exercise test. The research team will endeavour to ensure understanding 
including study procedures, risks, benefits and the patient’s right to withdraw.  
 
5.3 
Data collection 
 
Data collection involves: 
• 
Baseline demographic data 
• 
Laboratory sampling 
• 
Pre-operative questionnaires 
• 
Pre-operative risk scores 
• 
Post-operative clinical data 
• 
Post-operative questionnaires 
 
All clinical data will be collected locally and case report forms (CRFs) completed by study staff. 
The data will be anonymised at site and a unique alphanumeric study number allocated. The 
study will adhere to data protection regulations. Patients’ identities will be protected and their 
information held securely. 
 
5.3.1 
Baseline demographic data 
 
Case note review and routine pre-operative investigations: 
• 
Age 
• 
Sex 
• 
Ethnicity 
• 
Height and weight 
• 
Operation 
• 
Indication for operation 
• 
Alcohol consumption (units/week) 
• 
Smoking history (current and pack years; time since abstinence if applicable) 
• 
Metabolic equivalents 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
16 
• 
American Society of Anaesthesiology score 
• 
Clinical Frailty Score 
• 
Co-morbidity (including history of Covid-19 infection) 
• 
Drug history, including medication taken on day of test 
• 
Routine observations (blood pressure, oxygen saturations, respiratory rate) 
• 
Pre-operative ECG finding 
• 
Consultant Anaesthetist caring for the patient on the day of surgery’s perception of 
peri-operative risk as per their routine risk assessment 
 
5.3.2 
Laboratory sampling 
• 
Pre-operative NT-proBNP 
• 
High-sensitivity troponin assay (as per the NHS clinical laboratory of each recruiting 
centre): pre-operatively and days one and two post-operatively. These will be drawn 
contemporaneously with routine bloods. 
 
5.3.3 
Pre-operative questionnaires (Full details in Appendix 2) 
• 
Quality of Recovery-15 scale (QoR-15)48: a validated evaluation of the quality of post-
operative recovery. It will be performed pre-operatively for baseline score. 
• 
EQ-5D-5L49: EuroQol health-related quality of life scale 
• 
Patient perception of submaximal versus maximal exercise testing in CPET cohort 
 
5.3.4 
Pre-operative risk scores 
• 
Duke Activity Scale Index11: brief self-reported functional capacity scale (Appendix 2). 
• 
Revised Cardiac Risk Index50: commonly used risk score for cardiovascular 
complications after major elective noncardiac surgery. 
• 
Surgical Outcome Risk Tool51: commonly used risk stratification tool predicting 30 day 
mortality after non-cardiac surgery. 
• 
P-POSSUM12/V-POSSUM52: pre-operative risk scores incorporating physiology and 
surgical domains, predicting post-operative morbidity and mortality. 
• 
All pre-operative risk scores will be completed by study investigators, blinded to 
clinical team. It is permissable for clinical teams to use risk scores as per their usual 
practice. 
 
5.3.5 
Post-operative clinical data (Full details in Appendix 3) 
• 
Acute Kidney Injury (AKI) as defined by KDIGO consensus53 at day 7. If urine output is 
no longer recorded (as not perceived to be clinically necessary), AKI will be scored by 
serum creatinine only. 
• 
Major Adverse Kidney Events (MAKE)54 at day 30. MAKE is a composite of ≥30% 
decline in eGFR at baseline, renal replacement therapy of any duration and renal 
mortality. 
• 
Infective complications at day 7. These will include presence of fever >38.5◦C more 
than 24 hours following surgery; non-prophylactic antibiotic use and documentation 
of suspected site (chest/urinary/blood/wound/other). Adapted from StEP-COMPAC 
outcomes for infection and sepsis42. 
• 
Cardiovascular complications at day 7. As per StEP-COMPAC, these include myocardial 
infarction, cardiovascular death, non-fatal cardiac arrest, coronary revascularisation, 
PE/DVT and new-onset of atrial fibrillation38.  
• 
Major adverse Cardiac Events (MACE)38 at day 30, day 90 and at 1 year. MACE is a 
composite 
of 
myocardial 
infarction, 
non-fatal 
cardiac 
arrest, 
coronary 
revascularisation and cardiac death. 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
17 
• 
Pulmonary complications at day 7, encompassing atelectasis, pneumonia, acute 
respiratory distress syndrome (ARDS, as defined by Berlin criteria35) and pulmonary 
aspiration41. 
• 
Neurological complications at day 7 including 4AT55 score, and use of anti-delirium 
medications. 
• 
Admission to ICU at day 14 (or re-admission) 
• 
Days alive and out of hospital56 at day 30: validated patient-centred outcome that 
reflects mortality, length of hospital stay, readmissions and discharge to another 
health facility other than the patient’s home. 
• 
All-cause mortality at day 30, 90 and 1 year 
• 
Length of hospital stay +/- in-hospital mortality 
 
5.3.6 
Post-operative questionnaires 
• 
QoR-15 at day 2.  
• 
EQ-5D-5L at day 90 and 1 year.  
 
5.4 
Exercise Protocol 
 Patients will begin at rest, sitting on a chair. Heart rate will be recorded via one-lead ECG 
(Actiheart, CamNTech, Cambridge, UK). The ECG leads will remain in situ throughout the test 
and HR monitored by the investigator throughout. The participant will not be able to see their 
HR. To ensure baseline heart rate is accurate patients will sit still, without talking, for 5 
minutes. Baseline HR will be noted.  
 
5.4.1 
Orthostatic HRR 
The initial test will be orthostatic heart rate recovery. Patients will be asked to stand promptly, 
remain standing for three minutes and then to sit back down, until their heart rate is back to 
baseline57. 
 
5.4.2 
Step test 
Prior to the exercise, the patients’ age-predicted maximum heart rate will be calculated: 
 
Age predicted HRmax = (208-0.7 x age) 
 
The aim of the test will be for the patient to repetitively step onto and off a low box until they 
reach 60% predicted HRmax +/- 5% or the point of subjective limitation. Participants will be 
encouraged throughout to place alternate feet onto the top of the box, stand erect at the top 
of the box and place both feet fully on the ground at the end of the stepping “cycle”14. 
Standard phrases of encouragement will be used in a neutral tone58. Once the HR is 
approximately 60% predicted HRmax, the patients will maintain the effort for a further minute. 
At the end of the minute, patients will sit and rest. Heart rate will continue to be monitored 
for a further 5 minutes. A modified Borg score59 will be assessed at the beginning and end of 
the test as an indication of perceived workload. The step test also allows an estimate of work 
done to be calculated: 
 
Work done (J) = mass (kg) x height of step (m) x 9.8 (gravity) x total number of step cycles 
  
During the test, patients will be asked not to speak as this has been demonstrated to raise 
heart rate60.  
 
5.5 
Medical Management and Safety Reporting 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
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 Medical management will be according to the standard of care at each treating site and is not 
part of this research protocol. The investigator performing the submaximal exercise test will 
not be involved in the anaesthetic or surgical management for the patient’s procedure. If, 
either when interviewing the patient or during the submaximal exercise test, the investigator 
has concerns about the peri-operative fitness of the patient, the clinical team will be informed. 
Aside from this, the clinical team will not be aware of the HRR test results, or pre-operative 
risk scores unless performed separately by the attending anaesthetist as per their usual care. 
 
The submaximal exercise test will be terminated early if the patient demonstrates chest pain, 
intolerable dyspnoea, dizziness etc as per the ATS statement on the six minute walk test 
(6MWT)58. The exercise test will be performed in clinical areas, all of which are equipped with 
oxygen points and cardiac arrest trolleys, with clinical staff presence. All investigators will be 
trained in basic life support. 
 
Troponins and NT-proBNP will be blinded to the clinical teams. Blood tests will be linked-
anonymised and analysed at the local NHS laboratory. They will be processed in real time and 
screened by the team for grossly abnormal results. If abnormal results are identified, the study 
team will discuss the result with the patient and arrange further medical follow-up if required. 
 
5.6 
Covid-19 Considerations 
 We expect the Covid-19 pandemic will be abating by August 2021 when data collection is 
planned to start. However, there may still be potential for ongoing effects of the pandemic to 
affect the deliverability and validity of this study. 
 
5.6.1 
Deliverability 
 The NIHR have published guidance concerning commencement of non-Covid research. This 
study has been designed with the NIHR framework in mind particularly concerning viability, 
capacity and safety. Locally this study has been risk assessed at level 3a (lowest risk): where 
patient attend hospital for clinically required interventions and follow-up is done remotely.  
 
At present, all four centres’ infection control policy requires the wearing of a surgical face-
mask when in the hospital, unless there is a medical exemption. Therefore, all patients and 
investigators will wear face-masks for the duration of interview and exercise test, unless 
exempt. The wearing of a surgical face mask may affect heart rate61, however as this measure 
is likely to be in place for the foreseeable future it aids to the generalisability of the study 
moving forward. This will not affect the scientific validity of the test as we are looking at HRR 
relative to resting and submaximal heart rate. Submaximal exercise testing does not fulfil the 
criteria of aerosol-generating procedure (private correspondence, Health Protection Scotland) 
and therefore no further infection control measures need to be taken apart from ongoing 
good infection control hygiene and the above.  
 
5.6.2 
Scientific validity 
 Evidence continues to emerge on the multi-system effects of Covid-19 disease, particularly in 
regards to the increasing prevalence of “Long-Covid”. It is plausible that recent Covid-19 
infection, or development of “Long-Covid” syndrome after infection could be a confounder in 
this study. To mitigate against confounding, previous Covid-19 infection will be specifically 
investigated at patient interview with data recorded on date and severity of infection, along 
with co-morbidity relating to “Long-Covid”. 
 
6. 
Data Management 
6.1 
Data collection 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
19 
 Patient data will be collected locally via case report forms (CRFs) by one of the investigators 
or an appropriately trained research nurse. This data will be submitted electronically to a 
protected online database (Research Electronic Data Capture (REDCap), Vanderbilt University, 
Tennessee, USA) in linked-anonymised form with a unique alphanumeric study number 
allocated. The study will adhere to all data protection regulations. Patients’ identities will be 
protected and their information held securely. 
 
6.2 
Data storage 
 Anonymised patient data will be stored on password protected university and NHS hospital 
computers. A patient identifier list will be kept in a secure location within the Research 
Department of the hospital the patient was recruited from. 
 
The data from each patient will be sent in an anonymised format to either NHS or University 
computers where analysis will be carried out. The research teams will not have access to the 
patient details from the other centres. If a patient needs to be contacted for any reason, 
contact will be made via the local recruitment team. 
 
6.3 
Archiving 
 Study data will be archived for ten years after the completion of the trial. It will be filed and 
stored securely as per each local site’s guidelines. At the end of ten years, the dataset will be 
destroyed to DoD 5220.22-M standards. All data will be held in accordance with General Data 
Protection Regulations (2018). 
 
 7. 
Statistical Considerations 
Our group has developed novel indices for measuring heart rate recovery including area under 
the curve and non-linear mixed effects modelling33. This study is part of a higher degree 
programme (MD by research; Cara Hughes) which will encompass statistical methodology as 
an iterative process. The primary method of measuring HRR will be effort-corrected area 
under the curve (EC-AUC)62 but our other methods will also be examined. A formal statistical 
analysis plan will be written and agreed between the principal investigator (CH) and chief 
investigator (BS) prior to any data analysis. 
 
All statistical analysis will be carried out using R-studio. 
 
7.1 
Power calculation 
 A power calculation was performed based on the hypothesis that submaximal heart rate 
recovery will improve the AURROC for the prediction of post-operative myocardial injury from 
0.5 (null hypothesis) to 0.7. Based on prior incidence of PMI of 24.5%28 after non-cardiac 
surgery in patients at higher risk of cardiovascular complications, 90 patients will be required, 
with a type 1 error of 0.05 and power of 80%. Adding an expected 5% dropout rate, a sample 
size of 95 patients will be recruited between the four recruiting centres. MedCalc V19.7.2 was 
used to calculate the sample size. 
 
7.2  
Primary Outcome 
 Predictive ability of heart rate recovery of post-operative myocardial injury will be quantified 
by determination of area under the receiver operative characteristic curve.  
 
7.3 
Secondary Outcomes 
 Secondary outcomes such as post-operative complications, patient-reported outcome 
measures, clinical indicators and CPET substudy will be analysed using appropriate statistical 
methods. 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
20 
 
 
 Paired secondary outcomes will be assessed for normality. Comparison will be made using a 
paired t-test or Wilcoxon signed ranks test. ANOVA or Friedmann’s test will be used to assess 
differences between variables repeated over time. Association will be sought between HRR 
and appropriate variables using Pearson correlation coefficient or Spearman’s rank correlation 
coefficient as appropriate. 
 
 
8. 
Study Organisation 
8.1 
Sponsor 
 This study will be sponsored by the National Waiting Times Centre Board (Golden Jubilee 
National Hospital). 
 
8.2 
Administration 
 All routine clinical and non-clinical co-ordinations of the study will be the responsibility of the 
Principal Investigator (CH) in conjunction with the research team staff at each site. The Chief 
Investigator (BS) will assume responsibility for the overall management and conduct of the 
study. 
 
8.3 
Indemnity 
 
The NHS research indemnity scheme will apply. 
 
8.4 
Monitoring 
 This study will be sponsored by the National Waiting Times Centre Board (Golden Jubilee 
National Hospital). As such, the Research and Development department will monitor this 
research in line with the Research Governance Framework for Health and Community Care 
(Scotland). 
 
8.5 
Funding 
 
NIAA/VASGBI Trainee Research Development Awarded December 2020. 
 
9. 
Ethics and regulatory approval 
 The study will be conducted in accordance with the ethical principles of the Declaration of 
Helsinki. The study will be submitted to a Research Ethics Committee for approval. 
 
10. 
Protocol amendments 
 Any substantial amendments to the final protocol will be clearly documented and forwarded 
to the Research Ethics Committee for approval prior to the implementations via the IRAS 
process of Notification of Substantial Amendment.  
 
 
11. 
Dissemination 
 
The results of the study will be reported first to study collaborators. 
 
 Subsequently, we plan to communicate our results by reporting them to the funder and 
presentation at national meetings with publication in appropriate peer reviewed journals. 
 
 At the end of the study, all participants will be thanked in writing for their participation in the 
study and will be provided with a short summary of the trial findings. Further details about 
the trial results and final report will be available on request. 
 
12. 
Projected study timetable 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
21 
 The anticipated duration is 24 months. Set up will take six months from February 2021 and all 
centres will aim to start recruiting from August 2021, for one year. Follow-up questionnaires 
will be completed via telephone at three months post-operatively and at one year. We 
therefore anticipate the dataset for the primary outcome (post-operative myocardial injury) 
to be complete by August 2022.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1 – ATS Contraindications to exercise testing 
 

Study Protocol: VERVE 
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22 
Table 4 Reproduced from ATS Cardiopulmonary Exercise Testing guidelines63 
 
*Exercise patient with supplemental oxygen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 2 – Pre-operative Questionnaires 
Quality of Recovery scale – 1548 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
23 
 
 
 
 
 
 
 
EQ-5D-5L49 
 

Study Protocol: VERVE 
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24 
 
 
 
 
 
 
 
 
 
 
Appendix 3 – Secondary outcome definitions (alphabetical) 
 

Study Protocol: VERVE 
VERVE: validation of heart rate recovery as a peri-operative risk measure 
25 
1. 
Acute Kidney Injury (AKI) 
 
According to the KDIGO consensus definition of AKI53: 
 
 
Stage 
Serum Creatinine 
Urine output 
1 
1.5-1.9x baseline OR 
≥0.3mg/dL (≥26.5mmol/L) 
increase 
<0.5ml/kg/hr for 6-12 hours 
2 
2.0-2.9x baseline 
<0.5ml/kg/hr for ≥12 hours 
3 
3.0x baseline OR ≥4.0mg/dL 
(≥353.6mmol/L) increase OR 
initiation of renal replacement 
therapy 
<0.3ml/kg/hr for ≥24 hours OR 
no urine output for ≥12 hours 
 
If urine output is not measured/recorded, incidence of AKI will be solely based on serum 
creatinine or commencement of renal replacement therapy. 
 
2. 
Cardiovascular complications 
 
Myocardial infarction (MI) 
 Acute myocardial injury (20% change in troponin with at least one value above the 99th centile 
upper reference limit) with clinical evidence of acute myocardial ischaemia, including at least 
one of: 
• 
Symptoms of myocardial ischaemia 
• 
New ischemic ECG changes 
• 
Development of pathological Q waves 
• 
Imaging evidence of new loss of viable myocardium or regional wall motion 
abnormality consistent with an ischaemic aetiology 
• 
Identification of coronary thrombus by angiography or autopsy 
 
 
Cardiac death 
Death with a vascular cause, including deaths after an MI, cardiac arrest and cardiac 
revascularisation procedures. Does not include death after pulmonary embolism, 
haemorrhage, multi-organ failure or unknown cause of death. 
 
 
Non-fatal cardiac arrest 
 Successfully resuscitation from either documented or presumed ventricular fibrillation, 
sustained ventricular tachycardia, asystole or pulseless electrical activity requiring 
cardiopulmonary resuscitation, pharmacological therapy or cardiac defibrillation. 
 
Coronary revascularisation 
Percutaneous coronary intervention or coronary artery bypass graft surgery within 30 days of 
index surgery. 
 
Pulmonary embolism (PE) 
Requires one of the following: 
• 
High probability ventilation/perfusion lung scan 
• 
Intraluminal filling defect of segmental or larger artery on a helical CT scan 
• 
Intraluminal filling defect on pulmonary angiography 
• 
Positive diagnostic test for deep venous thrombosis (e.g. positive compression 
ultrasound) plus one of: 
o Non-diagnostic ventilation/perfusion lung scan 
o Non-diagnostic helical CT scan 

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26 
 
Deep venous thrombosis 
Requires one of the following: 
• 
Persistent intraluminal filling defect on contrast venography 
• 
Non-compressibility of one or more venous segments on B-mode compression 
ultrasonography 
• 
Clearly defined intraluminal filling defect on contrast enhanced CT 
 
Atrial fibrillation 
New onset of irregularly irregular heart rate in the absence of P waves lasting for at least 30 
seconds or for the duration of the ECG recording (if <30s). 
 
3.  
Infective complications  
 
Fever 
 Core body temperature over 38.5˚C more than 24 hours following surgery with two readings 
in a 12 hour period. 
 
Clinical suspicion of infection 
Use 
of 
non-prophylactic 
antibiotics 
PLUS 
documentation 
of 
suspected 
site 
(respiratory/urinary/blood/wound/other). 
 
4.  
Major adverse cardiac events (MACE) 
 
Composite outcome that includes: 
• 
Cardiac death 
• 
Myocardial infarction 
• 
Non-fatal cardiac arrest 
• 
Coronary revascularisation 
Measured at a pre-specified time e.g. 30 days after the index operation 
 
5.  
Major adverse kidney events (MAKE) 
 
Composite outcome that includes: 
• 
Renal mortality 
• 
Renal replacement therapy of any duration 
• 
≥30% decline in eGFR from baseline 
Measured at a pre-specified time e.g. 30 days after the index operation 
 
6. 
Neurological complications 
 
Delirium screening 
 Post-operative delirium is defined as delirium that occurs up to one week post-operatively or 
up until discharge if earlier than 7 days64. A snapshot 4AT test will be performed at day 7 if the 
patient remains in hospital. A score ≥4 is indicative of delirium. 
 
Use of anti-delirium medication 
Documentation of any anti-delirium medications given within 7 days postoperatively, 
including medication and dose given. 
 
Stroke 
New neurological signs (weakness, expressive/receptive difficulties) lasting over 24 hours or 
cerebral infarction or intracerebral haemorrhage on computed tomography or magnetic 
resonance imaging scan.  
 

Study Protocol: VERVE 
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27 
7. 
Pulmonary complications 
 
Composite of atelectasis, pneumonia, ARDS and pulmonary aspiration as described below: 
 
Atelectasis  
Diagnosed on chest radiograph or computed tomography 
 
Pneumonia 
Diagnosed using the US Center for Disease control criteria65: 
• 
Two or more serial chest radiographs with at least one following feature: 
o New or progressive and persistent infiltrate 
o Consolidation 
o Cavitation 
(One radiograph is sufficient for patients with no underlying pulmonary/cardiac 
disease) 
• 
AND at least one of: 
o Fever (>38.0˚C) with no other recognised cause 
o Leukopaenia (<4x109/L) or leucocytosis (>12x109/L) 
o Altered mental state with no other cause in adults >70 years old 
• 
AND at least two of: 
o New onset of purulent sputum/change in character of sputum/increased 
respiratory secretions/increased suctioning requirements 
o New onset/worsening cough, dyspnoea or tachypnoea 
o Rales or bronchial breath sounds 
o Worsening gas exchange (hypoxia/increased oxygen requirement/increased 
ventilator demand) 
 
Acute respiratory distress syndrome (ARDS) 
As defined by the Berlin Consensus criteria (2012)35: 
• 
Within one week ofa known clinical insult or new worsening respiratory symtoms 
• 
AND bilateral infiltrates onchest imaging, not fully explained by effusions, lobar/lung 
collapse or nodules 
• 
AND respiratory failure not explained by cardiac fluid/fluid overload (requires 
objective assessment) 
• 
AND supplemental oxygenation: 
o Mild = PaO2:FiO2 26.7-40.0kPa with PEEP or CPAP ≥5cmH2O 
o Moderate = PaO2:FiO2 13.3-26.6kPa with PEEP ≥5cmH2O 
o Severe = PaO2:FiO2 ≤13.3kPa with PEEP ≥5cmH2O 
 
Pulmonary aspiration 
Diagnosed by clear clinical history AND radiological evidence. 
 
Clavien-Dindo scale grading 
All reported postoperative complications will be graded on severity by using the Clavien-Dindo scale66: 
Grade I 
Any deviation from the normal post-operative course not requiring pharmacological 
treatment or surgical, endoscopic or radiological intervention. This does not include 
drugs such as antiemetics, antipyretics, analgesics, diuretics, electrolytes and 
physiotherapy. 
Grade II 
Requiring pharmacological treatment with drugs other than those described in Grade 
I. Includes blood transfusions and parenteral nutrition. 
Grade III 
Requires surgical, endoscopic or radiological intervention 
Grade IIIa 
Intervention not under general anaesthesia 

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VERVE: validation of heart rate recovery as a peri-operative risk measure 
28 
Grade IIIb 
Intervention under general anaesthesia 
Grade IV 
Life-threatening complication requiring critical care admission 
Grade IVa 
Single organ dysfunction (not including dialysis) 
Grade IVb 
Multi-organ dysfunction 
Grade V 
Death 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. 
Abbott TEF, Fowler AJ, Dobbs TD, Harrison EM, Gillies MA, Pearse RM. Frequency of surgical 
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VERVE: validation of heart rate recovery as a peri-operative risk measure 
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2. 
Members ATF, Kristensen SD, Knuuti J, et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: 
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doi:10.1093/eurheartj/ehu282 
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Glance LG, Lustik SJ, Hannan EL, et al. The Surgical Mortality Probability Model: derivation and 
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1018. doi:https://doi.org/10.1002/bjs.11148 
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Nash A. Data from: National Population Predictions: 2018-based. 2019.  
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