British Journal of Anaesthesia, 120 (3): 484e500 (2018)

doi: 10.1016/j.bja.2017.10.020
Advance Access Publication Date: 24 November 2017
Cardiovascular

Perioperative cardiopulmonary exercise testing

(CPET): consensus clinical guidelines on indications,
organization, conduct, and physiological
interpretation
D.Z.H. Levett1,2,10,*, S. Jack1,2,10, M. Swart3,10, J. Carlisle3, J. Wilson4,
C. Snowden5, M. Riley6, G. Danjoux7, S.A. Ward8, P. Older9,
M.P.W. Grocott1,2,10 and For the Perioperative Exercise Testing and
Training Society (POETTS)
1
Anaesthesia and Critical Care Research Area, Southampton NIHR Biomedical Research Centre, University
Hospital Southampton NHS Foundation Trust, Southampton, UK, 2Integrative Physiology and Critical
Illness Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton,
Southampton, UK, 3Department of Anaesthesia and Intensive Care, Torbay and South Devon NHS
Foundation Trust, Torquay, UK, 4Department of Anaesthesia and Intensive Care, York Teaching Hospital
NHS Foundation Trust, York, UK, 5Department of Anaesthesia and Intensive Care, Newcastle Upon Tyne
NHS Foundation Trust, Newcastle, UK, 6Belfast City Hospital, Belfast, UK, 7Department of Anaesthesia and
Intensive Care, The James Cook University Hospital, Middlesbrough, UK, 8Department of Exercise
Physiology, University of Leeds, Leeds, UK and 9Department of Physiology, Swinburne University,
Melbourne, Australia

*Corresponding author. E-mail: [email protected]

10
These authors contributed equally to the development of these guidelines.

This article is accompanied by an editorial: Improving the evidence-base for preoperative cardiopulmonary exercise testing by B.M. Biccard,
Br J Anesth 2018:120:419e421, doi:10.1016/j.bja.2017.12.007.

Abstract
The use of perioperative cardiopulmonary exercise testing (CPET) to evaluate the risk of adverse perioperative events and
inform the perioperative management of patients undergoing surgery has increased over the last decade. CPET provides
an objective assessment of exercise capacity preoperatively and identifies the causes of exercise limitation. This infor-
mation may be used to assist clinicians and patients in decisions about the most appropriate surgical and non-surgical
management during the perioperative period. Information gained from CPET can be used to estimate the likelihood of
perioperative morbidity and mortality, to inform the processes of multidisciplinary collaborative decision making and

Editorial decision: October 22, 2017; Accepted: October 22, 2017

© 2017 Published by Elsevier Ltd on behalf of British Journal of Anaesthesia.
For Permissions, please email: [email protected]

484
 Perioperative cardiopulmonary exercise testing - 485

consent, to triage patients for perioperative care (ward vs critical care), to direct preoperative interventions and opti-
mization, to identify new comorbidities, to evaluate the effects of neoadjuvant cancer therapies, to guide prehabilitation
and rehabilitation, and to guide intraoperative anaesthetic practice. With the rapid uptake of CPET, standardization is
key to ensure valid, reproducible results that can inform clinical decision making. Recently, an international Perioper-
ative Exercise Testing and Training Society has been established (POETTS www.poetts.co.uk) promoting the highest
standards of care for patients undergoing exercise testing, training, or both in the perioperative setting. These clinical
cardiopulmonary exercise testing guidelines have been developed by consensus by the Perioperative Exercise Testing
and Training Society after systematic literature review. The guidelines have been endorsed by the Association of Res-
piratory Technology and Physiology (ARTP).

Keywords: anaerobic threshold; cardiopulmonary exercise testing; perioperative medicine

Use of preoperative cardiopulmonary exercise testing (CPET) to consensus was achieved by e-mail. The guidelines were then
evaluate the risk of adverse perioperative events and inform the peer reviewed by the delegates at the National Perioperative
perioperative management of patients undergoing surgery has CPET meetings. Firstly, an item-by-item chaired open discus-
increased over the past decade, particularly in the UK.1,2 With sion took place in 2011 and the document was revised and
the rapid uptake of CPET, standardization is key to ensure valid, updated. Further point-by-point iterative discussion took
reproducible results that can inform clinical decision making. place in chaired open discussion at the National CPET Meet-
Recently, an international Perioperative Exercise Testing and ings in 2012, 2013, 2014, and 2016. Consensus was achieved for
Training Society (POETTS) has been established (www.poetts. elements without a firm evidence base. In this case, the rec-
co.uk). This body developed from the UK National Periopera- ommendations are based on what is considered to be good
tive CPET forum and has the specific aims of: (1) promoting the practice standards by experts in the field. This final version
highest standards of care for patients undergoing exercise was then refined and edited by the authors in late 2016 until all
testing, exercise training, or both in the perioperative setting authors were satisfied with the final document which was
and to promote the professional practice of exercise testing, then submitted for publication.
exercise training, or both in the perioperative setting; (2) pro-
moting and delivering training and education in exercise
Systematic review
testing, exercise training, or both in the perioperative setting
including advising on education and training curricula for The writing process was informed by multiple published sys-
medical and healthcare practitioners; (3) promoting the devel- tematic reviews of the relevant literature including Smith and
opment, conduct, and dissemination of audit, quality colleagues,6 Hennis and colleagues,7 and Moran and col-
improvement, research and innovation to further the develop- leagues.8 In addition, to identify recently published studies, we
ment of perioperative exercise testing, training, or both. These performed repeated updated PubMed systematic searches
clinical cardiopulmonary exercise testing guidelines have been during the development of this manuscript (until submission)
developed by consensus by the POETTS after systematic litera- based on the search strategy Hennis and Grocott7 and using
ture review. The guidelines have been endorsed by the Associ- the follow search terms: ‘CPET/surgery’, ‘CPEX/surgery’, ‘CPX/
ation of Respiratory Technology and Physiology (ARTP). The surgery,’ ‘cardiopulmonary/exercise testing/surgery’, ‘VO2
guidelines represent what is considered to be best practice by peak/surgery’, ‘VO2max/surgery’ ‘AT/surgery and ‘Anaerobic
expert consensus and by setting a standard the intention is to threshold/surgery.’
help all who do perioperative CPET to reach this standard. They
will be used to benchmark practice and subsequently will be Strength of recommendations and levels of evidence
revised in the light of new information or evidence.
To indicate the basis on which recommendations were made,
all evidence was classified according to an accepted hierarchy
Methods of evidence that was originally adapted from the US Agency for
Healthcare Policy and Research Classification.9 Each recom-
Guideline development
mendation is graded AeD based on the level of associated
An early set of UK CPET guidelines (unpublished) was pro- evidence using a scheme formulated by the Clinical Outcomes
duced by Helen Luery (University College London Hospitals, Group of the NHS Executive that has been used in NICE
UK), Jonathan Wilson (York, UK), John Carlisle, and Michael guidelines10 (see Supplementary Appendix S1).
Swart (Torbay, UK) in 2001, based on the work of Paul Older. In contrast to questions of clinical efficacy and effective-
The concept of consensus national guidelines was first ness, the practice recommendations within these guidelines
formally raised at the first National Perioperative CPET relate to the indications, organization, conduct, and physio-
Meeting at the Evidence Based Perioperative Medicine con- logical interpretation of perioperative CPET. Such questions
ference in July 2008 and formally discussed at the second are rarely, if ever, amenable to direct evaluation through
meeting in 2009. Following initial open forum discussion at the randomized controlled trials (RCTs); therefore, all recom-
third national CPET meeting in 2010, the authors produced the mendations are graded B (well-conducted clinical studies but
first draft of this manuscript based on systematic review of the no RCTs on the topic of recommendation; or extrapolated from
literature (see below), guidelines from other applications of RCT or systematic review), C (expert committee reports or
clinical CPET,3e5 established practice standards, and input opinions/clinical experiences of respected authorities OR
from experts in the field (B.J. Whipp and others). The recom- extrapolated from well-conducted clinical studiesdthis
mendations were reviewed by the authorship group until grading indicates that directly applicable clinical studies of
 486 - Levett et al.

good quality are absent or not readily available), or D (recom- (4) To direct pre-operative referrals/interventions to optimize
mended good practice standard based on the clinical experi- comorbidities (Grade C).
ence of the guidelines development group). (5) To identify previously unsuspected pathology (Grade B).
(6) To evaluate the effects of neoadjuvant cancer therapies
Guidelines scope including chemotherapy and radiotherapy (Grade B).
(7) To guide prehabilitation and rehabilitation training pro-
CPET evaluates the integrated physiological response to ex- grammes (Grade B).
ercise and provides an objective measure of exercise capacity (8) To guide intraoperative anaesthetic practice (Grade D).
(functional capacity or physical fitness). It also permits inter-
rogation of the aetiology of exercise intolerance when exercise
capacity is abnormal. Exercise capacity is predictive of post-
Contraindications for CPET
operative outcome,11 reflecting the physiological reserve
available to respond to the stress of surgery and postoperative Published contraindications to CPET have addressed its use as
recovery. This guideline is intended to provide guidance on the a diagnostic and prognostic tool for patients with cardiac or
use of CPET perioperatively. The use of CPET for other appli- respiratory disease, to monitor disease progression in chronic
cations has been comprehensively covered elsewhere.3e5,12e15 cardiorespiratory disease, to quantify exercise capacity, and to
evaluate likely causes of exercise intolerance.3,15 These are
largely based on the expert opinion of respected authorities.
Indications and contraindications for CPET Contraindications and relative contraindications to exercise
Indications testing in the perioperative setting are summarized in Table 1.
These are based on recommendations in other areas of CPET
CPET is indicated to provide an objective assessment of exer-
modified for the perioperative context to take into account the
cise capacity preoperatively and to identify the causes of ex-
specific patient population (Grade C). Patients with relative
ercise limitation. This information may be used to assist
contraindications should be directly supervised by a physician
clinicians and patients in decisions about the most appropriate
(Grade C). For relative contraindications to exercise testing, the
surgical and non-surgical management during the periopera-
risks and potential benefits of undertaking CPET should be
tive period. Studies support the use of CPET for risk prediction
considered on a patient-by-patient basis both before and during
in major abdominal surgery,16e18 colorectal surgery,19,20 uro-
the test (Grade D). If the risk-benefit relationship changes as the
logical surgery,17,21 hepatobiliary surgery,16,22 liver trans-
test progresses, the test can be terminated earlyda submaximal
plantation,23 bariatric surgery,24,25 vascular surgery,22,26
test (Grade D). For example, in a colorectal cancer patient with
thoracic surgery,27e29 and oesophagealegastric surgery,30e32
newly identified asymptomatic severe aortic stenosis, CPET
and also for guiding exercise-training interventions prior to
may be considered to delineate the functional impairment
surgery, immediately after surgery, or both.33,34 The evidence
caused by the valve stenosis. The test may help determine the
supporting CPET is continuously evolving and consequently
relative priority of valve replacement and tumour resection.
the indications for CPET require regular reassessment.
However, if the patient developed chest pain or hypotension
during the test, this would indicate critical stenosis and an
Recommendations: Indications for CPET increased risk of syncope, and should lead to test termination.

(1) To estimate the likelihood of perioperative morbidity and

mortality and contribute to preoperative risk assessment
Perioperative CPET service structure and
(Grade B).
(2) To inform the processes of multidisciplinary shared
supervision
decision-making and consent (Grade C). A perioperative CPET service should be managed and led by an
(3) To guide clinical decisions about the most appropriate level individual expert in perioperative CPET (Grade C). Periopera-
of perioperative care (ward vs critical care; Grade B). tive CPET expertise incorporates an understanding of the

Table 1 Absolute and relative contraindications for CPET (adapted from American Thoracic Society3). Patients with relative contra-
indications should be discussed with an appropriate clinician and the risks and benefits of testing evaluated. Patients with relative
contraindications should be directly supervised by a physician

Absolute contraindications Relative contraindications

Acute myocardial infarction (3e5 days)
Untreated left main stem coronary stenosis

Unstable angina
Asymptomatic severe aortic stenosis

Uncontrolled arrhythmia causing symptoms or
Severe untreated arterial hypertension at rest
haemodynamic compromise (>200 mm Hg systolic, >120 mm Hg diastolic)

Syncope
Tachyarrhythmias or bradyarrhythmias

Active endocarditis
Hypertrophic cardiomyopathy

Acute myocarditis or pericarditis
Significant pulmonary hypertension

Symptomatic severe aortic stenosis
Thrombosis of the lower extremity until treated

Uncontrolled heart failure for a minimum of 2 weeks

Suspected dissecting or leaking aortic aneurysm
Within 2 weeks of acute symptomatic pulmonary embolus

Uncontrolled asthma
Abdominal aortic aneurysm >8.0 cm

Arterial desaturation at rest on room air <85%
Electrolyte abnormalities

Advanced or complicated pregnancy
 Perioperative cardiopulmonary exercise testing - 487

equipment and exercise protocols, expertise in exercise Preparation for the exercise test (Grade C,
physiology and pathophysiology and an understanding of good practice recommendations, unless
perioperative risk.
otherwise stated)
Perioperative CPET testing and interpretation can be
divided into three distinct stages. Stage 1, CPET practitioner: Patient information and consent
the practicalities of test performance, including the exercise Patients should be provided with information on the process,
protocol, equipment operation and maintenance and quality risks, and benefits of CPET. The process of informed decision-
control. Stage 2, Advanced CPET practitioner: integration of making and consent should be documented and may involve
the physiological data to provide a comprehensive interpre- formal written consent. Patients should take their regular
tation of the patient’s exercise capacity and the main causes of medication but avoid caffeine, alcohol, cigarettes, and
exercise limitation, including the identification of undiag- strenuous exercise on the day of testing. For 2 h prior to the
nosed pathology. Stage 3, CPET competent perioperative test, patients should not eat and should drink only water.
physician: interpretation of the implications of the patient’s
exercise limitation for their perioperative risk and formulating
recommendations for preoperative interventions and periop- Risk of adverse events
erative care.
CPET is a relatively safe investigation, especially in individuals
The competencies required for each of these stages are
with no comorbidity. A review of the exercise testing literature
different. Within a CPET service different individuals may
(primarily in patients with cardiac disease), suggests an inci-
perform each of the three stages of the testing and inter-
dence of a complication requiring hospitalization of two or
pretation process. Alternatively, a single individual may be
less in 1000,5 of a major cardiac event of 1.2 per 10,000
able to perform all three stages. Stages 1 and 2 may be per-
tests,13,35 and of mortality of two to five per 100,000 clinical
formed by non-clinicians, but clinical expertise in perioper-
exercise tests.3,5 To date, no deaths have been reported during
ative medicine is required for stage three. Competence and
perioperative CPET in the UK.
expertise in each stage of the CPET process should be defined
by specific training and documented experience, rather than
defined medical roles (e.g. doctor, nurse, clinical physiologist; Baseline data collection
Grade C).5
Baseline data collection should include patient demographic
All competent CPET practitioners and advanced practi-
information, the reason for referral and the proposed surgery.5
tioners must be able to identify and manage adverse events in
The patient’s medical history should be reviewed with
relation to CPET by discriminating between normal and
particular attention to cardiac and respiratory disease to
abnormal responses to exercise including abnormal symp-
identify potential contraindications to exercise testing.5 A full
toms, hypertension, hypotension, abnormal arterial O2 satu-
drug history should also be taken to identify medication that
ration [measured by pulse oximetry (SpO2)] and ECG evidence
may interfere with the exercise response.5 A recent haemo-
of arrhythmia and ischaemia (Grade C).5 CPET practitioners
globin level should be reviewed, since anaemia may impair
and advanced practitioners must have appropriate knowledge
exercise capacity (Grade D).36,37
and experience in first aid and resuscitation (Grade C).5
A minimum of two members of staff should be directly
available for every test, one of whom should be a competent Conduct of the exercise test (Grade C, good
CPET advanced practitioner (Grade D). At least one member of
practice recommendations, unless otherwise
staff should have current intermediate life support compe-
stated)
tence and the other a minimum of current basic life support
with automated external defibrillator competence (defined by The exercise protocol, equipment, and quality control of
Resuscitation Council UK criteria, www.resus.org.uk; Grade perioperative CPET are discussed below. The recommenda-
C).5 A resuscitation team with advanced life support skills tions within this section are based on key position statements
(cardiac arrest team or paramedic team) must be immediately and policy documents from national and international
available (Grade C).5 A physician should be available to review specialist bodies that use CPET in other clinical contexts and
any patient who develops complications during a test (Grade represent good practice standards.3e5,12,13
C).5 High-risk CPET tests, including tests where relative con-
traindications are present (Table 1), should be directly super-
Exercise protocol (Grade C)
vised by a physician (Grade C).5
When a new service is being set up without established Cardiopulmonary exercise testing provides a global assess-
local expertise, formal mentoring from a suitably accredited ment of the integrated response of the pulmonary, cardio-
trainer is recommended (e.g. POETTS accreditation; Grade vascular, metabolic, and haematological systems. Key is the
D). CPET practitioners who will be performing and reporting integration of respired gas analysis (O2 and CO2 concentra-
perioperative CPET tests should have completed an tions) with ventilatory flow measurements, thereby enabling
accredited course, performed 25 tests under supervision, calculation of O2 uptake (V_ O2 ) and CO2 output (V_ CO2 ), typically
and reported at least 50 tests under supervision before on a breath-by-breath basis, under conditions of progressively
gaining accreditation and reporting independently (Grade increasing physiological stress imposed by a defined profile of
C).5 CPET practitioners should review or report 25 tests per external work rate (WR).
year to maintain their competence (Grade C).5 CPET practi- Heart rate (HR), SpO2, arterial blood pressure, and 12-lead
tioners who will be performing CPET tests but not inter- ECG (for rate, rhythm, and S-T segment morphology evalua-
preting tests should complete an accredited course and tion) should be monitored throughout the test.3e5,12,13 Resus-
perform a minimum of 25 tests under supervision before citation equipment including supplemental O2 must be
testing independently (Grade D). immediately accessible.3e5,12,13
 488 - Levett et al.

For perioperative CPET, the rapid ramp (or incremental) population tends to be overestimated by these equations; a
exercise test performed to the limit of tolerance should be reduction in the calculated value should therefore be consid-
used.38 The advantages of this protocol are as follows: (1) it ered (Grade D).
evaluates the exercise response across the entire range of
functional capacity; (2) the initial WR is low and there is a
CPET equipment (Grade C)
relatively short duration of high intensity exercise; (3) the
entire protocol is of short duration, with 8e12 min of exercise Test equipment should include an electronically-braked cycle
during the incremental phase; (4) it permits assessment of the ergometer and a metabolic cart capable of analyzing respired
normality or otherwise of the exercise response; (5) it permits flow, [O2], and [CO2] with a response time <90 ms to provide
identification of the cause of functional exercise limitation; breath-by-breath measurements of ventilatory and gas ex-
and (6) it gives an appropriate frame of reference for training or change variables, together with ancillary equipment for serial
rehabilitation targets. monitoring of SpO2, blood pressure, ECG, and perceptual re-
Submaximal tests, (stopping the incremental ramp above sponses (perceived exertion, dyspnoea).3,4,15,39 Perceptual re-
the anaerobic threshold but before peak exercise) were sponses such as perceived exertion and breathlessness can be
initially widely used in the perioperative setting, primarily assessed by the Borg scale or a visual analogue scale.43,44
because of safety concerns and may still be considered in
some clinical contexts, for example, in patients with angina or
Calibration and quality control (Grade C)
moderate to severe aortic stenosis. However, maximal tests to
the limit of tolerance provide additional information that may The accuracy and reproducibility of the values obtained during
have prognostic and diagnostic utility and are preferred. testing is dependent on meticulous quality control.3,4,15,39
Cycle ergometry has been used in all bar one of the pub- Calibration of primary sensors for flow and O2 and CO2 gas
lished perioperative CPET cohorts. Cycle ergometry permits measurement should be performed immediately before each
accurate determination of the external WR and thus, for exercise test. The calibration should consider barometric
example, evaluation of the V_ O2 eWR relationship, which is pressure, ambient humidity, and temperature. While the
difficult with a treadmill.39 Consequently, cycle ergometry precise calibration procedures will vary with the model and
(using an electromagnetically braked ergometer) is the manufacturer of the metabolic cart, there are certain under-
preferred mode of exercise for PCPET. For patients who are lying principles that should be followed.
unable to perform cycle ergometry, arm cranking may be The flow sensor should be calibrated for volume with a
considered, although the risk thresholds for this modality of precision syringe (typically 3 l) over a physiological range of
exercise in the perioperative setting have not been identified.40 flow rates. Calibration gas mixtures for the O2 and CO2 sensors
A period of approximately 3 min of resting data collection should be prepared by gravimetric weighing to ensure a con-
(rest phase) should be followed by 3 min of resistance-free centration accuracy of ±1%. Sensor calibration should be
pedalling (unloaded cycling phase) and then a continuous performed at two points, within the range for inhaled (21% O2
gradual, uniform increase in WR until the limit of tolerance is and 0% CO2 in N2) and exhaled gas compositions (e.g. 15% O2
attained (incremental phase). The ramp slope (W min1) is and 5% CO2 in N2). Because of the transport delay associated
selected to produce 8e12 min of exercise during the ramp with the gas concentration sensors (a phase delay typically in
phase.3 For healthy active individuals, ramp slopes of 15, 20, or the region of 250 ms), the flow and gas concentration signals
25 W min1 are common, while lower values in the range of have to be time-aligned prior to further processing. This phase
5e15 W min1 are more appropriate for most patients. Higher delay should be measured prior to each test rather than
ramp slopes in frail patients are likely to lead to premature test assumed, as small deviations from the correct value can have
termination and consequently a truncated period of data significant impact on gas exchange computations.4,15,29,39,45 It
acquisition, which precludes reliable test interpretation. Algo- is measured as the delay between the imposition of a step
rithms based on individual patient characteristics (age, height, change in gas concentration at the distal end of the sample
weight) are available to estimate the ramp slope required to line and the resulting gas concentration response at the
produce a test duration of approximately 10 minutes (i.e. within respective sensor (phase delay), and values should lie within
the recommended 8e12 min range). For example:41 the manufacturer’s stated range.
The performance of the gas exchange algorithms cannot be
_
ramp slope (W min1) ¼ (VO _
2peak e VO2unloaded )/100 assessed in the routine pretest calibration phase. This requires
simultaneous comparison of the metabolic cart responses
where: with those obtained with an accepted independent standard.
The contemporary (and expensive) ‘gold standard’ method
_ 1
VO 2unloaded (ml min ) ¼ 150 þ [6  weight (kg)] uses an automated gas exchange simulator. This comprises a
reciprocating piston system that generates ‘expired’ gas to
and for males: simulate metabolic rates by injecting a precision gas mixture
into a chamber at precisely metered rates to mix with inspired
_ 1
VO 2peak (ml min ) ¼ [height (cm) e age (yr)]  20 f air, thus allowing comparison of ‘measured’ breath-by-breath
values of V_ O2 , V_ CO2 , and ventilation (VE)
_ with predicted
or for females: values.46 It has been proposed that the measured outputs and
their variation with changes in pump frequency should lie
_ 1
VO 2peak (ml min ) ¼ [height (cm) e age (yr)]  14 within ~3%. Values falling outside this range should prompt a
comprehensive reassessment of the entire monitoring sys-
The validity of such predictive algorithms in a general tem.3 Small, progressive deteriorations in sensor performance
surgical population has not been established.42 Anecdotal ev- and sample line transit delay over time may have a significant
idence suggests that exercise capacity of the surgical patient effect on gas exchange computation. Validation against a gas
 Perioperative cardiopulmonary exercise testing - 489

exchange simulator may be performed annually as part of the Maximum voluntary ventilation can be estimated from FEV1
metabolic cart service. as (FEV1  35) or (FEV1  40).57,58 The patient should be famil-
A practical (and inexpensive) alternative is provided by iarized with the cycle ergometer and the breathing assembly
regular ‘biological quality control’ (conducted monthly or (facemask or breathing valve and mouthpiece), and should be
more frequently), utilizing responses of a ‘standard’ subject instructed to give their ‘best effort’ but counselled to stop if
(typically a member of the laboratory staff familiar with symptoms such as chest pain develop. The patient should be
testing procedures).13,39,47,48 It is recommended that the sub- discouraged from talking during the test, as this will
ject performs two sub-anaerobic threshold (AT) constant WR compromise data quality; an alternative method of commu-
tests, each of at least 6 min duration, with the steady-state nication should be established before commencing the test
_ , VCO
VO _ _
2 2 , and V E responses at each WR being obtained by (thumb up ¼ yes, thumb down ¼ no). The patient should un-
averaging data over the final 2 min of the test (i.e. when a derstand that they can stop at any time, whilst recognizing
steady state has been achieved; Fig. 1). This allows the devel- that the aim is to pedal for as long as possible. During testing,
opment of a serial quality control database comprising abso- data should be displayed in both tabular and graphical formats
lute VO_ , V_ CO , and V_ E responses at standardized WRs, as well to monitor for abnormalities; core variables are presented in
2 2
as derived indices such as the respiratory exchange ratio (RER, Table 2.
_
VCO _ _
2 =V O2 ) and the slope of the VO2  WR relationship The exercise test consists of four main phases: rest,
_ =DWR), which is relatively independent of age, gender,
(DVO unloaded cycling, ramp exercise, and recovery.
2
and fitness. Differences in ‘expected’ response can then be
identified, both in terms of previous subject performance and Rest (3 min)
also relative to normal population values. While there are no
formal recommendations for assigning a ‘significant’ change A minimum of 3 min of resting data should be recorded, with
relative to a quality control database, decisions could be based the ECG being monitored for ischaemia or arrhythmia. If hy-
on: (1) responses falling outside the database 95% confidence perventilation is present (RER >1.0) this should be allowed to
interval3; (2) V_ O2 at a given WR deviating by >5e10% of data- settle before commencing the next phase of the test. It is
base values15 or >10% of the predicted value,49 where VO _ important to note that sustained hyperventilation can pre-
2
pred ¼ [5.8  weight (kg)] þ 151 þ (10.1  W)50; or (c) DV_ O =DWR
2
cipitate a premature ‘false positive’ or ‘pseudothreshold’ for
between the two WRs deviating (above or below) from data AT estimation, which can obscure events triggered by the
base values or from a normal of ~10e11 ml min1 W1, with actual threshold (see False positives below).59 Also, if the RER
95% CI ~8.5e12.5 ml min1 W1.51e53 is persistently <0.7, the test should be halted as this is sug-
Ideally, the cycle ergometer should be calibrated at least gestive of inaccurate calibration and the calibration procedure
annually and whenever it is moved (which can disturb the should be repeated.
calibration), using a device such as a dynamic torque meter.
The calibration should be linear from 0 to ~400 watts, and in- Unloaded cycling (3 min)
dependent of pedalling cadence over a physiologically
Unloaded cycling allows functionally limited patients to
reasonable range.54e56 Sudden deviations in the normal slope
acclimate to pedalling. Three minutes is sufficient in healthy
value of the V_ O2 eWR relationship warrant investigation, both
individuals for HR, V_ O2 , V_ CO2 , and V_ E to attain new steady
of cycle ergometer and metabolic cart performance.
states prior to the ramp phase commencing. The patient is
encouraged to adopt a comfortable pedalling cadence, be-
Practicalities of test conduct (Grade C) tween 55 and 75 rpm throughout the test.3,4,15,39

Resting spirometry should be performed to measure forced

vital capacity and forced expiratory volume in 1 s (FEV1). Ramp phase (8e12 min)
It is recommended that this phase is started without providing
any cues to the patient, who should be instructed to continue
pedalling for as long as possible. The limit of tolerance is
defined as the point at which the patient is unable to maintain
the pedalling cadence despite encouragement. The Borg score
may be recorded at the end of the exercise to evaluate sub-
jective effort.

Recovery (~5 min)

Once the load is removed, the patient should be encouraged to
pedal for a further period to prevent venous pooling in the legs
and consequent syncope. Monitoring should continue until
any dysrhythmia or ST changes have reverted to baseline, HR
has fallen to within 10 beats min1 of resting values and blood
pressure has returned to baseline.

_
Fig 1. Biological calibration: steady-state VO2 at 20 and 60 W in a Indications for stopping the test (Grade C)
representative laboratory subject. The relationship between VO _
2
and work rate is 10 ml min1 W1dthus a 40 W increment in An exercise test may be terminated as a result of ostensive
work rate is associated with a 400 ml increment in VO _ . ‘good effort’ (i.e. with symptom limitation) or because of the
2
development of clinically-inappropriate symptoms. The
 490 - Levett et al.

Table 2 Key response variables reported for perioperative Table 4 Key elements in preoperative cardiopulmonary exer-
cardiopulmonary exercise testing cise testing interpretation

Exercise capacity variables 1. Determine the reason for cardiopulmonary exercise

Anaerobic threshold (AT) (ml min1 and ml kg1 min1) testing

Peak O2 uptake (VO_ peak) (ml min1 and ml kg1 min1) 2. Review pertinent medical history and laboratory
2

Peak work rate (WRpeak) (W) information
Cardiorespiratory variables 3. Note overall test quality, assessment of patient effort and
_ -work rate slope (DVO

VO _ =DWR) (ml min1 W1) reasons for test termination
2 2

Heart rate (HR) (beats min1)dresting and peak exercise 4. Use tabular and graphical presentation of the data

Heart rate reserve (HR) (beats min1)dpeak 5. Report exercise capacity using anaerobic threshold and
exercise ¼ maximum predicted heart ratedmeasured _
VO 2peak values
maximum heart rate 6. Report other indices related to perioperative risk e.g.

Oxygen pulse (ml beat1)dresting and peak exercise _ VCO
_
VE= 2 at the anaerobic threshold

Arterial blood pressure (BP; mm Hg)dresting and peak
7. Evaluate exercise limitation and primary cause(s) for this,
exercise
e.g. cardiovascular, respiratory, deconditioning

Arterial O2 saturation (SpO2;%)dresting and peak exercise
8. Comment on perioperative risk implications of the

Tidal volume (VT) (l or ml)dresting and peak exercise
exercise test and suggestions for further investigation/

Respiratory rate (RR) (bpm)dresting and peak exercise
_ (litres min1)dresting and peak exercise referral/preoperative interventions

Ventilation (VE)

Breathing reserve (BR) (litres min1 and % of VE _ at peak
exercise) (BR¼MVV-VEpeak)  

Ventilatory equivalent for O2 VE= _ VO_ a
dat AT or mini-
2 context of individualized risk of continuing the test and
mum value
_ VCO
_ a benefit from gaining more information.

Ventilatory equivalent for CO2 (VE/ 2 ) dat AT or min-
imum value  
_  VCO
_ _ _
2 slope DVE=DVCO2
a

VE (particularly if no definite
AT identified)
Interpretation of the exercise test

End-tidal partial pressure of O2 (PETO2 mm Hg)dresting and Interpretation of a PCPET includes two main elements: (1)
peak exercise
integration and interpretation of the physiological data to

End-tidal partial pressure of CO2 (PETCO2 mm Hg)dresting
and peak exercise
provide a comprehensive description of the patient’s exercise
Spirometry variables (resting) capacity and the main causes of exercise limitation. (Table 4);

Forced expiratory volume in 1 s (FEV1) (l) and (2) interpretation of the implications of the patient’s ex-

Forced vital capacity (FVC) (l) ercise limitation for their perioperative risk and recommen-

Maximum voluntary ventilation (MVV) d directly dations regarding preoperative interventions (beyond the
measured or estimated as FEV1  35e40 (litres min1)
scope of this guideline; to be addressed in a subsequent

Inspiratory capacity (IC) (l)
guideline).
While the former can be standardized, the latter is based on
a
Dimensionless if primary variables are presented in same units. incorporation of functional capacity into the overall patient
preoperative assessment. The latter is an evolving field with a
requirement for frequent (re-)evaluation of the clinical litera-
ture and will be the subject of a later guideline. In this guide-
Table 3 Indications for the premature termination of an ex- line we focus on the interpretation of exercise capacity, which
ercise test (adapted from American Thoracic Society3) is a fundamental consideration in perioperative risk evalua-
tion. We will also discuss the ventilatory equivalents for CO2
Angina as this is associated with surgical outcome in several surgical

>2 mm ST depression if symptomatic or 4 mm if
cohorts.17,26 It is likely that as the field develops other variables
asymptomatic or >1 mm ST elevation

Significant arrhythmias causing symptoms or
may be related to outcome and these guidelines will be
haemodynamic compromise reviewed and revised as appropriate. Detailed interpretation

Fall in systolic blood pressure >20 mm Hg from the highest of underlying cardiac and respiratory pathology is covered
value during the test elsewhere.3e5,12e15 An integrated approach to perioperative

Hypertension >250 mm Hg systolic; >120 mm Hg diastolic CPET interpretation and the key elements of a perioperative

Severe desaturation: SpO2 <80% (lower may be accepted in
CPET report are also considered.
patients with known underlying lung disease)

Loss of coordination

Mental confusion Data averaging and data presentation (Grade C, good

Dizziness or faintness
practice recommendations, unless otherwise stated)
The breath-by-breath data should be averaged prior to
graphical display and interpretation using, for example, a
reasons for stopping the test should be recorded, both from the moving average (e.g. middle five of seven breaths), a breath-
subject’s and the operator’s perspectives. For example, ‘The based average (e.g. three to five breaths), or a time-based
patient stopped pedalling due to fatigue’, ‘The patient failed to average (e.g. ~20 s), to reduce the influence of biological
maintain a cadence greater than 40 rpm for more than one ‘noise’.60,61
minute despite encouragement’, or ‘The patient felt light The procedures for data editing and data averaging should
headed’. Commonly accepted criteria for the operator termi- be applied consistently within a CPET laboratory; otherwise,
nating an exercise test prematurely are listed in Table 3. These results may be adversely influenced.62,63 The quality of the test
are not absolute criteria and should be interpreted within the should also be commented upon in the report.
 Perioperative cardiopulmonary exercise testing - 491

Key exercise response variables and their the mitochondrial O2 consumption at the cytochrome oxi-
physiological basis dase terminus of the electron transport chain.68 Thus,
dysfunction in the responses of the convective pulmonary or
The key response variables typically recorded during the CPET
vascular O2 fluxes, or in the diffusive pulmonary or muscle-
test are summarized in Table 2. A comprehensive description _
tissue O2 fluxes will result in an abnormally low VO 2max .
of these variables may also be found in key position state-
V_ O2peak may reflect the patient’s physiological limits but
ments and policy documents.3e5,12,13
this can only be assumed if there is a plateauing of the
_ eWR relationship as the limit of tolerance is approached.69
VO 2

Reporting exercise capacity or functional capacity Unfortunately not all individuals will exhibit a plateau during
(Grade C, good practice recommendations, unless rapid incremental exercise even when they have attained a
otherwise stated) physiological maximum.70,71 In the absence of a plateau in the
_
VO 2 response, additional criteria may be used to help support
The terms functional capacity, exercise capacity, and exercise _
VO representing a physiologically maximal effort,
2peak
tolerance are used synonymously to describe the patient’s including a peak HR within 10 beats min1 of the age-predicted
ability to perform exercise and thus provide insight into his/ maximum and a peak RER of >1.10.72 It should be noted,
her physiological reserve. Two variables are widely used to however, that pathology or medication may affect either or
describe exercise capacity in perioperative CPET: V_ O2peak and both of these criteria in a patient population, for example,
the AT. These variables are both associated with postoperative chronotropic incompetence or b-blockade reducing the
morbidity and mortality.8 maximum HR response or respiratory-mechanical flow limi-
tation limiting exercise before the generation of a metabolic
_
VO acidosis in severe chronic obstructive pulmonary disease
2peak ((see Table 5 for summary)
resulting in a peak RER < 1. Thus, an effort may be physio-
_
VO 2peak is a metabolic rate defined as the highest oxygen up- logically maximal without these criteria being attained and
take (V_ O2 ) attained on a rapid incremental test at end-exercise. consequently they should be interpreted with caution in the
As such, it is reflective of the patient’s ‘best effort’ but it may light of the entire exercise response. Furthermore, VO _
2peak may
not reflect what was potentially achievable for that patient (i.e. be affected by the patient’s volitional exercise effort.73
it is not necessarily a physiologically maximal end-point). Despite the uncertainty regarding the presence of physio-
The highest VO _ _ _
2 that could be attained
 by a patient is logical limitation at VO 2peak , importantly VO2peak has been
defined as the maximum V_ O2 V_ O2max ‘the oxygen uptake shown to predict both postoperative morbidity and mortality
during an exercise intensity at which actual oxygen uptake in surgical populations and so has predictive clinical utility.11
reaches a maximum beyond which no increase in effort can In addition, it is both easy to identify and reproducible. A
raise it’ (a physiological end point).64 Rigorous determination good patient effort is aided by familiarization prior to the test
of V_ O2max relies on demonstration of a plateau in VO _
2 in as well as encouragement by the investigator during the later
the face of increasing WR, e.g. VO _ increasing by
2 stages of the test.
<2 ml kg1 min1 65 ( or 50% of the predicted increase over 1 V_ O2peak should be calculated as an averaged value over a
minute). The classical approach for determining V_ O2max is short period extending from the end-exercise point back into
demanding as it requires the completion of several discrete the incremental phase to minimize the influence of breath-to-
exhausting constant WR tests.66,67 VO _
2max reflects the breath noise, i.e. capturing the true end-point without
attainment of a physiological limitation at one or more points weighting it unduly towards submaximal breath values.63,74 A
in the O2 transport pathway between the lungs and the site of reasonable choice is a period of ~20 s or ~three to five breaths,
with the value being reported, as an absolute value (ml min1
or litres min1) or indexed to bodyweight (ml kg1 min1). With
, good subject effort, VO _
2peak is independent of the WR incre-
Table 5 V O2;peak definition, identification and key
mentation rate.75 However, this is not the case for peak WR,
characteristics
which is progressively greater the faster the rate of WR in-
_
VO crease (i.e. the greater the incremental ramp gradient) because
2peak Definition, Measurement, and Key Characteristics
of the underlying V_ O2 response kinetics.75 As a consequence,
_
VO _
2peak is a metabolic rate defined as the highest VO2 peak WR varies with the ramp gradient and consequently is
attained on a rapid incremental test at end-exercise not as reproducible as V_ O2peak .
In summary, V_ O2peak is a measure of maximal exercise ca-
_
VO 2peak should be calculated as an averaged value over pacity but may be affected by volition. Practically, V_ O2peak is
~20 s or ~three to five breaths easy to identify and reproducible. Importantly, it predicts
_ 1 postoperative outcome in major surgical patients.
VO 2peak should be reported as an absolute value (ml min
or litres min1) and indexed to bodyweight (ml
kg1 min1 ))
Anaerobic Threshold (AT) (Table 6 for summary)
_
VO The AT provides an index of submaximal, sustainable exercise
2peak is reproducible and is independent of the ramp
gradient capacity, and if present cannot be volitionally influenced by
the patient. Importantly, it predicts postoperative complica-
_
VO 2peak may be affected by patient volition tions and mortality in a wide range of surgical populations
with more precision than other CPET variables.11
_
VO 2peak is associated with post-operative morbidity and The AT is a metabolic rate defined as the VO _
2 above which
mortality in the majority of clinical cohorts
arterial [lactate] first begins to increase systematically during
incremental exercise.76 The lactate accumulates as a
 492 - Levett et al.

AT Criterion 1: Excess VCO2 above the AT is identified using

Table 6 Anaerobic threshold (AT) definition, measurement the V-Slope method:
and key characteristics
The increasing anaerobic glycolysis above the AT results in
ATddefinition, identification, and key characteristics a progressive metabolic acidosis. This is buffered to an extent
by intra- and extracellular bicarbonate [HCOe 3 ] in the exer-
The AT is a metabolic rate expressed in ml kg¡1 min¡1 or cising muscle. Consequently, arterial [HCOe
_ 3 ] starts to decrease
ml min¡1. It is defined as the VO 2 above which arterial
as WR increases above the AT, essentially mirroring the
(lactate) first begins to increase systematically during
incremental exercise reflecting increased glycolysis. developing [lactate] increase. These buffering reactions
generate CO2 that is additional to the CO2 produced during
The AT should be identified using a three-criterion aerobic metabolism (i.e. ‘excess’ V_ CO2 ). Thus VCO _
2 is supple-
discrimination technique (Fig. 4) mented and the VCO _ V_ O relationship steepens at the AT
2 e 2

_ _ causing an inflection in the V_ CO2 eVO _

2 response. The AT is
AT Criterion 1: identify excess VCO 2 relative to VO2 above
identified by this inflection point in the VCO _ _
the AT by: 2 eVO2 response
and can be detected by the V-slope method (Fig. 2) or by the

Modified V-slope: (Fig 3) The tangential breakpoint in the modified V-slope method (Fig. 3).84,85 This inflection point has
_
VCO _
2  VO2 relationship from a line with a gradient of been demonstrated to coincide with the first point of sys-
_
one (‘line of one; ’ DVCO _
2 /DV O2 ¼ 1.0). The breakpoint is tematic increase in arterial [lactate] and decrease in arterial
identified by moving the line of one from the right until
_ _ _ [HCOe 3 ] and thus does not originate in either an acceleration of
it first impacts on the VCO 2 eVO2 relationship. The VO 2
at which this occurs is taken as the AT. aerobic metabolism or in acute hyperventilation relative to
OR CO2.84
_

V-slope: (Fig. 2) The inflection point in the VCO _
2 e VO2 V-slope method (Fig. 2). At the start of the incremental
relationship identified as the intersection point of the phase of the test, the V_ CO2 response initially lags behind that of
linear regression lines of the S1 (below AT) and S2 (above _
VO _
2 reflecting its slower response kinetics. The VCO2 then in-
AT) components. The initial kinetic portion of the rela- _ . The slope of the V_ CO eVO _
creases linearly with respect to VO 2 2 2
tionship and the portion above the respiratory
compensation point are excluded from the linear relationship (DV_ CO =DV_ O ) in this linear region has been
2 2
regression. termed S1 and has a value typically slightly less than one in
patients on a typical western diet (i.e. reflecting the influence of
AT Criterion 2: identify hyperventilation relative to oxygen the respiratory quotient). Immediately above the AT, the
(Fig. 4) _ _
gradient of the VCO 2  V O2 relationship becomes steeper as
_ VO
_ _eVO _ excess VCO _

The VE/ 2 2 relationship having been flat or 2 develops, with a slope termed S2. The AT is the
decreasing begins to increase and does not return to point at which the linear regression lines of the S1 and S2
baseline. components intersect (the S1eS2 inflection point). The initial
_

The PETO2VO 2 relationship having been declining or portion of the V_ CO2  VO _
2 relationship that is distorted by
flat begins to increase and does not return to the changes in body CO2 storesdthe ‘kinetic’ phase (approximately
baseline.
the first 60 s exercise) and the portion of the curve above the
AT Criterion 3: exclude hyperventilation relative to CO2 respiratory compensation point (RCP; defined as >15% change
(Fig. 4) at the AT inflection point identified by criteria 1 in gradient in V_ EeV_ CO2 relationship are excluded from the
and 2: analysis.84 In those cases in which there is not a sufficiently
linear S2 region, the first detectable point of VCO_
_ VCO
_ 2 acceleration

The VE/ 2 relationship remains constant or continues
_ VO
_ relative to V_ O2 can be used as an alternative AT estimator.
to decrease at the point where VE= 2 starts to rise
systematically. Modified V-slope method (Fig. 3). The modified V-slope

There is no reciprocal decrease in PETCO2 at the point method is an alternative to the V-slope method, which has
where PETO2 starts to rise systematically. particular utility when the V_ CO2 eV_ O2 relationship cannot be
partitioned into two linear segments (i.e. a curvilinear
response), which is common. This is based on the assumption
that the S1 slope should have a value of 1.0 or less (the highest
consequence of anaerobic glycolysis and its associated meta-
respiratory quotient, for carbohydrate, being 1.0) and that the
bolic acidosis. However, the causes of this remain con- _
S2 slope should have a value >1.0 (because of excess VCO 2 ).
troversial.15,77e82 The AT may also be termed the lactate _ _
Ensuring that the VO2 and VCO2 axes are scaled identically, the
threshold, lactic acidosis threshold, ventilatory threshold, or
effective S1eS2 inflection point can be estimated by ‘running
gas exchange threshold.15 In the perioperative CPET literature,
in’ a unitary tangent or ‘line of one’ (i.e. line with gradient
the term anaerobic threshold has been used consistently and _ _
DVCO 2 =DVO2 ¼ 1.0) from the right until it first impacts on the
is consequently preferred (Grade D). _ _ _
VCO 2  VO2 relationship. The VO2 at which this occurs is taken
The AT is conventionally estimated non-invasively from _
as the AT, as all higher data points manifest excess VCO 2 (i.e.
respired gas measurements using an incremental ramp exer-
with DV_ CO2 =DV_ O2 > 1.0.).
cise test.3,15,83 The AT should be identified using a three point
The V-slope and modified V-slope methods depend solely
discrimination technique as described by Whipp and col-
on the physicochemical reaction of metabolically-produced
leagues.83 The modified V-slope method can be used to iden-
_ hydrogen ions with bicarbonate and as such the occurrence
tify the inflection point in the CO2 output (VCO 2 ) response and
of the breakpoint is independent of chemoreceptor sensitivity
this should be supported by evaluating changes in the venti-
and the ventilatory response to exercise. The V-slope methods
latory equivalents and end-tidal partial pressures of O2 and
are therefore particularly useful for AT estimation in condi-
CO2 to confirm hyperventilation with respect to oxygen but not
tions characterized by poor respiratory chemosensitivity or
to carbon dioxide.83e85 The methods used to identify the AT
premature respiratoryemechanical limitation that prevent
are summarized in Table 6.
 Perioperative cardiopulmonary exercise testing - 493

Fig 2. Example of a V-slope estimation in a normal individual.

_
The VCO _
2  VO2 relationship is partitioned into linear S1 and S2
regions within the region of interest demarcated by the two
vertical lines (left: to exclude the initial kinetic phase of
response, approximately 60s; right: to exclude respiratory
compensation, >15% change in gradient of the VE _  VCO
_
2 rela-
tionship).84 Their point of intersection (vertical green line) rep-
_
resents the point at which ‘excess’ VCO 2 first becomes evident,
and is taken to represent the anaerobic threshold. See text for
further details.

Fig 4. Example of comprehensive anaerobic threshold estima-

tion for the normal individual depicted in Figures 2 and 3. (A)
_
The VCO _
2  VO2 relationship, with the modified V-slope index of
anaerobic threshold estimation. (B) The responses of the
ventilatory equivalents for CO2 and O2 (VE=VCO _ _ _
2 , VE=VO2 )
expressed as a function of VO _ VO
_ . The VE= _ relationship having
2 2
been flat begins to increase systematically while the VE= _
_ VCO
2,
continues to decrease. (C) The responses of the end-tidal PCO2
Fig 3. Example of a modified V-slope estimation for the normal and end tidal PO2 (PETCO2 and PETO2 ) expressed as a function of
_ . PET increases without a reciprocal decrease in PETCO2
VO
individual depicted in Figure 2. A unitary tangent or ‘line of one’ 2 O2
_
(black line, with a slope, ΔVCO _ because respiratory compensation for metabolic acidosis
2  ΔVO2 , ¼ 1.0) has been ‘run in’
_
to the VCO _ causing a reduction in PaCO2 does not occur until several mi-
2  VO2 relationship from the right. Its first point of
impact (vertical green line) represents the point at which excess nutes later for rapid incremental exercise tests. The estimated
_
VCO anaerobic threshold is marked with the vertical green line on all
2 first becomes evident, and is taken to represent the
anaerobic threshold. See text for further details. three plots. See text for further details.

At the AT, the excess VCO _

the development of a discernible V_ E response to excess V_ CO2 2 generated from anaerobic
glycolysis results in a proportional increase in V_ E. There is no
(e.g. chronic obstructive pulmonary disease).84
equivalent increase in V_ O2 at this point. Consequently VE _ is
AT Criterion 2: Hyperventilation relative to O2: the ventila- _
driven by VCO 2 and starts to increase at a greater rate with
tory equivalent for O2 and end tidal PO2 at the AT (Fig. 4) respect to VO _ ; i.e. hyperventilation relative to O2. This is
2
 494 - Levett et al.

Fig 5. Suggested Tabular Data minimum dataset for perioperative CPET report.
 Perioperative cardiopulmonary exercise testing - 495

_ V_ O and alveolar end-tidal PO2 (PETO2) both

reflected in VE= initially maintained above the AT because the normal
2
starting to increase at the AT. Thus at the AT the following compensatory hyperventilation expected with an exercise-
_ V_ O  V_ O relationship having been flat or
occur: (1) the VE= induced metabolic acidosis (which lowers the PaCO2 and
2 2
decreasing to a nadir begins to increase systematically and (2) thereby compensates for the falling pH) does not occur
_
the PETO2 eVO immediately at the AT for rapid incremental exercise.86e88
2 relationship having been declining or flat begins
to increase systematically. Rather, respiratory compensation is delayed to a somewhat
higher WRddefined as the RCP. The exact location of the RCP
AT Criterion 3: no hyperventilation relative to CO2: the
depends on factors such as the WR incrementation rate and
ventilatory equivalent for CO2 and end tidal co2 at the AT
peripheral (carotid body) chemoreflex responsiveness.89,90
_
The V_ CO2 eVO 2 (V-slope) relationship and hyperventilation This delay, which is possibly consequent to slow carotid che-
relative to oxygen do not alone provide a sufficiently rigorous mosensory response kinetics generates a phase of ‘isocapnic
criterion for AT estimation. It is important that non-specific buffering’ between the AT and RCP within which neither
hyperventilation (with an attendant fall in arterial PCO2 PETCO2 nor PaCO2 decline (i.e. there is no immediate hyper-
(PaCO2 )) due to factors such as anxiety, pain, or arterial hypo- ventilation relative to CO2 at the AT).90 To ensure that the in-
xaemia is first excluded as a cause of the excess VCO_
2 identi- flection point identified as the AT is not as a result of non-
fied by the V-slope method. This requires examination of the specific hyperventilation that could be from pain, hypo-
ventilatory consequences of the excess V_ CO2 . Below the AT, VE
_ xaemia or primary hyperventilation syndrome, hyperventila-
is proportional to V_ CO such that alveolar end-tidal PCO
2 2
tion relative to CO2 at the AT must be excluded by confirming
(PETCO2) and arterial PCO2 remain stable. This proportionality is _ VCO
the following: (1) VE= _
2 remains constant or continues to

Fig 6. Example of a nine-panel,

CPET ,
display for ,the normal individual depicted in Figures 2e4, (modified European Respiratory Society
format).
,
TOP ROW: panel 1: V CO 2 vs ,
V O2,; Panel 2: ,V O2, vs work
,
rate; and Panel 3:, HR and O2 pulse (V O2 =HR/HR error should read VO2/HR and
HR) vs V O2 . SECOND ROW: Panel 4: V E=V CO2 and V E=V O2 vs V O2 ; Panel 5: VE _ vs V CO ; and Panel 6: VT vs VE.
_ BOTTOM ROW Panel 7: PET and
, 2 , , , , O2
PETCO2 vs VO_
2 (SpO2 may be included); Panel 8: RER vs V O2 ; and Panel 9: unassigned, but here showing V E=V O2 and V E=V CO2 vs time.
Suggested clusters for interpretation: AT estimation (green vertical line), [panels: 1,4,7 (and 9)] cardiovascular limitation, (panels: 2,3,4,5)
respiratory limitation, (panels: 4,5,6 and 7). RER, Respiratory exchange ratio. See text for further details.
 496 - Levett et al.

decrease at the AT as the VE= _ V_ O starts to rise systematically threshold-like behaviour (i.e. the standard non-invasive criteria
2
and (2) the absence of a fall in PETCO2 at the AT. This is because for AT discrimination are met) but at a time when arterial
ventilatory compensation for the metabolic acidosis above the (lactate) has not yet started to increase. The clue to pseudo-
AT which causes a reduction in PaCO2 does not occur until threshold behaviour is a concurrent systematic fall in RER to
several minutes later during rapid incremental exercise tests abnormally low values (consequent to the transiently high CO2
(i.e.at RCP). storage rate) immediately prior to the supposed threshold.
Above the RCP towards the end of the exercise test, the Thus, the presence of prolonged volitional hyperventilation
_
VCO _ _ _
2  VO2 and VE  V CO2 relationships steepen, as respira- immediately prior to or at the start of a ramp test requires the
tory compensation develops in response to the metabolic AT estimate to be interpreted with caution.
acidosis of exercise; i.e. reflecting the loss of CO2 from arterial
stores as PaCO2 is driven down by hyperventilation.
Normal values and indexing exercise capacity
variables
Anaerobic Threshold Identification (Table 6 for summary)
Several series of reference values for incremental exercise test
In summary, rigorous AT estimation requires that support be indices including V_ O2peak have been published.15,91 The most
sought not only from excess VCO _
2 but also from the profiles of widely used in clinical practice are those produced by Hansen
the ventilatory equivalents and end-tidal partial pressures for and Jones.92,93 These values were obtained from North Amer-
O2 and CO2 to establish the development of hyperventilation ican populations and have not been specifically validated in a
relative to O2 but not with respect to CO2. This requires the UK surgical population. With these limitations in mind, refer-
demonstration that, coincident with the modified V-slope ence values are useful to identify an abnormal response and
break point, V_ E=VO
_
2 and PETO2 start to increase (i.e. hyper- the reference values used should be standardized within a
ventilation relative to O2), but with no coincident increase in CPET laboratory. A common convention used to relate
_ VCO
VE= _ measured VO _
2 or decrease in PETCO2 (i.e. no hyperventilation rela- 2peak to reference values is: >80% not abnormal or
tive to CO2). In practice, it can be the case that noisiness in the within the 95% confidence interval; 71e80% mildly reduced;
data set may preclude reliable discrimination of all three break 51e70% moderately reduced; and < 50% severely reduced.91 It
points simultaneously, in which case greater weight should be should be appreciated however that the majority of clinical
placed on the V-slope indices. cohorts in surgical patients have reported VO _
2peak as an abso-
lute value indexed to body weight rather than as a percentage
of predicted value.11 As a consequence the published risk
Automated Anaerobic Threshold
thresholds for surgical patients preoperatively are absolute
The V-slope method is used in the majority of commercial values of AT and V_ O2peak indexed to body weight. Indexing to
metabolic carts to identify an automated AT. These automated body weight may have implications for patients at extremes of
ATs should only ever be used as a guide and should be inter- bodyweight, potentially over-estimating risk in the morbidly
preted with caution. In the presence of a curvilinear V_ CO2 eVO
_
2 obese patient and under-estimating risk in cachectic patients.
relationship linear regression may not accurately identify the Despite this consideration, in morbidly obese bariatric pa-
AT. In addition, care should be taken to ensure that the kinetic tients, AT indexed to absolute body weight was more predictive
phase at the start of the incremental ramp and the portion of of outcome than AT indexed to body surface area or to ideal
the data above the respiratory compensation point are body weight.24 Caution should be used when interpreting ex-
excluded from the regression analysis, which requires manual ercise capacity values indexed to body weight in patients with
interrogation of the data. Finally, automated V-slope methods a low BMI. Indexing to ideal bodyweight may be considered.
do not use confirmation of the AT by the ventilatory criteria
discussed above and thus, particularly in the presence of noisy _ VCO
_
Ventilatory equivalents for carbon dioxide VE= 2
data, may not accurately identify the AT.
The ventilatory equivalent for carbon dioxide (VE= _ VCO
_
2 ) is the
ratio of minute ventilation ðV_ EÞ to CO2 output (V_ CO2 ) and as
Anaerobic Threshold - False positives or pseudothresholds
such is an index of ‘ventilatory efficiency.’ Greater-than-
Transient volitional hyperventilation occurring just prior to the normal values indicate that either the physiological dead
start of a ramp exercise test or in its early stages can compro- space fraction of the breath (dead space/tidal volume, reflective
mise AT estimation and cause a pseudothreshold, where the of pulmonary gas exchange efficiency) is abnormally increased,
criteria for an AT can be identified but before the onset of the PaCO2 is decreased (e.g. acute hyperventilation), or both.3,15
exercise-induced metabolic acidosis.59 In such circumstances, Thus, V_ E=VCO _
2 gives insight into the efficiency of ven-
acute hyperventilation causes acute wash-out of CO2 from tilationeperfusion matching in the lung and the efficiency of
rapidly exchanging body stores. Consequently, at the start of gas exchange. The slope of the linear V_ E=VCO _
2 relationship
the test, a greater-than-normal proportion of the metabolic CO2 _
ΔVE=Δ V_ CO2 , the ventilatory equivalent for CO2 at the AT
production will initially be diverted into the depleted body _ V_ CO
(VE= 2AT ) or, if the AT cannot reliably be estimated, the
stores to recharge them back to normal levels, with less minimum value of V_ E=V_ CO2 (V_ E=VCO _
2min ) are numerically
therefore reaching the lungs and less being cleared at the similar.15 This allows the investigator to choose which of the
mouth. Over this period, the VCO _ _
2 eV O2 slope and RER are thus three is most amenable to measurement in the test. The values
abnormally low. When the CO2 stores have subsequently been are elevated in heart failure, respiratory disease, and pulmo-
repleted, V_ CO2 and RER will be restored towards normal levels, nary hypertension.3,15,94 Furthermore, elevated V_ E=VCO _
2 is
resulting in a relative steepening of the V_ CO2 eV_ O2 relationship predictive of mortality and disease progression in cardiac fail-
and an apparent threshold. This relative acceleration of V_ CO2 ure,95e97 and mortality and other outcomes in chronic
relative to V_ O2 will, in turn, elicit proportional increases in VE_ obstructive pulmonary disease and other respiratory dis-
and therefore V_ E=VO_ , but no change in V_ E=VCO
2
_
2 . This creates eases.14,98,99 In the perioperative setting, V_ E=VCO _
2 at the
 Perioperative cardiopulmonary exercise testing - 497

anaerobic threshold is associated with morbidity and mortality Summary

in hepatobiliary surgery,100,101 abdominal aortic aneurysm
The dynamic metabolic challenge imposed by perioperative
surgery,26,102 urological surgery,103 and mixed surgical co-
_ V_ CO CPET provides an objective means of evaluating exercise ca-
horts.17 Recent thoracic surgical cohorts suggest the VE= 2
pacity. It can be used to evaluate chronic comorbidities and
slope may be more predictive of postoperative mortality and
_ may enable identification of new pathology that requires
pulmonary complications than VO 2peak , although this requires
treatment, optimization, or both preoperatively. The data
further clarification.104e106 However, an association between
_ VCO
_ derived from CPET may be used to inform collaborative
VE= 2 and surgical outcome has not been identified in all
(shared) decision-making and the process of consent, to triage
cohorts, with some studies reporting no predictive associa-
patients to high dependency care, and to direct individualized
tion.16 Further studies are required to clarify the additional risk
exercise training programmes pre- and postoperatively. If
conferred by abnormal ventilatory efficiency in addition to
CPET data are to help determine surgical patients periopera-
impaired exercise capacity.
tive care, it is essential that CPET procedures are reproducible
and of high quality. This requires laboratory equipment to be
The perioperative CPET report (Grade C, good maintained, calibrated, and validated regularly. Standardized
exercise protocols with standardized graphical display of key
practice recommendations, unless otherwise
variables to describe exercise capacity, and to investigate
stated) possible causes of exercise intolerance should be employed.
It is recommended that the perioperative CPET report in- These guidelines provide direction for clinicians performing
cludes: (1) reason for referral, relevant past medical history, and interpreting CPET on perioperative patients.
and drug history; (2) CPET data, presented in tabular form and
graphically; (3) a description of the patient’s exercise capacity
and its normality or otherwise; (4) a summary of the cause(s) of
Authors’ contributions
exercise limitation if exercise capacity is abnormal; (5) a Developed concept and reviewed literature to establish stan-
statement about the risk implications of the exercise limita- dards: D.Z.H.L., S.J., M.P.W.G., M.S., J.C., C.S., G.D., J.W., M.R.,
tion and other identified abnormalities (Grade D); and (6) P.O., S.W.
suggestions for possible referrals and interventions preoper- Wrote first draft of the paper: D.Z.H.L., S.J., M.P.W.G., M.S., J.C.
atively (Grade D). Critical revision and review of the paper: D.Z.H.L., S.J.,
An example of a tabular report with a suggested minimum M.P.W.G., M.S., J.C., C.S., G.D., J.W., M.R., P.O., S.W.
data set is presented in Fig. 5. In addition it is conventional
practice to present CPET data graphically in the report in a
multipanel format, typically with eight or nine panels Acknowledgements
(Fig. 6).3,4,15 It should be emphasized that the difference be- These guidelines have been endorsed by the Association of
tween the original Wasserman and the European Respiratory Respiratory Technology and Physiology. We would like to
Society formats lies more in data presentation rather than in thank the late Professor Brian Whipp who contributed signif-
overall content. An advantage of the European Respiratory icantly to these written guidelines both directly and via his
Society format in the perioperative setting is that the panels mentorship of several of the authors. We also thank Helen
required for AT estimation are conveniently placed in a single Luery and the presenters and delegates at the UK PCPET
column to aid discrimination decisions across the three cri- meeting and courses, as well as other courses we have atten-
terion indices (a practice that has been adopted in the updated ded, who have helped to refine the ideas presented within
Wasserman 2011 format15). For this reason, the European these guidelines.
Respiratory Society format tends to be preferred for perioper-
ative CPET, with the option for including a ninth panel as a
non-assigned panel that can usefully be used for tailoring test Declarations of interest
results to allow, for example, tracking of temporal responses D.Z.H.L.: spouse of M.P.G.W. M.P.W.G.: Unrestricted grant to
of interest (Fig. 6). Interpretation with regard to normality is institutiondSphere Medical Ltd; Honorarium and travel sup-
done against published normal-value databases and port for lecturedEdwards Lifesciences; travel and accom-
algorithms.3,15,91 modationdSmiths Medical Ltd.

Risk thresholds in perioperative CPET Funding

Specific recommendations about risk thresholds and recom- Some work undertaken at University Southampton NHS
mendations for perioperative care are outside the remit of Foundation TrustdUniversity of Southampton NIHR Respira-
these guidelines. As surgical and perioperative practice tory Biomedical Research Unit, which received a portion of
evolves, risk thresholds are likely to change. Furthermore, it is funding from the UK Department of Health Research
likely that the variables used to predict risk are likely to evolve Biomedical Research Units funding scheme. All funding was
and expand. Practitioners should evaluate local data and unrestricted. The funders had no role in study design, data
published cohorts on a regular basis to guide these recom- collection, and analysis, decision to publish, or preparation of
mendations. Further research is required to accurately the manuscript.
enumerate the absolute risk of morbidity and mortality asso-
ciated with different levels of functional capacity. National
data collection is planned by POETTS, to provide access to
Appendices: Supplementary data
contemporaneous risk threshold data. A summary of current Supplementary data related to this article can be found at
case cohorts is presented in Supplementary Appendix S2. https://doi.org/10.1016/j.bja.2017.10.020.
 498 - Levett et al.

References 18. Older P. Cardiopulmonary exercise testing as a screening

test for perioperative management of major surgery in
1. Simpson JC, Sutton H, Grocott M. Cardiopulmonary ex- the elderly. Chest 1999; 116: 355e62
ercise testingda survey of current use in England. 19. West MA, Parry MG, Lythgoe D, et al. Cardiopulmonary
J Intensive Care Soc 2009; 10: 275e8 exercise testing for the prediction of morbidity risk after
2. Huddart S, Young EL, Smith RL, Holt PJ, Prabhu PK. Pre- rectal cancer surgery. Br J Surg 2014; 101: 1166e72
operative cardiopulmonary exercise testing in Eng- 20. West MA, Lythgoe D, Barben CP, et al. Cardiopulmonary
landda national survey. Perioper Med (Lond) 2013; 2: 4 exercise variables are associated with postoperative
3. American Thoracic Society. ATS/ACCP statement on morbidity after major colonic surgery: a prospective
cardiopulmonary exercise testing. Am J Respir Crit Care blinded observational study. Br J Anaesth 2014; 112:
Med 2003; 167: 211e77 665e71
4. European Respiratory Society. Clinical exercise testing 21. Prentis JM, Trenell MI, Vasdev N, et al. Impaired cardio-
with reference to lung diseases: indications, standardi- pulmonary reserve in an elderly population is related to
zation and interpretation strategies. ERS Task Force on postoperative morbidity and length of hospital stay after
Standardization of Clinical Exercise Testing. European radical cystectomy. BJU Int 2013; 112: E13e9
Respiratory Society. Eur Respir J 1997; 10: 2662e89 22. Ausania F, Snowden CP, Prentis JM, et al. Effects of low
5. Myers J, Arena R, Franklin B, et al. Recommendations for cardiopulmonary reserve on pancreatic leak following
clinical exercise laboratories: a scientific statement from pancreaticoduodenectomy. Br J Surg 2012; 99: 1290e4
the American Heart Association. Circulation 2009; 119: 23. Prentis JM, Manas DM, Trenell MI, Hudson M, Jones DJ,
3144e61 Snowden CP. Submaximal cardiopulmonary exercise
6. Smith TB, Stonell C, Purkayastha S, Paraskevas P. Car- testing predicts 90-day survival after liver trans-
diopulmonary exercise testing as a risk assessment plantation. Liver Transpl 2012; 18: 152e9
method in non cardio-pulmonary surgery: a systematic 24. Hennis PJ, Meale PM, Hurst RA, et al. Cardiopulmonary
review. Anaesthesia 2009; 64: 883e93 exercise testing predicts postoperative outcome in pa-
7. Hennis P, Meale P, Grocott M. Cardiopulmonary exercise tients undergoing gastric bypass surgery. Br J Anaesth
testing for the evaluation of perioperative risk in non- 2012; 109: 566e71
cardiopulmonary surgery. Postgrad Med J 2011; 87: 550e7 25. McCullough PA. Cardiorespiratory fitness and short-term
8. Moran J, Wilson F, Guinan E, McCormick P, Hussey J, complications after bariatric surgery. Chest 2006; 130:
Moriarty J. Role of cardiopulmonary exercise testing as a 517e25
risk-assessment method in patients undergoing intra- 26. Carlisle J, Swart M. Mid-term survival after abdominal
abdominal surgery: a systematic review. Br J Anaesth aortic aneurysm surgery predicted by cardiopulmonary
2016; 116: 177e91 exercise testing. Br J Surg 2007; 94: 966e9
9. Eccles M, Mason J. How to develop cost-conscious 27. Brutsche MH, Spiliopoulos A, Bolliger CT, Licker M,
guidelines. Health Technol Assess 2001; 5: 1e69 Frey JG, Tschopp JM. Exercise capacity and extent of
10. Mann T. Clinical Guidelines: using clinical guidelines to resection as predictors of surgical risk in lung cancer. Eur
improve patient care within the NHS. London: NHS Execu- Respir J 2000; 15: 828e32
tive; 1996 28. Benzo R, Kelley GA, Recchi L, Hofman A, Sciurba F.
11. Moran J, Wilson F, Guinan E, McCormick P, Hussey J, Complications of lung resection and exercise capacity: a
Moriarty J. The preoperative use of field tests of exercise meta-analysis. Respir Med 2007; 101: 1790e7
tolerance to predict postoperative outcome in intra- 29. Brunelli A, Charloux A, Bolliger CT, et al. ERS/ESTS clin-
abdominal surgery: a systematic review. J Clin Anesth ical guidelines on fitness for radical therapy in lung
2016; 35: 446e55 cancer patients (surgery and chemo-radiotherapy). Eur
12. Palange P, Ward SA, Carlsen KH, et al. Recommendations Respir J 2009; 34: 17e41
on the use of exercise testing in clinical practice. Eur 30. Forshaw M, Strauss D, Davies A, et al. Is cardiopulmo-
Respir J 2007; 29: 185e209 nary exercise testing a useful test before esoph-
13. Balady GJ, Arena R, Sietsema K, et al. Clinician’s Guide to agectomy? Ann Thorac Surg 2008; 85: 294e9
cardiopulmonary exercise testing in adults: a scientific 31. Older P, Smith R, Courtney P, Hone R. Preoperative
statement from the American Heart Association. Circu- evaluation of cardiac failure and ischemia in elderly
lation 2010; 122: 191e225 patients by cardiopulmonary exercise testing. Chest 1993
14. Puente-Maestu L, Palange P, Casaburi R, et al. Use of ex- Sep; 104(3): 701e4
ercise testing in the evaluation of interventional efficacy: 32. Jack S, West MA, Raw D, et al. The effect of neoadjuvant
an official ERS statement. Eur Respir J 2016; 47: 429e60 chemotherapy on physical fitness and survival in pa-
15. Wasserman KHJ, Sue D, Stringer W, Sietsema K, Sun XG, tients undergoing oesophagogastric cancer surgery. Eur J
Whipp BJ. Principles of exercise testing and interpretation. 5th Surg Oncol 2014; 40: 1313e20
ed. Philadelphia: Lippincott Williams and Wilkins; 2011 33. West MA, Loughney L, Lythgoe D, et al. Effect of pre-
16. Snowden CP, Prentis JM, Anderson HL, et al. Submaximal habilitation on objectively measured physical fitness
cardiopulmonary exercise testing predicts complications after neoadjuvant treatment in preoperative rectal can-
and hospital length of stay in patients undergoing major cer patients: a blinded interventional pilot study. Br J
elective surgery. Ann Surg 2010; 251: 535e41 Anaesth 2015; 114: 244e51
17. Wilson R, Davies S, Yates D, Redman J, Stone M. Impaired 34. Barakat HM, Shahin Y, Khan JA, McCollum PT, Chetter IC.
functional capacity is associated with all-cause mortality Preoperative supervised exercise improves outcomes
after major elective intra-abdominal surgery. Br J Anaesth after elective abdominal aortic aneurysm repair: a ran-
2010 domized controlled trial. Ann Surg 2016; 264: 47e53
 Perioperative cardiopulmonary exercise testing - 499

35. Myers J, Bellin D. Ramp exercise protocols for clinical and cycle ergometer exercise. Eur J Appl Physiol Occup Physiol
cardiopulmonary exercise testing. Sports Med 2000; 30: 1988; 57: 140e5
23e9 54. Russell JC, Dale JD. Dynamic torquemeter calibration of
36. Plumb JO, Otto JM, Grocott MP. ʻBlood doping’ from bicycle ergometers. J Appl Physiol 1986; 61: 1217e20
Armstrong to prehabilitation: manipulation of blood to 55. Van Praagh E, Bedu M, Roddier P, Coudert J. A simple
improve performance in athletes and physiological calibration method for mechanically braked cycle er-
reserve in patients. Extrem Physiol Med 2016; 5: 5 gometers. Int J Sports Med 1992; 13: 27e30
37. Wright SE, Pearce B, Snowden CP, Anderson H, Wallis JP. 56. Clark J, Greenleaf J. Electronic bicycle ergometer: a sim-
Cardiopulmonary exercise testing before and after blood ple calibration procedure. J Appl Physiol 1971; 30: 440e2
transfusion: a prospective clinical study. Br J Anaesth 57. Gandevia B, Hugh-Jones P. Terminology for measure-
2014; 113: 91e6 ments of ventilatory capacity; a report to the thoracic
38. Whipp BJ, Davis JA, Torres F, Wasserman K. A test to society. Thorax 1957; 12: 290e3
determine parameters of aerobic function during exer- 58. Campbell SC. A comparison of the maximum voluntary
cise. J Appl Physiol Respir Environ Exerc Physiol 1981; 50: ventilation with the forced expiratory volume in one
217e21 second: an assessment of subject cooperation. J Occup
39. Porszasz J, Stringer W, Casaburi R. Equipment, measure- Med 1982; 24: 531e3
ments and quality control in clinical exercise testing. Shef- 59. Whipp B. Physiological mechanisms dissociating pul-
field: European Respiratory Society; 2007 monary CO2 and O2 exchange dynamics during exercise
40. Loughney L, West M, Pintus S, et al. Comparison of ox- in humans. Exp Physiol 2007; 92: 347e55
ygen uptake during arm or leg cardiopulmonary exercise 60. Lamarra N, Whipp BJ, Ward SA, Wasserman K. Effect of
testing in vascular surgery patients and control subjects. interbreath fluctuations on characterizing exercise gas
Br J Anaesth 2014; 112: 57e65 exchange kinetics. J Appl Physiol (1985) 1987; 62: 2003e12
41. Wasserman KHJ, Sue D, Stringer W, Whipp BJ. Principles of 61. Whipp BJ, Rossiter HB. The kinetics of oxygen uptake:
exercise testing and interpretation. 4th ed. Philadelphia: physiological inferences from the parameters. London: Rout-
Lippincott, Williams and Wilkins; 2004 ledge; 2005
42. Ahmadian HR, Sclafani JJ, Emmons EE, Morris MJ, 62. Johnson JS, Carlson JJ, Van der Laan RL, Langholz DE.
Leclerc KM, Slim AM. Comparison of predicted exercise Effects of sampling interval on peak oxygen consump-
capacity equations and the effect of actual versus ideal tion in patients evaluated for heart transplantation.
body weight among subjects undergoing cardiopulmo- Chest 1998; 113: 816e9
nary exercise testing. Cardiol Res Pract 2013; 2013, 63. Myers J, Walsh D, Sullivan M, Froelicher V. Effect of
940170 sampling on variability and plateau in oxygen uptake.
43. Borg GA. Psychophysical bases of perceived exertion. J Appl Physiol 1990; 68: 404e10
Med Sci Sports Exerc 1982; 14: 377e81 64. Hill AV, Long CN, Lupton H. Muscular exercise, lactic acid
44. Stark RD, Gambles SA, Lewis JA. Methods to assess and the supply and utilization of oxygen. VI. The oxygen
breathlessness in healthy subjects: a critical evaluation debt at the end of exercise. Proc R Soc Lond B Biol Sci 1924;
and application to analyse the acute effects of diazepam 97: 127e37
and promethazine on breathlessness induced by exer- 65. Shephard RJ, Allen C, Benade AJ, et al. The maximum
cise or by exposure to raised levels of carbon dioxide. Clin oxygen intake. An international reference standard of
Sci (Lond) 1981; 61: 429e39 cardiorespiratory fitness. Bull World Health Organ 1968;
45. Lamarra NWB. Measurement of pulmonary gas exchange. 38: 757e64
Champaign, IL: Human Kinetics; 1995 66. Mitchell JH, Sproule BJ, Chapman CB. The physiological
46. Huszczuk A, Whipp B, Wasserman K. A respiratory gas meaning of the maximal oxygen intake test. J Clin Investig
exchange simulator for routine calibration in metabolic 1958; 37: 538e47
studies. Eur Respir J 1990; 3: 465e8 67. Taylor H, Buskirk E, Henschel A. Maximal oxygen intake
47. Atkinson G, Davison RC, Nevill AM. Performance charac- as an objective measure of cardio-respiratory perfor-
teristics of gas analysis systems: what we know and what mance. J Appl Physiol 1955; 8: 73e80
we need to know. Int J Sports Med 2005; 26(Suppl 1): S2e10 68. Wagner PD. New ideas on limitations to VO2,max. Exerc
48. Macfarlane D. Automated Metabolic gas analysis sys- Sport Sci Rev 2000; 28: 10e4
tems: a review. Sports Med 2001; 31: 841 69. Hawkins MN, Raven PB, Snell PG, Stray-Gundersen J,
49. Porszasz J, Blonshine S, Cao R, Paden HA, Casaburi R, Levine BD. Maximal oxygen uptake as a parametric
Rossiter HB. Biological quality control for cardiopulmo- measure of cardiorespiratory capacity. Med Sci Sports
nary exercise testing in multicenter clinical trials. BMC Exerc 2007; 39: 103e7
Pulm Med 2016; 16: 13 70. Myers J, Walsh D, Buchanan N, Froelicher VF. Can
50. Wasserman K, Whipp BJ. Exercise physiology in health maximal cardiopulmonary capacity be recognized by a
and disease. Am Rev Respir Dis 1975; 112: 219e49 plateau in oxygen uptake? Chest 1989; 96: 1312e6
51. Neder JA, Nery LE, Peres C, Whipp BJ. Reference values 71. Day J, Rossiter H, Coats E, Skasick A, Whipp B. The maxi-
for dynamic responses to incremental cycle ergometry in mally attainable VO2 during exercise in humans: the peak
males and females aged 20 to 80. Am J Respir Crit Care Med vs. maximum issue. J Appl Physiol 2003; 95: 1901e7
2001; 164: 1481e6 72. Howley ET, Bassett Jr DR, Welch HG. Criteria for maximal
52. Hansen JE, Sue DY, Oren A, Wasserman K. Relation of oxygen uptake: review and commentary. Med Sci Sports
oxygen uptake to work rate in normal men and men with Exerc 1995; 27: 1292e301
circulatory disorders. Am J Cardiol 1987; 59: 669e74 73. Malhotra R, Bakken K, D’Elia E, Lewis GD. Cardiopulmo-
53. Hansen JE, Casaburi R, Cooper DM, Wasserman K. Oxy- nary exercise testing in heart failure. JACC Heart Fail 2016;
gen uptake as related to work rate increment during 4: 607e16
 500 - Levett et al.

74. Ward SA. Muscle-energetic and cardio-pulmonary progressive cycle ergometer test. Am Rev Respir Dis 1985;
determinants of exercise tolerance in humans: muscle- 131: 700e8
energetic and cardio-pulmonary determinants of exer- 94. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Exercise
cise tolerance in humans. Exp Physiol 2007; 92: 321e2 pathophysiology in patients with primary pulmonary
75. Whipp BJ. The bioenergetic and gas exchange basis of hypertension. Circulation 2001; 104: 429e35
exercise testing. Clin Chest Med 1994; 15: 173e92 95. Arena R, Myers J, Aslam SS, Varughese EB, Peberdy MA.
76. Wasserman K, McIlroy M. Detecting the threshold of Peak VO2 and VE/VCO2 slope in patients with heart fail-
anaerobic metabolism in cardiac patients during exer- ure: a prognostic comparison. Am Heart J 2004; 147:
cise. Am J Cardiol 1964; 14: 844e52 354e60
77. Brooks G. The lactate shuttle during exercise and re- 96. Sarullo FM, Fazio G, Brusca I, et al. Cardiopulmonary
covery. Med Sci Sports Exerc 1986; 18: 360e8 exercise testing in patients with chronic heart failure:
78. Connett RJ, Sahlin K. Control of glycolysis and glycogen prognostic comparison from peak VO2 and VE/VCO2
metabolism. Oxford: Oxford University Press; 1996 slope. Open Cardiovasc Med J 2010; 4: 127e34
79. Myers J, Ashley E. Dangerous curves: a perspective on 97. Guazzi M, Adams V, Conraads V, et al. EACPR/AHA Sci-
exercise, lactate, and the anaerobic threshold. Chest entific Statement. Clinical recommendations for cardio-
1997; 111: 787e95 pulmonary exercise testing data assessment in specific
80. Gladden LB. Lactate metabolism: a new paradigm for the patient populations. Circulation 2012; 126: 2261e74
third millennium. J Physiol 2004; 558: 5e30 98. Neder JA, Berton DC, Muller PT, et al. Ventilatory in-
81. Clanton TL, Hogan MC, Gladden LB. Regulation of cellular efficiency and exertional dyspnea in early chronic
gas exchange, oxygen sensing, and metabolic control. obstructive pulmonary disease. Ann Am Thorac Soc 2017;
Comp Physiol 2013; 3: 1135e90 14: S22e9
82. Lindinger MI, Whipp BJ. The anaerobic threshold: fact or 99. Dumitrescu D, Nagel C, Kovacs G, et al. Cardiopulmonary
misinterpretation?. Oxford: Elsevier; 2008 exercise testing for detecting pulmonary arterial hyper-
83. Whipp B, Ward S, Wasserman K. Respiratory markers of tension in systemic sclerosis. Heart 2017; 103: 774e82
the anaerobic threshold. Adv Cardiol 1986; 35: 47e64 100. Junejo MA, Mason JM, Sheen AJ, et al. Cardiopulmonary
84. Beaver WL, Wasserman K, Whipp BJ. A new method for exercise testing for preoperative risk assessment before
detecting anaerobic threshold by gas exchange. J Appl pancreaticoduodenectomy for cancer. Ann Surg Oncol
Physiol 1986; 60: 2020e7 2014; 21: 1929e36
85. Sue DY, Wasserman K, Moricca RB, Casaburi R. Metabolic 101. Junejo MA, Mason JM, Sheen AJ, et al. Cardiopulmonary
acidosis during exercise in patients with chronic exercise testing for preoperative risk assessment before
obstructive pulmonary disease. Use of the V-slope hepatic resection. Br J Surg 2012; 99: 1097e104
method for anaerobic threshold determination. Chest 102. Grant SW, Hickey GL, Wisely NA, et al. Cardiopulmonary
1988; 94: 931e8 exercise testing and survival after elective abdominal
86. Whipp BJ. The coupling of ventilation to pulmonary gas ex- aortic aneurysm repair dagger. Br J Anaesth 2015; 114: 430e6
change during exercise. New York: Dekker; 1991 103. Tolchard S, Angell J, Pyke M, et al. Cardiopulmonary
87. Whipp BJ. Control of the exercise hyperpnea: the unan- reserve as determined by cardiopulmonary exercise
swered question. Adv Exp Med Biol 2008; 605: 16e21 testing correlates with length of stay and predicts com-
88. Ward SA. Commentary on “Mechanism of augmented plications after radical cystectomy. BJU Int 2015; 115:
exercise hyperpnea in chronic heart failure and dead 554e61
space loading” by Poon and Tin. Respir Physiol Neurobiol 104. Brunelli A, Belardinelli R, Pompili C, et al. Minute
2013; 189: 203e10 ventilation-to-carbon dioxide output (VE/VCO2) slope is
89. Wasserman K, Whipp BJ, Koyl SN, Beaver WL. Anaerobic the strongest predictor of respiratory complications and
threshold and respiratory gas exchange during exercise. death after pulmonary resection. Ann Thorac Surg 2012;
J Appl Physiol 1973; 35: 236e43 93: 1802e6
90. Whipp BJ, Davis JA, Wasserman K. Ventilatory control of 105. Shafiek H, Valera JL, Togores B, Torrecilla JA, Sauleda J,
the ʻsocapnic buffering’ region in rapidly-incremental Cosio BG. Risk of postoperative complications in chronic
exercise. Respir Physiol 1989; 76: 357e67 obstructive lung diseases patients considered fit for lung
91. Puente-Maestu L. Reference values in adults. Plymouth: cancer surgery: beyond oxygen consumption. Eur J Car-
Latimer Trend; 2007 diothorac Surg 2016; 50: 772e9
92. Hansen J, Sue D, Wasserman K. Predicted values for 106. Torchio R, Guglielmo M, Giardino R, et al. Exercise
clinical exercise testing. Am Rev Respir Dis 1984; 129: ventilatory inefficiency and mortality in patients with
S49e55 chronic obstructive pulmonary disease undergoing sur-
93. Jones N, Makrides L, Hitchcock C, Chypchar T, gery for non-small-cell lung cancer. Eur J Cardiothorac
McCartney N. Normal standards for an incremental Surg 2010; 38: 14e9

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