Received: 3 February 2021 | Revised: 16 February 2021 | Accepted: 19 February 2021

DOI: 10.1111/nmo.14120

TECHNICAL NOTE

Chicago classification version 4.0© technical review: Update

on standard high-resolution manometry protocol for the
assessment of esophageal motility

Mark R. Fox1 | Rami Sweis2 | Rena Yadlapati3 | John Pandolfino4 |

Albis Hani5 | Claudia Defilippi6 | Tack Jan7 | Nathalie Rommel8

1
Department of Gastroenterology and
Hepatology, University Hospital Zürich, Abstract
Zürich, Switzerland
The Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for es-
2
Digestive Function: Basel, Laboratory
and Clinic for Motility Disorders and
ophageal motility disorders using metrics from high-­resolution manometry (HRM). A
Functional Digestive Diseases, Arlesheim, key feature of CCv.4.0 is the more rigorous and expansive protocol that incorporates
Switzerland
3
single wet swallows acquired in different positions (supine, upright) and provocative
Center for Esophageal Diseases, Division
of Gastroenterology, University of testing, including multiple rapid swallows and rapid drink challenge. Additionally, solid
California San Diego, La Jolla, CA, USA bolus swallows, solid test meal, and/or pharmacologic provocation can be used to
4
Feinberg School of Medicine,
identify clinically relevant motility disorders and other conditions (eg, rumination)
Department of Medicine, Northwestern
University, Chicago, IL, USA that occur during and after meals. The acquisition and analysis for performing these
5
Pontificia Universidad Javeriana-­Hospital tests and the evidence supporting their inclusion in the Chicago Classification pro-
San Ignacio, Bogota, Colombia
6 tocol is detailed in this technical review. Provocative tests are designed to increase
University Hospital, University of Chile,
Santiago, Chile the diagnostic sensitivity and specificity of HRM studies for disorders of esophageal
7
University College London Hospital, motility. These changes attempt to minimize ambiguity in prior iterations of Chicago
London, UK
8
Classification, decrease the proportion of HRM studies that deliver inconclusive diag-
Translational Research in GastroIntestinal
Disorders (TARGID, University of Leuven, noses and increase the number of patients with a clinically relevant diagnosis that can
Leuven, Belgium direct effective therapy. Another aim in establishing a standard manometry protocol
Correspondence for motility laboratories around the world is to facilitate procedural consistency, im-
Mark R. Fox, Digestive Function: Basel, prove diagnostic reliability, and promote collaborative research.
Laboratory and Clinic for Motility
Disorders and Functional Digestive
Diseases, Klinik Arlesheim, CH-­4144
Arlesheim, Switzerland.
Email: dr.mark.fox@gmail.com

1 | I NTRO D U C TI O N reflux monitoring.1,2 Over 15 years, technological advances in data

acquisition and presentation of physiological measurement have
Patients who present with esophageal symptoms in whom mucosal emerged, and these have been accompanied by changes in the clas-
and structural disorders have been excluded by endoscopy and who sification of esophageal motility disorders.3-­5 We are now in a bet-
do not respond to empirical treatment are recommended to have ter position now to visualize and understand esophageal function
esophageal physiology studies such as manometry and ambulatory than at any time in the past. High-­resolution manometry (HRM)

Abbreviations: CCv4.0, Chicago classification version 4.0 ©; DCI, distal contractile interval (DCI); DL, distal latency; EGJ, esophago-­gastric junction; EGJOO, esophago-­gastric junction
outflow obstruction; HRM, high-­resolution manometry; IEM, ineffective esophageal motility; IRP, integrated relaxation pressure; MRS, multiple rapid swallows; RDC, rapid drink
challenge; RIP, respiratory inversion point; STM, solid test meal; UES, upper esophageal sphincter.
Mark R. Fox, Rami Sweis as a co-­f irst authors.

Neurogastroenterology & Motility. 2021;33:e14120. wileyonlinelibrary.com/journal/nmo © 2021 John Wiley & Sons Ltd | 1 of 16
https://doi.org/10.1111/nmo.14120
2 of 16 | FOX et al.

technology and the Chicago Classification of esophageal motil-

ity disorders are well established in clinical practice; however, the Key points
methodology used to assess esophageal motility and function con- • The Chicago Classification version 4.0 (CCv4.0) of es-
tinues to develop. Novel methods designed to improve the diagnos- ophageal motility disorders for high-­resolution manom-
tic performance of HRM investigation have been developed and etry was agreed by an international development group
validated. Surveys suggest that many of these are already applied using RAND UCLA Methodology.
in neuro-­gastroenterology motility laboratories.6 These “adjunctive” • The key advance of the CCv4.0 protocol is the inclusion
or “provocative” tests are now included in the Chicago Classification of positional change and provocative testing in HRM
version 4.0© (CCv4.0) protocol.7 studies
This technical review provides a detailed description of these • Appropriate normative values must be applied because
techniques and the evidence that supports the use of “provocative” there is variation in findings with position and with bolus
tests in clinical practice. The appropriate use of these methods can consistency.
improve diagnostic accuracy and, in the context of the CCv4.0, help • If no conclusive evidence of a motility disorder is iden-
establish a conclusive diagnosis of esophageal motility disorder.8 tified in the primary position and/or if findings do not
The aim of this major revision is to provide more personalized med- explain patient presentation, then swallows in the sec-
icine that can guide individual therapy decisions based upon patient ondary position and /or with provocation tests should
presentation, investigation findings and preference. be performed.
• Concordant findings in the secondary position and with
provocation increase strength of confidence of the clas-
2 | M E TH O D S sification and diagnosis.
• A solid test meal, post-­prandial monitoring, or pharma-
One working group led by two-­chairs (MF, NR) and consisting of cologic provocation can be considered if no conclusive
eight members was dedicated to development of a standard HRM diagnosis can be established by the CCv4 protocol, to
protocol. As detailed in the main CCv4.0 document, each proposed resolve discordant findings or if the study fails to explain
statement underwent two rounds of independent ranking by the patient symptoms.
entire CCv4.0 development group according to the RAND UCLA • If no conclusive diagnosis can be established by the full
Methodology to determine appropriateness of each statement CCv4 HRM, then additional investigations such as bar-
(Table S1). Statements with a median score of 7 or higher and/or ium esophagogram or Endo-­FLIP should be performed.
≥80% agreement were adopted as CCv4.0 recommendations. The
final protocol reflects this process and also discussions within and
between working groups tasked with reviewing published evidence.
This technical review reports the final recommendations for the providing circumferential pressure data either from an array of radi-
CCv4.0 HRM protocol. ally arranged sensors around a central core or miniaturized “sleeve
sensors”. The CCv4.0 working group recommends using a solid-­state
HRM catheter with less than 2 cm sensor spacing. However, rec-
2.1 | High-­resolution manometry ognizing that some labs will not have access to this assembly, the
protocol and classification can be performed with water-­perfused
A variety of modern HRM systems are commercially available, all of catheters if appropriate normative values are used. Additionally, a
which incorporate a large number of sensors, ideally 1 per centim- correction for hydrostatic effects is required if water-­perfused ma-
eter, on a flexible catheter which is passed from the nares, through nometry is applied in the upright position. High-­resolution imped-
the esophagus and into the stomach. Pressure data from these sen- ance manometry is recommended, though not required by CCv4.0,
sors are usefully presented as a compact, color-­coded topographic to assess not only pharyngeal function, but also intra-­bolus pressure
plot of esophageal pressure activity, known as “Clouse plots”, in and bolus clearance through the EGJ. This combined technology is
memory of Ray Clouse who adopted this technique in seminal the subject of separate articles.11-­13
9,10
publications. Water-­perfused and solid-­state HRM systems are All HRM systems provide a simultaneous and integrated assess-
available. The former is comprised of thin (micro-­capillary) plastic ment of pharyngeal, esophageal and lower esophageal sphincter
tubes with tiny holes that open at various intervals along the length function in real time. Although the information presented is similar,
of the catheter. Changes in pressure within the esophagus alter there are differences between technologies and systems produced
resistance to the flow of water and this is converted into a signal by manufacturers that can influence pressure measurement. It is
by external transducers located at the perfusing pump. The latter important that appropriate normative values should be applied that
acquires pressure information from miniaturized pressure sensors have been acquired using the same technology and methodology as
arranged along a catheter, with most modern solid-­state catheters applied in individual clinical studies.
FOX et al. | 3 of 16

BOX 1 High Resolution Esophageal Manometry Standard Protocol: Chicago Classification version 4.0©

PRE-­PROCEDURE
Prior to procedure patients should fast for at least 4 hours and informed consent should be obtained
The CC4.0 Working Group recommends using a solid state high-­resolution manometry catheter with <2 cm sensor spacing with com-
bined impedance sensors. However, the protocol and classification can be performed with water perfused catheters if appropriate
normative values are used.

STUDY PROCEDURE
Study begins in supine position [use supine normative values]
• ≥60 seconds adaptation period
• Document position with at least 3 deep inspirations
• ≥30 seconds baseline period
• 10 supine wet (5 ml) swallows
• 1 multiple rapid swallow sequence (multiple rapid sequence may be repeated up to 3 sequences if failed attempt or abnormal
response)
Change position to upright [use upright normative values]
• ≥60 seconds adaptation period
• Document position with at least 3 deep inspirations
• >30 seconds baseline period
• ≥5 upright wet (5 ml) swallows
• 1 rapid drink challenge
If no clinically relevant motility disorder is found consider the following manometric tests
• In a patient with high probability of a missed diagnosis, especially EGJ outflow obstruction: Solid test swallows, solid test meal,
and/or pharmacologic provocation (ie, amyl nitrite, cholecystokinin) in the upright position to assess for obstruction
• For suspected rumination/belching disorder: Post-­prandial high-­resolution impedance observation
If equivocal results are found and/or there is suspicion for an EGJ outflow obstruction that does not fulfill criteria for achalasia,
consider the following supportive tests
• Timed barium esophagram, preferably with tablet
• Endoluminal functional lumen imaging planimetry (FLIP)
Although the protocol designed by the CC4.0 team is considered to be the optimal protocol, clinicians can modify this protocol based
on limited resources and time as long as normative values are applied and other positions and provocative tests are used appropri-
ately. Physicians choosing to begin the study in the upright position should perform 10 upright swallows.
REPORTING: In addition to CC 3.0 metrics, final report should include baseline measures of the esophagogastric junction (EGJ) and
symptoms experienced during the study and within 15 seconds of a motility dysfunction.

2.2 | Testing protocol assessment of EGJ motility and function is the topic of a separate
technical review. The primary measurements from esophageal HRM
Prior to the procedure, patients should fast for at least 4 hours (sips are acquired during a series of 5–­10 ml single wet swallows. A key
of clear fluid allowed) and informed consent should be obtained. change in CCv4.0 is that these are taken in the supine and in the
Following catheter placement, the patient assumes the supine or upright, seated position. Additionally, provocative tests are now rec-
lateral position. A minimum of 60 seconds of quiet rest allows for ommended to increase diagnostic sensitivity and specificity of HRM
an adaptation period, following which catheter position is confirmed studies. A summary of the standard protocol is provided for refer-
using a minimum of three deep inspirations. Next, a baseline pe- ence (Box 1, see also Graphical Summary).7
riod of at least 30 seconds is captured to enable identification of The assessment of esophageal motility in the supine position
anatomic landmarks including the upper esophageal sphincter (UES), originated from the use of water-­
p erfused catheter with 4 to
lower esophageal sphincter (LES), respiratory inversion point (RIP), 8 pressure sensors. These studies were performed with the pa-
and basal EGJ pressure. Following any position change and an adap- tient lying flat to eliminate the influence of hydrostatic pressure
tion period, this sequence of measurements can be repeated. The and single wet swallows were acquired because the data was easy
4 of 16 | FOX et al.

F I G U R E 1 Effect of position on esophageal motility in a healthy subject. The esophageal contraction tends to be slower, better
coordinated and more vigorous in the supine (left panels) than the upright, seated (right panels) position. As a consequence, the proportion
of ineffective, hypotensive contractions is often higher in the upright position. Appropriate normative values must be applied. Image
Courtesy of Digestive Function: Basel at Klinik Arlesheim

to interpret even when presented as multiple line plots. With acquire pressure measurements in the upright position without
the introduction of HRM, validation studies against the existing having to correct for hydrostatic pressure and the presentation
“conventional manometry” systems were performed using the of data in topographic Clouse plots facilitates the analysis of the
14,15
existing protocol. Normative values from healthy individu- more complex pressure activity that occurs during normal drink-
als were published using the conventional methodology,16-­18 and ing and eating. 22,23 Data acquisition in two positions and inclusion
this became the foundation of the Chicago Classification versions of provocative tests can prolong data acquisition and variation in
1.0–­3 .0. 3-­5 A HRM protocol based on single wet swallows is simple findings between tests can complicate the interpretation of HRM
and quick to perform and analyze. Further, results can be inter- findings. The CCv4.0 working group recognizes that increased time
preted across all systems, technologies and expertise with a rea- required for data acquisition and analysis could be a barrier to im-
sonably high level of agreement.19,20 Thus, with publication of the plementation; however, the full protocol can be completed within
Chicago Classification, physiologists and clinicians started to use 15 minutes and the inclusion of this information increases diag-
the same terminology and methods, with rapid uptake of the tech- nostic sensitivity and specificity for clinically relevant diagnosis of
nology in clinical and research practice. 21 Notwithstanding these esophageal motility disorders. 24-­36 “Inconclusive” findings on wet
advantages, as experience with this technology increased, the lim- swallows can often be confirmed by these tests and, conversely,
itations of the conventional protocol have become evident. HRM discordant findings in the secondary position and/or with provoca-
with single water swallows in the supine position lacks sensitivity tion should prompt reconsideration of the diagnosis. However, if a
and specificity for certain motility disorders and, thus, diagnoses conclusive classification of findings is not possible based on HRM
based on these findings are often inconclusive. In many cases, this studies alone, then the use of corroborating supportive testing
can be addressed by the introduction of “provocative” tests that with timed barium esophogram (with tablet, barium-­soaked bread
assess esophageal motility not only in the supine position but also or similar solid bolus marker) and/or functional lumen imaging
in the physiological, upright position. This is technically possible probe may be required. 37,38 Ultimately, outcome studies will iden-
because developments in hard and software make it possible to tify the most informative protocol in different clinical scenarios.
FOX et al. | 5 of 16

2.3 | Patient position position (Figure 2). Recent studies indicate that the majority of
EGJOO cases diagnosed in the supine position are false positive and
The full CCv4.0 HRM protocol is optimal, especially in research stud- do not persist when the patient moves to the upright position. 24,25
ies; however, clinicians can modify this protocol to adapt to available Based on this evidence, the CCv4.0 recommends that swallows are
resources and time. Many labs commence the HRM protocol with a acquired in both positions. In particular, abnormalities of esophageal
series of wet swallows (ie, 5–­10 ml water or dilute normal saline if motility seen in either position, especially when unexpected, should
impedance is used) with the patient supine or in a lateral position. be re-­evaluated with the patient shifted to the alternative position.
Others will commence clinical studies with the patient seated in a
chair or on an examination couch. If the alternate position is not
applied in all cases, then the limitations of an abbreviated protocol 2.3.1 | CC4 recommendation
must be recognized, and appropriate normative values applied.
Compared to swallows in the supine position, esophageal The CCv4.0 protocol can commence in either position (Table 1).
contractions in the upright position have increased velocity and
decreased vigor (distal contractile interval (DCI)) because gravity re- 1. Patients begin with 10 small volume wet swallows in the supine
duces the mechanical work required to transport the bolus through position. If a conclusive diagnosis is not made (eg, type I or
the esophagus (Figure 1). 22,23 In a large prospective study of healthy II achalasia), then this is followed by at least 5 swallows in
subjects and patients with swallowing disorders studied in both the upright position to exclude anomalies that are seen more
positions, diagnostic agreement between positions was 67%, with frequently in the supine position (eg, false-­
positive diagnosis
reduced concordance primarily due to increased prevalence of inef- of EGJOO).
fective esophageal motility (IEM) in the upright position. When IEM 2. Patients begin with 10 small volume wet swallows in the upright
was excluded or position specific normal values were applied, con- position. If a conclusive diagnosis is not made, then this can be
24
cordance between upright and supine analysis improved to 90%. followed by at least 5 swallows in the supine position to exclude
The most common reason for the residual lack of diagnostic agree- anomalies that are seen more frequently in the upright position
ment was esophago-­gastric junction outflow obstruction (EGJOO), (eg, false-­positive diagnosis of IEM). This may not be required if
which is reported more frequently in the supine than the upright normal, effective motility is observed in the upright position and

F I G U R E 2 EGJ outflow obstruction with IRP >15 mm Hg is more frequently observed with wet swallows in the supine, than the upright
position. Many such cases are artefactual, are not associated with increased intra-­bolus pressure and are related to pressure on individual
sensors as the catheter passes through the EGJ. If discordant findings are present, then provocative tests are helpful to identify individuals
with clinically relevant disease. Image courtesy of Oesophageal Laboratory, University College London
6 of 16 | FOX et al.

TA B L E 1 The CCv4© HRM Protocol can be commenced in the

drink challenge (RDC), ingestion of more viscous material (yogurt,
supine or the upright position. If the full protocol is not completed,
then a shortened version combining selected HRM tests can apple sauce), single solid swallows (eg, bread, marshmallow, dump-
be applied. The protocol working groups recommendations for lings) or asking the patient to consume a test meal (their own food or
required and optional tests for “supine first” and “upright first” a standardized pre-­prepared meal). Except for MRS, these are nor-
studies are presented mally performed with the patient in the upright position because it is
Upright difficult to drink and eat normally when lying flat. Viscous swallows
CCv4© HRM Protocol Supine first study first study are not discussed further because there is limited evidence that this
Primary position 5–­10 ml Required Required improves test sensitivity of esophageal studies, especially if solid
water ×10a swallows are included in the protocol. Pharmacological provocation
Alternate position 5–­10 ml Required Optional can also be performed during the HRM protocol to help support a
water ×5–­10 diagnosis of a primary disorder of EGJ motility and function.39 This
Multiple Repeated Required Optional technique is detailed in supplementary information included with
Swallow ×1–­3b the main CCv4.0 publication and is the topic of recent papers.40,41
Rapid Drink Challenge ×1 Required Required Inclusion of such techniques increases the time required to
c
Single Solid Swallow ×5–­10 Optional Required perform HRM and requires more expertise in interpreting the re-
Solid Test Meal ± Post-­ Optional Optional sults. Provocative tests were referred to, but not included, in the
prandial Observation previous iteration of the Chicago Classification because norma-
a
If a conclusive diagnosis of achalasia type 1 or 2 is made from 10 wet tive values were lacking and there was insufficient evidence sup-
swallows in primary position, then further maneuvers are not required. porting the clinical utility of this approach. A recent, international
b
The purpose of MRS is primarily to document peristaltic reserve. Three survey of 91 esophageal centers reported that 77% included rapid
MRS are required only if an augmented MRS post-­contraction is not
drink challenge, 63% included solids and 18% included a test meal in
present after 1 or 2 attempts.
c their routine clinical practice6; however, these were not applied in a
If the purpose of solid swallows is to document peristaltic reserve
(eg, in reflux patients), then the presence of an effective esophageal consistent manner, non-­standard methods were applied and there
contraction in >2/10 swallows may be adequate. If it is to assess was no agreement as to the interpretation or reporting of findings.6
whether abnormal motility is the cause of patient symptoms then a An important feature of the CC4.0 is the integration of provoc-
minimum of 10 swallows is required.
ative tests in the assessment of esophageal motility and function.
Recommendations are made as to which tests should be included in
during provocative tests (see below); however, this has not yet routine clinical investigations and which can be reserved for specific
been confirmed in clinical studies. patient groups. Standards have been agreed for the acquisition of
provocative test and their analysis, interpretation and reporting.
The CCv4.0 working group acknowledges that the recommenda-
tion to acquire single wet swallows in both the supine and the up-
right positions plus the inclusion of “provocative” tests increases the 2.5 | Multiple rapid swallows (MRS)
time required to perform and analyze HRM studies. It is accepted
that acquisition of wet swallows in both positions may not be nec- Swallowing normally leads to an almost instantaneous, “deglutitive”
essary in routine clinical practice, especially if the findings in the ini- inhibition of the esophageal body and relaxation of the LES medi-
tial position are expected (Table 1). However, if measurements are ated by the release of nitric oxide from inhibitory neurons. In healthy
acquired only in one position, then position appropriate “normative subjects MRS enhances this phenomenon and, when completed, in-
values” are applied. What is essential is that the protocol acquires hibition is often followed by a relatively high-­pressure (augmented)
sufficient information to provide a conclusive diagnosis that explains ‘post-­
contraction’ to clear the esophagus of swallowed material
patient symptoms (if relevant) and guides appropriate management (Figure 3). This sequence of events can provide useful information
for the individual patient. regarding the esophagus's intrinsic neuromuscular function.42 MRS
is generally performed in the supine position (studies in the upright
position are lacking). Normative values have not been established in
2.4 | Provocative tests a large population of healthy subjects and further work is required
also to confirm diagnostic thresholds in patients with motility disor-
Swallowing small volumes of fluid in the supine or upright position ders. Notwithstanding these issues, it has been shown that impaired
does not represent normal behavior, and very rarely reproduces pa- deglutitive inhibition of the EGJ and esophageal body during MRS
tients’ symptoms. As such, single wet swallows may lack sensitivity can help to identify achalasia and peristaltic disorders (eg, esopha-
for clinically relevant disorders. To address this issue, “provocative” geal spasm, hypercontractile disorders), respectively.43 Additionally,
tests have been introduced, to demonstrate peristaltic reserve, in- the presence of an augmented post-­contraction following MRS can
duce abnormal motility and reveal the cause symptoms during the be used as a marker of peristaltic reserve. This appears to be espe-
investigation. These include multiple rapid swallows (MRS), rapid cially useful when IEM is diagnosed during single wet swallows.44
FOX et al. | 7 of 16

F I G U R E 3 Multiple Rapid Swallows (MRS) is a physiological test that increases deglutitive inhibition of the esophageal contration and
EGJ by asking the subject to swallow five times in quick succession. Subsequently, in healthy subjects, the MRS post-­contraction is often
augmented (more vigorous than normal). MRS highlights failure of deglutitive inhibition in patients with achalasia, esophageal spasm and
hypercontractile disorders. Additionally, the lack of augmentation in the post-­MRS contraction can indicate a lack of contractile reserve (ie,
ability to respond to physiological or iatrogenic challenge). Image courtesy of Digestive Function: Basel at Klinik Arlesheim

Augmentation is present if the distal contractile interval (DCI) is it can be performed also in the upright position. An intact response
higher in the MRS post-­contraction than the average DCI from a se- to MRS is defined as absence of esophageal body contractility
ries of single water swallows performed in the same position (failed (DCI <100 mm Hg•s•cm) with complete deglutitive inhibition of the
swallows not included in this analysis).35 The absence of an aug- LES during the repetitive swallows, with an augmented post-­MRS
mented contraction following MRS in esophageal studies performed contraction. Augmentation is present if the DCI is in the normal
is associated with increased likelihood of post-­operative dysphagia range (ie, DCI >450 mm Hg.cm.s) and any of three post-­contractions
in patients referred for consideration of anti-­reflux surgery.34-­36 The have increased contractile vigor compared to the mean DCI from
post-­MRS contractile response is variable, and the working group non-­failed single water swallows in the same position (ratio >1). The
recommends that the test is repeated up to three times to assess if post-­MRS contraction needs to be true peristaltic contractility and
peristaltic reserve is present if there is a failed or ineffective post-­ not artifact or pressurization.32,35,44,47
35,45
MRS contraction.

2.6 | Rapid drink challenge (RDC)

2.5.1 | CC4 recommendation
The Rapid Drink Challenge (RDC) is designed to replicate nor-
In CCv4.0, the multiple rapid swallow test has been standardized mal drinking behavior in the upright position and is the provoca-
such that, through a syringe, the operator offers 2 ml aliquots of tive test most commonly used in clinical practice. 6 Rapid intake
fluid in sequence, each separated by a few seconds, to produce a of water by a series of swallows induces deglutitive inhibition of
cumulative series of five swallows to make up to 10 ml.35,42,46 The the esophageal body with complete EGJ relaxation and opening
CCv4.0 protocol includes this test in the supine position; however, (Figure 4A). This is similar to MRS; however, the large volume of
8 of 16 | FOX et al.
FOX et al. | 9 of 16

F I G U R E 4 Rapid Drink Challenge (RDC) is performed by asking the subject to drink a large volume of water (100–­200 ml) by a series of
swallows. The rate can be controlled by drinking through a straw. In healthy subjects, similar to MRS, RDC highlights deglutitive inhibition
during repeated swallows (upper panel). Additionally, the presence of a normal contraction sequence following the RDC is a specific marker
of normal contractility; however, this is not observed in all healthy controls. Rapid Drink Challenge (RDC) highlights failure of deglutitive
inhibition in patients with achalasia (lower panel). In this case the patient had inconclusive findings with normal IRP during wet swallows (left
panel). RDC revealed conclusive evidence of achalasia with pan-­esophageal pressurization and IRP >50 mm Hg. The patient responded to
pneumatic dilatation. Images courtesy of Functional GI Laboratory, Zürich University Hospital.

water ingested during RDC fills the esophagus and this can high- 2.6.1 | CC4 recommendation
light resistance to flow, especially at the EGJ (Figure 4B). Clinical
studies show that the addition of RDC increases the sensitivity CCv4.0 recommends that RDC is performed in the upright posi-
of HRM for functional EGJOO (eg, subtype achalasia) and struc- tion to minimize the likelihood of aspiration, to reproduce normal
tural EGJOO (eg, stricture, tight fundoplication), diagnoses that drinking behavior and induce symptoms. The patient should drink
can be missed during single water swallows. 27,28,30,31,44 The test a minimum 100 ml (ideally 200 ml) water by a series of rapid water
is easy to perform and results are highly reproducible. Standard swallows without stopping. The drink is often ingested through a
metrics have been validated for the analysis of RDC during HRM straw to ensure that water is ingested at a steady rate. Deglutitive
studies and normal values for deglutitive inhibition and EGJ re- inhibition of esophageal body contractions (DCI) and EGJ func-
laxation. EGJ function can be assessed using the standard 4 s tion (IRP) are measured during the series of swallows. An intact
integrated relaxation pressure (IRP) metric. RDC-­IRP >12 mm Hg response to RDC is defined as absence of esophageal body con-
(with Medtronic equipment) accurately identifies achalasia, even tractility (DCI <100 mm Hg•s•cm) with complete deglutitive in-
in patients with normal IRP during single water swallows in whom hibition of the LES during the RDC. When assessing response to
functional obstruction is only evident during esophageal filling. 30 RDC, IRP >12 mm Hg especially if accompanied by pan-­esophageal
RDC-­IRP >8 mm Hg (with Medtronic equipment) increases test pressurization >20-­30 mm Hg (both with Medtronic software) are
sensitivity and has good specificity for all causes of EGJOO. 27 criteria for outflow obstruction. 27,28,31,32,48 RDC is especially rec-
Inhibition of esophageal body contractility can be assessed quali- ommended as a provocative test in patients with suspected EGJ
tatively or quantitatively using the DCI tool during rapid drink- outflow obstruction and achalasia in whom IRP does not reach diag-
ing. Lack of deglutitive inhibition with peristaltic or simultaneous nostic thresholds with single water swallows.
contractions (DCI >100 mm Hg•s•cm) during RDC is typical in
esophageal spasm and hypercontractile motility. Abnormal post-­
RDC contractions are also seen in many patients with these diag- 2.7 | Single solid swallows
noses. Conversely, although the presence of a normal contraction
sequence following the RDC is a specific marker of normal con- There has been interest for many years in including solid swallows
tractility; this is not present in all healthy controls. 27,28,48 in tests of esophageal function, such as ‘bread-­barium’ imaging stud-
Characteristic findings during RDC include a normal (“hypo- ies,38,49 to identify the causes of abnormal esophageal function and
pressive”) pattern shared by healthy subjects and patients with symptoms. Conventional manometry with line plot presentation of
IEM, that discriminates patients with non-­obstructive hypercon- esophageal pressure activity may be more difficult to interpret for
tractile motility or achalasia (sensitivity 80% and specificity 93%), solid than liquid swallows.50 This is because more than one pharyn-
(ii) impaired deglutitive inhibition (“brief hyperpressive” pattern) geal swallow are often required to ingest solids and multiple esopha-
in patients with non-­obstructive hypercontractile disorders (eg, geal contractions may be required to transport the bolus through the
distal spasm, hypercontractile esophagus), and (iii) impaired EGJ esophagus and into the stomach. The introduction of HRM with con-
function (“prolonged hyperpressive” pattern) with increased RDC-­ tinuous presentation of esophageal pressure data allow rapid acqui-
IRP that discriminates achalasia and EGJOO from other patients sition and analysis of solid bolus swallows in clinical practice. Initial
28
groups (sensitivity 70% and specificity 85%). Additionally, the studies standardized the methodology and analysis. It was confirmed
occurrence of typical symptoms during RDC in patients referred that healthy subjects and patients often take two pharyngeal con-
for investigation of dysphagia or other esophageal symptoms tractions to swallow a single solid bolus; however, if taken within 4
confirms the clinical relevance of any motility disorder identified seconds, this has no effect on subsequent esophageal contraction. 51
during testing. 29 Clinical studies have shown that RDC can help to Further, the esophageal response to solid bolus swallows is variable.
establish a conclusive diagnosis in patients with borderline HRM In some healthy subjects only 1 in every 4–­5 pharyngeal swallows
findings during single water swallows. 26-­31 Furthermore, up to 17% is followed by an effective esophageal contraction.51 Studies dem-
of patients with esophageal symptoms but normal wet swallows onstrated that IRP was higher for single solid compared to single
have abnormal RDC findings that require further investigation by wet swallows due to increased viscous resistance (Figure 5). The es-
addition of solid swallows to the HRM protocol and /or other di- ophagus responds to this challenge with better coordinated (fewer
agnostic tests. 31 large breaks in the contractile front), slower (increased DL) and more
10 of 16 | FOX et al.

F I G U R E 5 Effect of bolus consistency on esophageal motility in a healthy subject. The esophageal contraction tends to be faster (shorter
distal latency), less well coordinated (larger break in contractile front) and less vigorous (lower DCI) in wet swallows (left panel) than solid
swallows (right panel). Additionally the IRP is increased for solid swallows due to higher viscous resistance to bolus passage through the
EGJ. Appropriate normative values must be applied. Solid swallows can augment peristaltic motility in health and, as in the case presented,
demonstrate contractile reserve in patients with ineffective motility during water swallows. Image courtesy of Oesophageal Laboratory,
University College London.

vigorous contractions (increased DCI). 23,50-­52 The established princi- 2.7.1 | CC4 recommendation
ples of the Chicago Classification are applied to establish a diagno-
sis. Normative values have been published for single solid swallows, HRM measurements during single solid swallows are acquired in a
and the measurements and diagnosis were found to be reproducible, manner similar to single wet swallows. A series of solid bolus swal-
with good intra-­and inter-­observer reproducibility. 23,53,54 lows, typically with 1–­2 cm cube of buttered bread, soft biscuit,
Clinical studies indicate that inclusion of solid swallows in the dumpling or cake, are taken into the mouth, chewed, and swal-
HRM protocol increase the diagnostic yield for motility disorders, lowed once the patient is ready. Single solid swallows may require
especially EGJOO, compared to single water swallows and the oc- two pharyngeal swallows; however, otherwise, at least 30 seconds
currence of symptoms during this provocative test supports the should be allowed between swallows such that there is minimal
clinical relevance of HRM findings.14,24,26,31,33 Additionally, effec- interference between esophageal contractions. If included in the
tive contractions after ingestion of solid bolus indicates the pres- HRM protocol, then at least 5 solid swallows should be performed
ence of peristaltic reserve in patients with IEM with single water (10 swallows preferred). Standard metrics are used to analyze the
swallows. The physiological and clinical relevance of this observa- HRM pressure measurements. Appropriate normative values must
tion is illustrated by studies in gastro-­e sophageal reflux disease be applied. The diagnostic threshold for pathological EGJ func-
patients and patients with functional dysphagia. IEM is common tion is IRP >25 mm Hg (using Medtronic software) and effective
in patients with all forms of GERD; however, effective contrac- esophageal contractions are defined by the presence of peristalsis
tions (ie, preserved peristaltic reserve) are present in significantly (DL >4.5 seconds) with no more than a small break in the contractile
more patients with non-­e rosive disease than in those with reflux front (<3 cm) and vigorous contractility (DCI >1000 mm Hg.cm.s).
esophagitis or Barrett's esophagus. 55,56 In the same way, clinical At least 20% of single solid swallows should produce an effective
studies have shown that patients with <20% effective contrac- contraction as defined above. Less than this defines the presence of
tions during a series of solid swallows have a high likelihood of IEM for solids and is associated with a high likelihood of dysphagia
reporting dysphagia. 24,26,33 during the test.
FOX et al. | 11 of 16

2.8 | Solid test meal meals (eg, soft boiled rice, bread) and for personally selected “cul-
prit” foods. 60
As for single water swallows, the use of single solid swallows to Case series and an increasing number of outcome studies show
assess esophageal motility can be considered non-­p hysiological. that this information produces clinically relevant results that can
Moreover, this highly regulated and slow manner of eating may guide effective therapeutic decisions, especially in the diagnosis
not provoke abnormal motility or cause esophageal symptoms. and management of EGJOO (Figure 7). Inclusion of a test meal
During a test meal pharyngeal swallows occur in rapid succession in the HRM protocol identified abnormal motility in 70% of pa-
and are not always followed by effective esophageal contractions tients with dysphagia after anti-­reflux surgery, compared to 30%
(Figure 6). HRM during normal eating produces complex pressure with single water swallows. 26 Approximately half the patients had
measurements that can be subject to over-­interpretation. To ad- EGJOO identified only during the solid meal and many of these
dress this and ensure that the method can be applied in routine had good outcomes following pneumatic dilatation of the EGJ/
clinical practice, efforts have been made to simplify and standard- fundoplication wrap. 26 In a recent case series, the sensitivity
ize the analysis using standard metrics that allow the findings to for clinically relevant, symptomatic EGJOO for HRM with a test
57
be classified using established Chicago Classification metrics. meal was 85% compared to 54% for single water swallows and
This method has been validated and shown to be reproducible. 54% for barium esophogram. 31 Of 97 patients diagnosed with pri-
Normative values have been published and diagnostic thresholds mary EGJOO, 29 received ‘achalasia-­like therapy’ (eg, pneumatic
for patients with motility disorders have been defined. 51 Several dilatation) of whom 26 had a good clinical outcome, 8 had opioid
clinical series have shown that inclusion of a standardized test induced esophageal dysmotility and were treated with opioid re-
meal that requires a minimum 20 pharyngeal swallows to ingest duction or peripheral opioid antagonists, whereas 48 did not re-
significantly increases diagnostic yield for major motility disor- quire therapy. 31
ders and can increase the diagnostic yield for clinically relevant, Further, testing can be extended into the post-­p randial pe-
major motility disorders and identify the cause of symptoms in the riod to help induce, and classify functional disorders including
majority patients tested. 26,33,58,59 The composition of the meal volume reflux, rumination syndrome and supra-­g astric belching
may not be critical with similar results reported for standardized (Figure 8). 57,61-­6 3 For this purpose combined HRM with impedance

F I G U R E 6 Representative excerpt from HRM recording of a solid test meal ingested by a normal, healthy subject. Image Courtesy of
Digestive Function: Basel at Klinik Arlesheim
12 of 16 | FOX et al.

F I G U R E 7 Water swallows (left panel) and start of solid test meal (right panel) in a patient with dysphagia for solids and normal
endoscopy. The inclusion of solid swallows increases diagnostic sensitivity for motility disorders especially, as in this case, EGJ outflow
obstruction. Additionally, the close temporal association of abnormal motility with symptoms supports the clinical relevance of the finding.
Image Courtesy of Digestive Function: Basel at Klinik Arlesheim

is optimal to document retrograde movement of intra-­luminal con- "culprit meal". Ideally, the meal should require 20–­3 0 pharyngeal
tents (liquid or air); however, rapid increases in gastric pressure swallows to complete. Symptoms should be recorded concurrently
>25–­3 0 mm Hg (“R waves” caused by voluntary, albeit uncon- in the electronic record. The time allowed to complete a 200 g test
scious, contraction of the abdominal musculature) associated with meal is maximum 8 min. (median 6 min.) with failure to complete the
typical patient symptoms are characteristic of these behavioral meal within this time considered to be abnormal and "symptomatic".
disorders. 62,63 Regardless of the solid meal used, the same metrics and diagnos-
tic thresholds can be applied, with the findings classified using the
CCv4.0 template. The recommended analysis of HRM findings dur-
2.8.1 | CC4 recommendation ing a test meal is simple. The number of pharyngeal swallows and
effective esophageal contractions required to complete the meal
The CCv4.0 does not require the inclusion of a test meal in routine is counted (defined as for single solid swallows). In normal, healthy
clinical studies; however, this option should be considered in pa- subjects at least 20% of pharyngeal contractions are accompanied
tients referred for investigation of esophageal symptoms if single by an effective esophageal contraction. Abnormal EGJ function is
water swallows and other provocative tests have either not identi- present when ≥2 swallows have an IRP of >25 mm Hg (using the
fied a cause for patient symptoms or if the findings are inconclusive Medtronic system), spasm where ≥2 swallows have a distal latency
and /or do not guide management. It may also identify peristaltic re- of <4.5 seconds and hypercontractile esophagus when ≥2 esopha-
serve in patients with IEM on water swallows and confirm whether geal contractions have DCI >8000 mm Hg.s.cm. The close temporal
this finding is clinically relevant (ie, symptomatic or predictive of association of abnormal motility with typical symptoms supports
poor outcome after surgery). The protocol can be undertaken either the clinical relevance of the HRM findings, including IEM as defined
with a standardized test meal or for the patient to bring in their own by >80% ineffective swallows during the test meal.58
FOX et al. | 13 of 16

F I G U R E 8 Post-­prandial observation with combined high-­resolution impedance manometry can identify the causes of symptoms that
occur after meals. Transient LES relaxations (TLESRs) are often observed, however, a high frequency of these events after meals is consistent
with the diagnosis of gastro-­oesophageal reflux disease. In this case of a patient with volume regurgitation after meals, reflux and belching
were associated with TLESRs; however, repetitive volume regurgitation was caused by rumination. This was confirmed by the presence of
rapid increase in gastric pressure (>25 mm Hg) coincident with LES and UES relaxation and immediately followed by typical symptoms. Image
courtesy of Digestive Function: Basel at Klinik Arlesheim

F I G U R E 9 Two alternate algorithms to guide the use of provocative tests during the CCv4.0 Protocol are provided. Left panel: Protocol
commencing with wet swallows in the supine position. Right panel: Protocol commencing with wet swallows in the upright position. In
both provocative tests that increase the sensitivity and specificity for detection of clinically relevant esophageal motility disorders are
recommended.

3 | CO N C LU S I O N These tests have been validated and both normative values and
pathological thresholds have been established. Further, there is evi-
The key advance in this iteration of the CC4.0 protocol is the inclu- dence that each can increase diagnostic sensitivity and/or specificity
sion of positional change and provocative testing in HRM studies. for esophageal motility disorders.
14 of 16 | FOX et al.

There is consensus that wet swallows still provide the basis for John Pandolfino https://orcid.org/0000-0002-4993-9559
diagnosis by esophageal HRM. The CCv4.0 protocol recommends Tack Jan https://orcid.org/0000-0002-3206-6704
starting with a series of single wet swallows in either the supine or Nathalie Rommel https://orcid.org/0000-0001-5675-7334
the upright position. If a conclusive diagnosis has not been estab-
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How to cite this article: Fox MR, Sweis R, Yadlapati R, et al.
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