Systematic Review of Pharyngeal and Esophageal Manometry in Healthy or Dysphagic Older Persons (>60 years)

We undertook a systematic review of swallowing biomechanics, as assessed using pharyngeal and esophageal manometry in healthy or dysphagic older individuals aged over 60 years of age, comparing findings to studies of younger participants. PRISMA-P methodology was used to identify, select, and evaluate eligible studies. Across studies, older participants had lower upper esophageal sphincter (UES) resting pressures and evidence of decreased UES relaxation when compared to younger groups. Intrabolus pressures (IBP) above the UES were increased, demonstrating flow resistance at the UES. Pharyngeal contractility was increased and prolonged in some studies, which may be considered as an attempt to compensate for UES flow resistance. Esophageal studies show evidence of reduced contractile amplitudes in the distal esophagus, and an increased frequency of failed peristaltic events, in concert with reduced lower esophageal sphincter relaxation, in the oldest subjects. Major motility disorders occurred in similar proportions in older and young patients in most clinical studies, but some studies show increases in achalasia or spastic motility in older dysphagia and noncardiac chest pain patients. Overall, study qualities were moderate with a low likelihood of bias. There were few clinical studies specifically focused on swallowing outcomes in older patient groups and more such studies are needed.


Introduction
Dysphagia is increasingly recognized as an important consideration when assessing older patients or community-dwelling older people [1][2][3][4][5]. The consequences of impaired swallowing can impact on both life expectancy and quality of life. Malnutrition, dehydration, pulmonary aspiration, and increased choking risk may result from dysphagia in older persons [1][2][3][4][5], however depression due to impaired quality of life or the social isolation caused by an inability to eat a meal normally, are less well recognized potential consequences [6].
Failure to recognize or adequately address swallowing and feeding problems in older individuals could trigger a downward spiral of sarcopenia and frailty leading to impairment of physical function, leading to further swallowing impairment and worsening sarcopenia/frailty. In some cases, sarcopenia may result in or contribute to dysphagia [7][8][9]. Even healthy, community-dwelling, older individuals are "at risk" due to reduced swallowing functional reserve [10], and this applies more so to hospitalized or institutionalized individuals [11].
Pharyngeal and upper esophageal sphincter manometry has to overcome a number of technical challenges that relate to the rapidly changing and widely varying pressures across the

Methods
The study design was based on the 2015 version of the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) [26,27]. The focus of our study was on studies evaluating participants over 60 years of age (either healthy volunteer groups or dysphagics, separately) who underwent pharyngeal or esophageal manometry studies with outcomes compared to young healthy controls (in healthy volunteer studies) or younger patients (in dysphagia).

Eligibility Criteria
Inclusion and exclusion criteria for studies are included as Table 1. Table 1. Inclusion and exclusion criteria.

Inclusion Criteria Exclusion Criteria
Case control, Cohort, and Observational. RCT (drug trails and therapeutic interventions), Review, Cases, and Case series. At least one group ≥ 60 years of age.
Study focused on single disease process e.g., achalasia Either healthy volunteers or a patient population with dysphagia included.
Surgery or radiotherapy involving the pharynx, UES or esophagus Technical details of manometry procedure described. Anorectal manometry For pharyngeal studies the use of solid state sensors, 3 cm or less ("low-resolution") or spaced at 1 cm or less "high-resolution" (HRPM).
For pharyngeal studies sensor spacing less than 3 cm For esophageal studies both "low-resolution" (> 1 cm sensor spacing) and "high-resolution" (<1 cm or less) without or with impedance (HRM/HRIM).
Language other than English (LOTE) without available translation (simultaneous publication of English translation for LOTE articles).

Participants
Definitions of aging vary. The definition used when referring to the older population is individuals aged 60 years of age and older. This definition is in keeping with the World Health Organization formal definition of older age [28], however an age of 65 and older is mostly in keeping with a majority view of the terms 'aged', 'older', 'elderly', or 'geriatric'. Our original intention was to use 65 as a cut-off, however many important studies of age-related manometry changes used sixty as age cut-off and for this reason we concluded to use 60 years of age. The comparator was human participants between 18 and 59 years of age.

Interventions
Participants had to undergo manometry using standard manometry equipment. Reports had to include details on the equipment used, technical details on sensor technology, sensor spacing, and catheter configuration and, in addition, participant posture, volume, consistency, and type of the boluses swallowed.

Comparators
Normative values had to be either standardized for the equipment configuration or reported based upon inclusion of a young participant comparator group.

Outcomes
There are no universally agreed criteria for the interpretation of pharyngeal manometry. For an interpretation of pharyngeal manometry related to functional outcomes such as pulmonary aspiration risk and pharyngeal residue see Cock & Omari [29].
The UES is tonically contracted, and needs to neurogenically deactivate to relax and open. UES resting or basal pressures give some indication of this basal tone. Another important aspect measured during pharyngeal manometry relates to opening of the UES, or cricopharyngeal/UES dysfunction [30,31] whereby UES opening is inadequate for the size/volume of the bolus swallowed due a non-opening and/or nonrelaxing UES high pressure zone. UES dysfunctions commonly result from neurogenic or myogenic causes affecting UES relaxation and UES opening extent [32][33][34]. Restricted opening commonly leads to increased intrabolus pressure above and pressure gradient across the sphincter, provided pharyngeal contractility is sufficiently propulsive [35]. Pharyngeal contractility is commonly reported as a peak pressure (PeakP) per sensor or average across a region. Some studies also reported the duration of the pharyngeal swallow. Combining both pressure and duration with length, pressure "contractile integrals" are also described per region, with a global "Pharyngeal contractile integral" (PhCI) [36].
In summary, the outcomes reported for pharyngeal studies were 1.
UES opening extent on radiology or impedance base (UES Max Adm in milliSievert-mS) 4.
Intrabolus pressure above sphincter (IBP in mmHg at 1 cm above UES).

5.
Pharyngeal contractility-(PeakP or PhCI) and duration (milliseconds-ms) As a broad principle the "classical criteria" were considered for conventional esophageal manometry studies [37] and the "Chicago classification criteria" for HRM [17][18][19]. As these criteria have gone through several iterations it was deemed reasonable if studies were reported by the prevalent criterion version at the time of the study. Esophagogastric junction (EGJ) barrier function including lower esophageal sphincter (LES) resting pressure and relaxation forms a critical component of the manometric assessment of esophageal function. Following on from this, distal esophageal contractility leads to the completion of bolus flow through the EGJ. Few studies specifically report on proximal esophageal contractility in older subjects [38,39]-no comprehensive assessment of this aspect was possible and more studies are needed. A few studies reported on esophageal peristaltic success.
In summary, outcomes reported for esophageal studies were as follows.

2.
Lower esophageal sphincter relaxation pressure (integrated relaxation pressure in 4 s IRP4 in mmHg).

4.
Contractility of the distal esophagus (as mean peak pressure in mmHg or distal contractile integral-pressure × length × duration in mmHg.cm.s).

Settings
There were no restrictions on the setting.

Language
English language articles were included. Articles in other languages were only included if a full translation in English was simultaneously published.

Search Strategy & Data Management
A search was undertaken for English language articles dated 1948 to 2018 using the search terms manometry AND age/aging/elderly/older AND either pharynx/pharyngeal plus high-resolution or esophagus/esophageal. Studies of anorectal manometry were excluded.
Cross-referencing and the author's own collections were used to supplement the search strategy.

Information Sources
The literature search strategy was developed using medical subjects headings (MeSH) terms related to manometry in older subjects. Medline (OVID interface, 1948 onwards), Pubmed at https: //www.ncbi.nlm.nih.gov/pubmed, and Web of Science core collection v5.29.

Data Management and Selection Process
Records of all searches (titles only) were saved in a folder on a password protected and fire walled personal computer. Eligible (articles) were saved in PDF format in a shared folder and, where needed, printed out for reading. Titles, abstracts and, where necessary, article text was scanned to assess eligibility for inclusion if the study contained data on a participant group as defined (see Table 1). Searches were undertaken by author CC and screened for inclusion by authors CC and TO independently.

Data Collection Process
Data reporting was specific for methodology during manometry. Differences in equipment (e.g., catheter specifications/diameter [39,40]) may account for different values for the same variable. Interpretation of data should be undertaken with this knowledge and as such, rather than performing a meta-analysis, "functional" interpretation was applied to the data ( Table 2).

Data, Outcomes and Prioritization
Consideration was given to the functional and clinical relevance of findings. Pharyngeal and esophageal studies were grouped into those in healthy volunteers or symptomatic patients. Technical data on the analyses are included in Table 4.

Risk of Bias
Bias was assessed as per Table 8.5 in the Cochrane Handbook for Systematic Reviews of Interventions at http://handbook-5-1.cochrane.org/. Possible bias was assessed for each of the six domains described: selection, performance, detection, attrition, reporting, and other sources of bias. Results for biases are included in the results section below.

Data Synthesis
Due to heterogeneity in measurement techniques and the potential for catheter configuration or measurement technique to influence results, methodology was focused on regional changes related to functional swallowing outcomes.
Studies in patients (but not healthy volunteers) were rated for quality (very high to low from A-D) and strength of recommendation (strong or weak for or against) with the overriding question on whether the study results/outcomes were likely to change clinical management. An adaptation of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scale for diagnostic tests, specifically adapted for esophageal manometry was applied (Table 2) [41,42]. Study quality was modified as described within GRADE [41,42]  Weak recommendation for (2)/↑ Low Quality (C) e.g., Low Resolution Manometry Weak recommendation against (2)/↓ Very low quality (D) Strong recommendation against (1)/↓↓

Literature Search and Study Characteristics
The results of the literature search for pharyngeal manometry ( Figure 1) and esophageal manometry ( Figure 2) are reported in Figures 1 and 2. Two hundred and fifteen studies of pharyngeal manometry and nine hundred and twenty seven studies of esophageal manometry were retrieved. During the "Web of Science" search, alternate possibilities such as "anorectal" were specifically excluded. Terms such as "aging" or "older" produced more focused results, as compared to broad search terms such as "age".

Study Quality and Bias
Quality of six diagnostic studies (one pharyngeal, four esophageal, and one in both) between older and young cohorts are summarized in Table 5. No study achieved more than a moderate quality or strength of recommendation for diagnostic manometry in older people.

Increase in "abnormal" studies 2B
The risk of bias in studies of esophageal or pharyngeal manometry in healthy volunteers/patients was considered low overall.

Discussion
Based on this systematic review, the dominant age-related changes in swallowing physiology include (i) greater UES restriction, (ii) increased pharyngeal contractility, (iii) decreased distal esophageal contractility, and (iv) reduced LES relaxation. Major esophageal motility disorders, achalasia, and distal esophageal spasm in particular, may be more prevalent with age.
Abnormalities of UES relaxation and opening have been repeatedly reported in both healthy volunteers and dysphagia patients of advanced age. Associated features include increased hypopharyngeal intrabolus pressure, a biomechanical consequence of restriction, and increased pharyngeal contractility which may be compensatory response to restriction. Some authors have postulated decreased sphincter compliance [32,46]; and there is limited evidence suggesting reduced UES relaxation [34,39,47,48]. In contrast, dysphagia patient data suggests decompensation of swallowing indicated by weaker pharyngeal contractility with age. Readers are referred to a review of pharyngeal manometry by Cock and Omari [29].
Data on LES resting pressure are inconsistent, with different studies showing lower, higher, and unaltered LES pressure. However data on reduced LES relaxation with age are more reliable, particularly for subjects over 80 years. Data on esophageal contractility suggests reduced peristaltic amplitude with age contributes to a greater likelihood of peristaltic failure. When major motility disorders have been reported, achalasia and spastic esophageal motility were the most common diagnoses. Age-related loss of central and/or enteric nervous system functions are a likely cause of these changes [63]. Changes in esophageal compliance have been shown with aging, which may relate to loss of elastic tissues, or neuromuscular changes [64]. Such changes may contribute to the esophageal changes seen in our review. Readers are also referred to more recent reviews by Gyawali et al. [22] and Carlson and Pandolfino [65] on HRM and esophageal pressure topography in clinical practice.
Our review identified very few clinical studies reporting manometry findings in older dysphagia patients. Given the burgeoning aging population in developing countries, more studies of older patient groups are needed to address this knowledge gap. Future studies should also focus attention on patients and subjects that are older than 85 years of age (the so-called "older old") as data available suggests this as the threshold for manifestations of the most extreme forms of pharyngo-esophageal dysfunction.

Limitations
Whilst our search strategy identified many papers, some relevant studies may have been missed because inclusion of older patients was not mentioned in the title or listed in keywords. We did assess several papers which clearly contained data gathered in older subjects, but in which results for the older portion of the cohort were not distinguishable. Some studies were also excluded because they included subjects aged below our applied threshold of sixty years. Some studies tended to focus on certain aspects, such as lower esophageal sphincter relaxation, whilst omitting description of other features. Supplementary data tables may be one way for authors to address the need for clarity and still provide a more comprehensive summary of their data.

Conclusions
The aging process alone leads to changes in swallowing function, most notably UES restriction and esophageal dysmotility. More clinical studies, across the older age range, and reporting consistent biomechanical endpoints, are needed.
Funding: This research received no external funding.