Evaluation of Spontaneous Swallow Frequency in Healthy People and Those With, or at Risk of Developing, Dysphagia: A Systematic Review and Meta-Analysis.


 BackgroundDysphagia is a common, and frequently undetected, complication of many neurological disorders and of sarcopoenia in ageing persons. However it is difficult to detect dysphagia clinically until the point of visible aspiration, and there are relatively few trained speech and language therapists, whose time and remit are limited to those with obvious disorders. Reduction in spontaneous swallowing frequency (SSF) has been mooted as a possible proxy for dysphagia. We therefore conducted a systematic review of the literature to describe SSF in both the healthy population, and in disease specific populations, in order to assess its utility as a screening tool to identify dysphagia.MethodsWe searched Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases. Metadata were extracted, collated, and analysed via a random effects model to give quantitative insight.ResultsThree hundred and twelve articles were retrieved, with 19 meeting inclusion and quality criteria. Heterogeneity between studies was high (I2 = 98%), in part, due to the variety of methods for swallow identification reported. The mean SSF in Healthy younger groups was 0.98/min [CI: 0.78; 1.23]. In the Parkinson’s groups mean SSF was 0.59/min [0.41; 0.85]. Mean SSF in Healthy older, Higher risk and Dysphagic populations were similar (0.21/min [0.12; 0.37], 0.26/min [0.14; 0.85]), (0.27/min [0.17; 0.43] respectively).ConclusionsSSF is a novel, non-invasive clinical variable which warrants further explorations as to its potential to identify persons at risk of dysphagia. Larger, well-conducted studies are needed to develop objective, standardised methods for detecting SSF, and develop normative values in healthy populations.

A number of swallow screening tools and techniques may have a place in dysphagia screening; these include questionnaires, observations and clinical history. However, outside of the stroke population, there is no consensus on best practice; each professional chooses their preferred technique [5]. Questionnaires are an effective way to screen community and secondary care patients [6] but remain subjective with varying degrees of diagnostic accuracy due largely to the involuntary nature of the patients' condition. Importantly, there is currently no validated bedside screening tool for objective automated screening of dysphagia and aspiration risk outside of stroke care. Clinical assessment and research in hospital-acquired and aspiration pneumonias are hampered by an inconsistent approach to measuring dysphagia.
We and others are assessing the utility of spontaneous swallowing frequency (SSF) [7] in this role. SSF is the rate of swallowing over a prolonged period without purposeful intervention; reduced SSF is mooted as an indicator of dysphagia in clinical populations that include: post-stroke [7]; head and neck cancer [24]; Parkinson's disease [26]; and the elderly [13,14,15]. Recent advances in technology have enabled an assortment of cheap, non-invasive swallow detectors. Surface EMG, sound analysis and other techniques have the potential to offer a low-cost, simple, acceptable screening test that might be deployed with only limited training across these and other vulnerable clinical populations, such as children.
Yet since swallowing is one of the most common and readily observed of all physiological processes, it seems remarkable that there is no consensus as to what constitutes a normal SSF, even in a healthy adult population. To illustrate the scale of uncertainty, we noted early research conducted by Lear et al. [8] suggesting that humans swallow between 203-1008 times per day (0.14-0.7/min), with a mean swallow frequency of 585 per day. Whereas recently, Rudney et al. [9] reported that a healthy human will swallow spontaneously between 18 and 400 times an hour (0.3-6.7/min). These two normal ranges for SSF cover two orders of magnitude, and are barely compatible with one another. A cursory review of the literature suggests further variability with age, aetiologies and comorbidities. In the context of developing a dysphagia screening test, there is no scope to move forward without a better understanding of this aspect of basic swallow physiology.
In this review we assess the literature relating to the identi cation of spontaneous swallow rates in healthy populations and in clinical populations with, or at risk of developing, dysphagia. Speci cally, we wish to: Report the spontaneous swallowing frequency in normal and clinically relevant groups.
Advise on the utility of SSF as a screening tool to identify risk of dysphagia.

Methods
Details of the protocol for this systematic review were registered on PROSPERO and can be accessed at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID= CRD42019134061.

Search strategy and selection criteria
We conducted electronic searches to identify relevant primary research articles using the following databases: MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. See Table 1 for the full search strategy. Table 1. Electronic search strategies to identify primary research articles on spontaneous swallow frequency Citations were excluded by a single rater if they: had no abstract; included no human data; or made no reference to spontaneous swallow rate. Abstracts and where appropriate full articles were then reviewed in more detail. Papers were excluded if they: presented only an abstract and not a full paper; included data only from sleeping subjects (i.e. no awake control); did not measure SSF directly (i.e. SSF was predicted using other variables); and if they only reported data from populations under the age of 18 years.

Data extraction
Where articles met the inclusion criteria, a single rater extracted the following data: sample size; study population/aetiology; study controls; population ages; swallow frequency; standard deviation of swallow frequency between subjects; swallow identi cation method; length of swallowing recordings; statistical signi cance of SSF between observational and/or intervention groups; and additional information where appropriate -for example, correlational statistics and study information.

Quality assessment
A full assessment of the quality of the papers was conducted using the NHLBI Study Quality Assessment tools [10]. Two independent raters scored each paper and rated them of poor, fair or good quality (see Appendix A).

Data analysis
We conducted meta-analysis for the whole group, and for sub-groups of subjects as follows: Healthy younger below 60 years of age; Healthy older of 60 years or more; Dysphagic, with documented dysphagia; Parkinson's, with a diagnosis of Parkinson's disease; Higher risk, with aetiologies associated in the literature with dysphagia that do not t into the other categories e.g. post stroke patients without documented dysphagia.
In each analysis, the outcome measure was the log-transform of the mean spontaneous swallow frequency (SSF) expressed in units of swallows per minute.

Assessment of study heterogeneity
Heterogeneity is a measure of inconsistency between the groups and studies making up a meta-analysis. High heterogeneity means that the groups are so different that they cannot be considered as samples from the same population. In this case, a random-effects meta-analysis is indicated and the results must be treated with caution; a pooled estimate of the outcome measure may not be meaningful. Heterogeneity was assessed for all groups separately, and for the whole group.

Estimate of population spontaneous swallow frequency
We estimated the central value and con dence intervals for SSF using a random effects model and inverse variance weighting to pool the studies. We report for all groups separately and for the whole group.
The Meta and Metafor packages from the R programming language [11] were used for data analysis.

Results
From 312 abstracts found by our search strategy, 19 full papers were included in this review ( Figure 1). They are summarised in Tables 2 and 3. Author, year  2) EMG (using wire electrodes inserted into the genioglossus muscle).
*Repeated in both tables as paper included data from both observational and interventional sub-studies. The 19 papers reported a mixture of observational (n = 9 case-control or cross-sectional) and interventional (n = 10, non-randomised pre-post intervention) studies. As such, ve were rated of good quality, six as fair/good quality, seven as fair quality, with a single paper of poor quality (Appendix A). The raters agreed that the poor quality paper [12] failed in a number of key areas, including: an inadequate de nition of the study population; no sample size justi cation; high risk of researcher bias due to lack of blinding or confounding variables; and insu cient detail with regard to the study controls and inclusion/exclusion criteria.
Small groups of highly disparate aetiologies were reported, often n=10 or fewer with the largest single group being n=47. This increases the likelihood that signi cant comorbidities be present in some groups and not in others. For example, hypersialorrhea is prevalent in patients with Parkinson's disease (PD) and Wilson's disease, which may increase swallowing frequency even in those with swallowing di culties.

Swallow assessment methods
Tables 2 and 3 present detail of the different swallow assessments, and ultimately show that there is no standardised way in which to measure spontaneous swallowing. There was little consistency in identi cation of persons with dysphagia, timing of observations, or methods for detecting swallows. There was a single report (Murray et al. [13]) of Fibre-endoscopic Evaluation of Swallow (FEES). We excluded Murray's data from metaanalysis because the FEES investigation is invasive; as we explain later, this likely cannot be considered comparable with the other non-invasive methods.

Meta-analysis
For 30 groups in 19 papers there was an estimate of spontaneous swallow frequency in either a healthy or clinically relevant population (Tables 2 and 3). The meta-analysis is presented as a Forest plot in Figure 2. The outcome measure MLN is the log transformed (geometric) mean of the groups from the relevant studies.

Estimate of spontaneous swallow frequency
The best estimate of overall SSF is 0.41 [0.31; 0.54] /min. The high heterogeneity will be explained at least in part by the anticipated differences between the sub-groups. To consider the sub-groups, the range of SSF in healthy younger was 0.47-1.7 /min, healthy older 0. 13

Discussion
There is insu cient evidence to describe normative values for SSF in either healthy populations or clinically relevant groups. It is also not possible to determine whether SSF is a clinically useful screening tool for dysphagia at present. It was clear from the analysis that data on swallow frequency from different centres, using different technologies or different methodologies, cannot reliably be compared. However, from the intervention studies in table 3, it appears that differences in a swallow index measured in the same centre using the same study design are sensitive to clinical condition or to intervention. This seems reasonable since in this situation the major methodological differences are controlled. Nevertheless the relation of any measure of SSF with a physiologically meaningful reference standard cannot be assumed.
Effect of age and gender on spontaneous swallow frequency Despite high heterogeneity, there is a negative correlation of SSF with age. Healthy young (< 60 years) have a mean SSF of 0.98 while healthy old have a mean SSF of 0.21. Simply, older people swallow less. This is in agreement with the works of Crary et al. [14] and Tanaka et al. [15], both of whom report signi cantly higher SSF in young normal (healthy) subjects when compared to elderly normal (healthy) subjects using the same swallow detection technology (see Table 2). However, note that mean SSFs across even the healthy young group are highly variable and do not give a reliable indication of what a true 'normal' SSF is.
As with all correlation studies, cause and effect is di cult to assess. The reduced SSF with advanced age may be directly implicated in dysphagia. If so, it is surprising that SSF is so similar across the elderly population, irrespective of dysphagia risk. If some other age-related process causes dysphagia then SSF is merely a convoluted method of estimating age.
Finally, one conference abstract reported a higher rate of spontaneous swallow in women [16]. This is an important area to investigate, but no full papers have yet been published assessing the effect of gender on SSF.
The role of spontaneous swallow frequency in clinical practice Accurate measurement of SSF may be the most appropriate reference for basic research in swallow physiology. If instead we consider the diagnosis of dysphagia as our criterion, then a validated clinical assessment by SALT may be a more appropriate reference standard. Crary et al. [7] compared SSF to a clinical assessment, reporting that a threshold of 0.4 swallows/min showed high sensitivity (0.96) but low speci city (0.68) for dysphagia. The workers suggest SSF may be a useful screening tool but lacks the speci city for a de nitive diagnosis. Our data would agree; those at heightened risk of dysphagia have a much lower SSF than younger healthy participants.
With the exception of PD, the mean SSF was in every other case lower than Crary's threshold. Note however that this is the mean SSF; sensitivity and speci city are de ned on a patient-by-patient level.

Secretion management and interventions to increase SSF
Interventions to increase swallowing frequency have been used to aid in secretion management and have increased understanding in conditions where hypersalivation and resultant drooling is common, namely, Parkinson's [17,18] and Wilson's Disease [19]. PD is also associated with increased risk of dysphagia. More than 80% of patients are predicted to develop dysphagia following disease onset [20]. Figure 3 suggests that PD patients have a lower SSF than healthy younger subjects but they appear to swallow more regularly than other atrisk groups. This may be explained by known and unknown cases of hypersalivation in this patient population [17]. Moreover, SSF reported across studies involving PD patients is highly variable, potentially due, in part, to the risk of associated conditions such as dysphagia that have not been diagnosed. Such con icting variables make it di cult to determine the true value of using SSF in this population.
Interventions to stimulate swallows appeared to be successful though these studies were often not blinded or randomised so were open to bias, and it is di cult to know to what degree any improvements could be considered clinically signi cant. Four studies were effective at increasing SSF in groups with dysphagia; two found facio-oral tract therapy to signi cantly increase swallow rate [21,22] one used gustatory stimulation [23], and one successfully applied vibrations to stimulation the larynx in a dysphagic group [24]. Studies reported that these interventions have the potential to improve swallow function in those with dysphagia via the measurement of SSF, but no studies report long term outcomes.
It remains unclear what a normative swallow rate is and what a clinically signi cant change in rate may be.
Nevertheless he pre-and post-intervention data reported maybe give useful insight for researchers and clinicians to consider in the future when treating these patient groups.

SSF measurement methodologies
Heterogeneity between studies was high, particularly with regard to methods used to assess SSF. A variety of techniques were used to measure spontaneous swallows, most frequently with the single or combined use of: electromyography (EMG), acoustic/sound recording, respiratory bellows/transducers (around the ribcage), bellows/transducers located around the larynx, or scoring by a trained observer. Other techniques included auscultation, beroptic endoscopic evaluation (FEES), and magnetic resonance imaging (MRI).
A clinically useful measure of SSF should have good validity, i.e. should give comparable results to a reference standard. A reference for the measurement of SSF (i.e. the detection of swallows over prolonged periods of time) does not currently exist. Nevertheless any clinical physiological measurement -sphygmomanometry for example -is predicated on the idea that the measurement indicates the underlying blood pressure irrespective of the speci c technology. There is general consensus as to what constitutes a swallow, and so there is objectively a 'correct' SSF, at least in principle. If measurements disagree to the extent reported here, we cannot avoid the conclusion that some (or possibly all) technologies are generating incorrect data.
To resolve these issues, comparative studies between several measures of SSF are needed. Only one group compared two systems for measuring SSF [14], the rst an acoustic recording technique, the comparator a comprehensive multichannel physiologic recording with surface EMG, swallow apnoea, and cervical auscultation.
There was no signi cant difference in SSF between the two methods (0.85 /min vs. 0.81 /min). Super cially this suggests that a microphone alone might be used to record swallows. Perhaps more importantly, the consistency between two different technologies might suggest that the technology works well and that other methodological factors (for example: the use of long-term ambulatory use versus lab-based investigations with prescribed activities) is responsible for the poor agreement between centres.
FEES is a well-used and reliable method for assessing a single swallow and may be an appropriate reference standard for an event-by-event comparison, a form of criterion validity. Large scale validation studies of SSF instrumentation are required before systematic trials in clinical populations, with data involving known swallows and potential artefacts. In order to ensure high speci city with regards to swallow detection, designs must rule out noise artefacts in addition to reliably identifying all swallows.

Conclusion
SSF is a novel, non-invasive clinical variable which warrants further explorations as to its potential to identify persons at risk of dysphagia. Larger, well-conducted studies are needed to develop objective, standardised methods for detecting SSF, and develop normative values in healthy populations in order to answer this question.