Systematic evaluation of cough‐anorectal pressure responses in health and in fecal incontinence: A high‐resolution anorectal manometry study

Anorectal manometry is the most commonly performed test of anorectal function. The cough‐anorectal response is frequently assessed as part of a routine manometric investigation but has not previously been the subject of detailed analysis. This study systematically examined anorectal pressure responses to cough in health and evaluated the impact of parity and symptoms of fecal incontinence (FI) on measurements.


| INTRODUC TI ON
Anorectal manometry is the principal diagnostic tool to assess anal sphincter dysfunction in fecal incontinence (FI). Anal resting pressure, a primary indicator of internal anal sphincter function, and voluntary squeeze increment pressure, a measure of external anal sphincter and likely puborectalis contractility [1][2][3] are the most recognized and consistently reported measures of anal function. 4 However, although mean resting pressures and squeeze increments are generally regarded as being reduced in FI compared to healthy subjects, only approximately one-third of individual patients have anal hypotension, and only two-thirds of patients have voluntary anal hypocontractility. [5][6][7] Accordingly, for such a high proportion of symptomatic individuals to exhibit "normal" function, either there are suprasphincteric factors of equal or greater importance for continence than anal barrier function (eg, rectal sensation, compliance, stool form, and volume etc.), or traditional measures (rest and squeeze) lack specificity to have dependable diagnostic value.
Indeed, the limited utility of these measures to distinguish between health and disease has hindered their acceptability as clinically meaningful measures of anal function for decades. [8][9][10][11] High-resolution anorectal manometry (HR-ARM), with improved spatiotemporal resolution, may allow for assessment of other, or more subtle features of anorectal function including visualization of dynamic events and simultaneous pressure measurement at multiple levels. Novel measures may enhance diagnostic value and utility of the technique. For example, several guidelines and best practice documents advocate assessment of anorectal pressure responses to cough as part of the manometry protocol. 9,[11][12][13] Indeed, 83% of 107 centers responding to an international survey of manometry practice 4 reported that they routinely performed a cough maneuver.
However, despite its perceived simplicity, the method for analysis and reporting of cough varied widely, with most respondents (42%) reporting only qualitative impression of muscle recruitment. Of quantitative measures, maximum anal pressure was most common (28/89 centers or 31%).
The involuntary external anal sphincter contractile response to cough 14 is mediated by a spinal reflex 15 and may be observed during other activities which increase intra-abdominal pressure including sneezing and postural changes, 16 or inflating a rectal balloon. 17 A "normal" cough response on manometry has a measurable increase in anal pressure, the duration, and amplitude of which is believed to exceed the increase in cough-generated rectal pressure, so that anal sphincter barrier function is maintained despite the intra-abdominal/intra-rectal pressure challenge. 9,[11][12][13] A "post-cough relaxation" or drop in anal resting pressure following a sudden increase in abdominal pressure by coughing 18 or by blowing up a balloon 17 may be seen in some individuals and is akin to the "early relaxation" pattern observed by Gowers 19 in response to mucosal irritation during coughing.
While cough-anorectal pressure responses have been documented previously, 18,[20][21][22] no study has applied HR-ARM to qualitatively and quantitatively study changes with parity (in health) and with disease (fecal incontinence). This was the aim of the current study through systematic, retrospective analysis of HR-ARM recordings. sponse is yet to be studied systematically using highresolution manometry.
• Qualitative and quantitative evaluation of cough pressure revealed important differences between nulliparous and parous healthy women and patients with fecal incontinence, which were not appreciated by traditional metrics (resting and squeeze).
• An abnormal cough-anorectal pressure response may represent more subtle anal sphincter dysfunction, which is influenced by parity.
vaginal hysterectomy and primary sphincter repair in the case of 3rd or 4th degree tears sustained during childbirth). For parous groups to be comparable for age, all patients over the age of 72 years were deselected (n = 6) prior to further analysis.
All subjects (HVs and patients) underwent HR-ARM and assessment of rectal sensation to balloon distension. In addition, all patients with FI (but not HV) also underwent endo-anal ultrasonography and a proportion (36/57, 63%) underwent defecography. All tests were performed and interpreted in accordance with departmental protocols. [27][28][29] During defecography, as part of the standardized protocol, maintenance of continence was evaluated following insertion of barium contrast, both during transfer of the patient to the commode, and also under fluoroscopy on instruction to cough.

| Technical specifications and test procedure
All participants underwent investigation using a 12F solid-state catheter (UniTip: UniSensorAG, Attikon, Switzerland) incorporating 12 unidirectional pressure transducers each embedded within a silicone gel cuff. Prior to the study, the catheter was immersed in tepid water for at least 3 minutes to pre-wet sensors, which were then zeroed. Data acquisition and visualization were performed using a commercially available manometric system (Solar GI HRM V.9.1, Medical Measurement Systems, Enschede, The Netherlands). Data were generated at 10 Hz.
Manometry was performed using a ratified protocol. 18

| Cough selection
Each HR-ARM trace (irrespective of health or disease status) was examined for trace quality and presence of single, discrete cough (as opposed to multiple, rapid coughs, which are frequently observed). A study was included in the final analysis if: (a) at least one single cough had been performed, (b) there were discernible and distinct anal and rectal pressure areas, and (c) "traditional" resting and squeeze pressures could be measured. Traces with artifacts affecting the quality of the recording were excluded. When two coughs had been performed as per protocol, the first single, analyzable cough was used for analysis.

| Development of measures
Qualitative and quantitative assessment of each cough were performed independently by two practitioners with previous experience in performing and analyzing HR-ARM (AR and KG). Measures were first developed in the healthy cohort and subsequently applied to the FI group.
For qualitative assessment of cough morphology, a "standard view" of the cough was created by taking a 15-second window surrounding the cough and setting the pressure scale from −5 to 140 mm Hg. Cough morphology was determined by the "shape" of the pressure contour and the perceived temporal relationship between rectal and anal pressure changes. Images were reviewed offline and disputes resolved through discussion. During online analysis, the period immediately after each cough was inspected and a "post-cough relaxation" 30  The following were derived offline: • absolute anal-rectal pressure difference (maximum anal pressure during cough minus maximum rectal pressure during cough); • anal-rectal duration difference (anal pressure duration minus rectal pressure duration); • incremental anal-rectal pressure difference (maximum anal increment during cough minus maximum rectal increment during cough). This measure describes the "excess" sphincteric pressure generated once the abdominal pressure rise ("cough effort") has been accounted for.
Traditional measures of anal function (resting pressure and squeeze increment) were also evaluated in all subjects, as previously described. 18

| Statistical analysis
Values were expressed as means with 95% confidence intervals.
The 5th and 95th percentiles in healthy parous and nulliparous women were calculated to define upper and lower limits of normality for resting pressure, squeeze increment, and cough parameters.
Differences between groups were analyzed using ANOVA with Bonferroni post hoc analysis for multiple comparisons. Independent Kruskal-Wallis with Bonferroni correction was used if homogeneity of variance was violated. A P value <.05 was considered significant.
All statistical analyses were conducted using SPSS version 26 (IBM Corp, Armonk, NY, USA).

| Patients
Of 137 incontinent parous women attending the department within the study period, 57 met inclusion and exclusion criteria. Median age was 43 years (range 28-72), with median number of births being 2 (range: 1-7). In total, 86% reported some form of insult to the perineal or sphincteric region during at least one delivery (this included perineal tears, episiotomies, and forceps). Overall, 51% had either a forceps-assisted delivery or sustained a 3rd or 4th degree tear on at least one occasion. Three women (5.2%) had only given birth by cesarean section, and only 7% (4/57) had had vaginal deliveries without complications. St Marks incontinence score ranged from 11 to 22 (median 16). With regard to presenting symptoms, 49% of patients had passive incontinence and 54% had urge incontinence (12% both passive and urge symptoms). Fifty-eight percent of patients also reported fecal urgency and 33% complained of other symptoms (such as evacuatory difficulties).
Defecography was performed in 36/57 individuals. There was evidence of neostool leakage either passively on transfer to commode, or on instruction to cough in 23 patients (64%). At least one significant abnormality 29 was reported in 47% (large and/or retaining rectocele in 12, obstructing intussusception in 4, and non-relaxing pelvic floor in 1). Overall, 22% had both leakage and a structural abnormality; 8% had no leakage or structural abnormality (normal defecography or functional deficit only).

| Clinical utility of cough measures
Twenty-five (43.9%) patients had no disorder of anal tone or con-

| DISCUSS ION
To our knowledge, this study is the first to systematically compare anorectal pressure changes during coughing in healthy nulliparous and parous women and in patients with FI using HR-ARM.
The main findings of this study were: 1. considering the anal canal as a single functional unit, we were able to measure some degree of anal sphincter response to cough in all subjects; 2. qualitative identification of six "prototype" morphologies of the cough-anorectal response. The most common in both health and disease was a "teardrop" appearance, characterized by a longer duration of anal compared to rectal pressurization. In contrast, a "spear" or "spear (upper)" morphology were both more common in FI than health, manifest as a more simultaneous rectal and anal response; spear (upper) was unique to the FI group, and was char- These findings merit discussion with reference to previous literature. In healthy individuals and individuals with high spinal lesions, the anal response to a rise in abdominal pressure is increased anal sphincter EMG activity and, on manometry, greater maximum anal pressure compared to intra-rectal pressure. 17 Our results are consistent with these findings, since 98% of healthy volunteers main- Early manometry studies identified reduced anal resting pressure in two-thirds of incontinent patients; 31,32 however, other studies have shown that a subject with low resting pressure may also be perfectly continent, 9 demonstrating the overlap between health and disease. In the current study, anal resting pressure was the same between all groups, despite nulliparous subjects being significantly younger compared to asymptomatic and symptomatic parous women. Voluntary squeeze increment discriminated between continent and incontinent subjects, but failed to show a difference between nulliparous and parous healthy volunteers.
This is despite consideration of parity being reported as essential for correct interpretation of manometric results, 18   also showed that the amplitude of electrical response to coughing was greatest in patients with more innervated trunk musculature, suggesting this was due to their ability to generate higher intra-abdominal pressure. Finally, the potential to respond reflexively may be dependent on parity.

| Study limitations
There are several limitations to our study. Firstly, nulliparous women were younger than parous healthy and incontinent women.
However, though aging is thought to impact primarily internal anal sphincter tone, we saw no difference in anal resting pressure between groups and hence it is unlikely that aging played a significant role in our findings. Secondly, maximum pressure responses to coughing were lowest in the incontinent group who also had the lowest intra-abdominal/rectal pressure increment indicating that they coughed with the least effort (likely for fear of incontinence). Given the retrospective nature of our study, we were unable to standardize cough effort to maintain a consistent "challenge" to sphincters of all individuals as was achieved in some previous studies. 35 Since lower intra-abdominal pressure rise may lead to smaller degrees of anal sphincter response, 38  Difficulties in recruitment of healthy volunteers may introduce bias in the selection of subjects and data thus obtained. 8 As far as we know, all asymptomatic volunteers included in this study met the appropriate criteria for healthy volunteers; however, we cannot guarantee the results obtained are representative of all healthy females, particularly with regard to ethnicity and BMI. 41 We took a consistent approach to choosing eligible patients, manometry traces, and single, discrete coughs included in the study to reduce bias. We did not endeavor to compare intra-individual variation in cough response but recognize this to be an important focus of future work given the recommendation that the cough maneuver is repeated in standard manometry protocols. 11 Finally, our interpretation of qualitative cough morphologies suggests that pressure changes during coughing can vary between distal and proximal parts of the anal canal. Given their polar extremities, these differences may be related to the type of muscle tissue (smooth or striated) that predominates. EMG studies describe the cough response as an external anal sphincter reflex, 14 so the true cough reflex may be expected to occur in the distal or mid anal canal. We observed an attenuated or absent response associated with spear (upper) morphology in some individuals, in whom reflex contraction could be truly absent. However, because high-resolution anorectal manometry is unable to reliably differentiate between puborectalis, internal and external anal sphincter contributions to pressure, we considered the anal canal as a single unit for quantitative measures. We also considered the maximum pressure measurement to be representative of anal response to cough irrespective of the level at which it occurred within the defined sphincteric or rectal area of interest.

| Potential for clinical application
A key question is whether cough measurements could have future clinical utility, especially since anorectal manometry including the cough challenge already forms part of routine assessment following traumatic childbirth in many parts of the world. 4 While we present evidence of an "additional yield" of abnormal findings using detailed cough metrics in a proportion of patients with FI who had normal standard metrics, a further interesting finding is that we could also detect differences in sphincter function between asymptomatic nulliparous and parous women. Vaginal delivery is a risk factor for fecal incontinence due to mechanical or neurogenic damage imposed upon (predominantly) the striated sphincter muscle; 42 however, there is often a considerable time lag between injury and symptom onset. 43 During this lag period, further insult to pelvic floor function (menopause, subsequent vaginal delivery, persistent straining etc.) may occur. Evidence of subclinical predisposition to pelvic floor weakness and consequent incontinence before symptoms present may allow for preventive measures (such as pelvic floor exercise or Caesarian section) to be taken in at risk individuals. 44 Subclinical neuropathy may also explain persistent anal dysfunction following sphincter repair in a proportion of patients. 45 Accordingly, detailed examination of cough-anorectal pressures suggests that the analrectal incremental pressure difference may be able to identify potential subclinical sphincter dysfunction in women following childbirth, even in the absence of symptoms. For a similar cough effort, the anal-rectal incremental pressure difference was significantly lower in parous continent and incontinent women compared to the nulliparous group. Conversely, no such significant difference was observed between parous continent and parous incontinent women. Whether this is a useful biomarker of subclinical injury and future risk would require a longitudinal study.

| CON CLUS ION
Undoubtedly, the role of HR-ARM in identifying disorders of tone and contractility remains though the need for more intense stratification within normative datasets is recognized. We present a promising basis for interpreting cough clinically, though future prospective studies are needed to fully understand its potential. Furthermore, in-depth analysis of the cough-anorectal reflex, an under-utilized yet routinely performed maneuver, appears to have the potential to identify subclinical sphincter dysfunction in parous and in fecally incontinent women compared to asymptomatic nulliparous women.
These results present the opportunity to reconsider HR-ARM not only as an "expensive hobby", 46 but as an important tool for identification of at risk individuals in whom preventive measures may serve to halt progression of subclinical anal dysfunction into life-altering disease. Where FI symptoms are already established, evaluation of sphincter function with a dynamic maneuver like cough, which challenges the sphincter barrier response, may be more clinically valid than static measures.

ACK N OWLED G EM ENTS
We are grateful to Ms Anne Brokjaer for performing some of the healthy volunteer studies. We also wish to thank Dr Sahar

Mohammed, Mrs Ann Curry, Mrs Karyn Grimmer and Ms Tatenda
Marunda for undertaking some of the clinical studies.

D I SCLOS U R E S
MS and EVC have received honoraria for teaching from Laborie; CHK has received financial remuneration from Medtronic Inc. as speaker fees and for expert advisory committees; AMPR and KGZ none to declare. This work has been submitted in abstract form to UEG 2020 and has been accepted for poster presentation.