# Autonomic Testing in Functional Gastrointestinal Disorders: Implications of Reproducible Gastrointestinal Complaints during  Tilt Table Testing

Authors: Shaista Safder; Thomas C. Chelimsky; Mary Ann O'Riordan; Gisela Chelimsky
Journal: Gastroenterology Research and Practice
 (2009)

---

## Abstract

Background: The pathophysiology of functional abdominal pain (FAP) is unknown. The upright portion of a tilt table test triggers typical symptoms in certain children.
Aim: To compare the pathophysiology and treatment response of children with FAP whose gastrointestinal symptoms (GI) were replicated (RGI) by tilt table testing (TTT) to those in whom TTT did not have this effect (NRGI).
Methods: An IRB-approved retrospective review of the autonomic laboratory database identified all children tested for GI complaints. We compared results of TTT, Valsalva maneuver, deep breathing and the axon reflex sweat test. Overall treatment response and that specific to fludrocortisone was ranked from 1 to 5, with 1 “much worse,” 3 “neutral,” and 5 “much better.”
Results: 32/76 identified children had reproducible symptoms on TTT (RGI) and 44 did not (NRGI). The RGI group was younger, had a shorter duration of symptoms, more postural tachycardia syndrome (POTS) and benefited more from fludrocortisone (73% in RGI vs. 25% in NRGI).
Conclusion: Dividing patients with FAP according to the effect of TTT on their symptoms appears to delineate 2 fundamentally different groups, with potentially different pathophysiologies and treatment responses. A prospective study is needed.


---

## Body

## 1. Introduction

Functional
gastrointestinal disorders (FGID) affect a large percent of children and
effects quality of life. The exact prevalence of FGID in children is unknown. One
study found 10–20% of children suffer from chronic abdominal pain [1]. Also, 6% of middle school
students and 15% of high school students fulfill the criteria for irritable
bowel syndrome [2]. These children have a
decreased quality of life with increased school absenteeism, decreased play
time, and other significant impairments.According to the
proposed biopsychosocial conceptualization of functional gastrointestinal
disorders, the autonomic nervous system links the psychosocial factors with the
pathophysiological elements [3]. A role for abnormal autonomic
nervous system function is increasingly recognized which may not be limited to
the gastrointestinal tract. In pediatrics, exploratory studies have found
autonomic dysregulation in pediatric FGID [4–6].  FGID’s have been associated with orthostatic
intolerance (OI), mainly postural tachycardia syndrome (POTS) and syncope [4, 6], but other associations have
not been carefully evaluated. Three main types of orthostatic disorders have
been described in patients undergoing tilt table testing (TTT): postural tachycardia
syndrome (POTS), reflex syncope, and orthostatic hypotension (OH).POTS is defined as an increase in heart rate (HR)  from supine
to standing position of greater than 30 bpm, without sustained drop in blood
pressure. This definition has a stronger clinical implication if the increase
in heart rate is associated with symptoms replicating the chief complaint for
the testing, like dizziness, headache, nausea, and so forth. The symptoms of POTS and
many of the symptoms of functional gastrointestinal disorders, particularly
dyspepsia, overlap. When Sandroni et al. [7] described the symptoms
associated with POTS including dizziness, lightheadedness, and lower extremity
weakness, they also reported frequent associated symptoms of dyspepsia, such as
nausea, bloating, early satiety, and abdominal pain.  In addition, patients with POTS who have an
associated autonomic neuropathy harbor more gastrointestinal symptoms than
those who do not [5].This association
also holds true when explored from the reverse, gastrointestinal
perspective.  Children with chief
complaints of abdominal pain and diagnosed with functional gastrointestinal
disorders have dizziness (58%), headaches (52%), while 10% have prominent
fatigue, and 5% have episodes of loss of consciousness [8–10]. Sullivan et al. [6], also described similar
findings in children with functional gastrointestinal disorders, with
lightheadedness and fatigue in 46%, however this study was limited by a small
sample size and a skewed population that was sampled .We have frequently
observed the reproduction of gastrointestinal symptoms when the subject is
upright during the head-up tilt table test.
The clinical implications and associated outcome of such findings have
not been evaluated. The purpose of this study was to determine, through a
review of comprehensive autonomic testing performed in children with functional
gastrointestinal disorders if replication of symptoms during tilt test is
associated with a different treatment outcome than when symptoms are not
present during TTT.


## 2. Material and Methods

### 2.1. Study Design

A retrospective University
Hospitals Case Medical Center Institutional Review Board approved chart review
was conducted from the Pediatric Autonomic Laboratory database containing 419 pediatric
records between 1994 and 2007. From this group, we selected only those children
referred for gastrointestinal (GI) complaints (n=76). We excluded children with
a known organic gastrointestinal disease or genetic/metabolic abnormality. Most
of the children had been referred to the Autonomic Clinic by their pediatric
gastroenterologist or general pediatricians for evaluation of dysautonomia as a
possible cause of their gastrointestinal complaints.


### 2.2. Testing

All patients underwent 4 tests of
autonomic function including 3 tests of cardiovascular function (the
cardiovascular responses to deep breathing, to the Valsalva maneuver, and to
tilt table testing) and one test of sweating, the sudomotor axon reflex
response. The patients stopped any medications that could affect autonomic
function for 5 half-lives prior to testing, such as beta-blockers, caffeine,
anticholinergic medications, and so forth.TTT consisted
of 20-minute supine rest on a motorized tilt table prior to an upright tilt to70°.  Continuous BP and HR were monitored
noninvasively in the supine position for 3 minutes, and upright for 10 to 40
minutes.  The diastolic BP normally decreases
less than 10 mmHg, and the systolic BP, less than 20 mmHg, and HR should
increase less than 30 bpm [9].Deep breathing consists of 6 deep
breaths per minute, with the HR variation calculated from the best
6 of 12 cycles (normal values in this age group > 22 bpm [11]). Results are reported as the
average difference between inspiration and expiration of the 5 best breaths.
For the Valsalva maneuver, the subject maintains a 40 mmHg pressure gradient
with an open glottis for 15 seconds, while HR and blood pressure (BP) are
continuously monitored. The Valsalva ratio consists of the fastest HR during
pressure exertion (termed phase II, sympathetically mediated) divided by the
lowest HR after pressure release (termed phase IV, parasympathetically
mediated). Normal values depend on age [11].Sudomotor axon reflex response to
the iontophoresis of acetylcholine (10% with a 2 mA current for 5 minutes,
recording sweat output for 10 minutes, “QSART”) across the skin of the feet,
calves, hands and upper arms, was measured by standard methods [12].  Normal values vary by body site and gender,
and were not considered abnormal unless abnormal axon reflex response found in 2
sites were outside of the range of normal, defining the presence of an
autonomic neuropathy.


### 2.3. Data Analysis

Patients were divided into two
groups on the basis of their symptoms during the TTT: patients with
reproducible GI complaints (RGI) and those without (NRGI). The response to
treatment was scored from 1 to 5 with 1 “much worse,” 2 “little worse” 3 “neither
better nor worse,” 4 “somewhat better” and 5 “much better.”  The score of 5 was reserved for patients whose
symptoms resolved completely. For
analysis purposes, subjects with a “somewhat better” response (rating of 4) and
those with a “much better” (response rating of 5) were collapsed into a single
group and compared to all others. Thus a favorable treatment response was≥ 4 out of 5 on the  symptom response scale.Three orthostatic disorders were
defined for this group of patients: POTS required an increase in (HR) of
greater or equal to 30 bpm in the first 10 minutes of upright position during
tilt test associated with symptoms, and without a drop in blood pressure.  While the adult definition also accepts an
absolute heart rate of 120 bpm we did not include this criterion in this
population, since 120 bpm may be represent a normal (HR) in younger
children. Reflex syncope required an abrupt drop in blood pressure and often
(HR) (over 3 minutes or less) leading to syncope or pre-syncope. OH was defined by a
sustained drop in blood pressure or≥20 mmHg systolic or ≥10 mmHg
diastolic in the first 3 minutes of the tilt study. Patients with an orthostatic disorder who
also had syncope were classified in the group with the orthostatic disorder, as
this was considered to be the underlying process.  For example, if a patient had POTS and
syncope, they were placed in the POTS group.The study population was
described overall and by group.  Nominal
variables were described by frequencies and percents.  Continuous variables were described using the
appropriate measures of central tendency and dispersion.  Groups were compared using two-sample tests
of significance.  Nominal variables were
compared using Fisher’s exact test, and continuous variables were compared
using either a two-sidedt test, or Wilcoxon rank sum test, depending on the
distribution.  All analyses were done
using SAS, v 9.1 (the SAS Institute, Carey, NC).  The level of significance was set at 0.05.


## 2.1. Study Design

A retrospective University
Hospitals Case Medical Center Institutional Review Board approved chart review
was conducted from the Pediatric Autonomic Laboratory database containing 419 pediatric
records between 1994 and 2007. From this group, we selected only those children
referred for gastrointestinal (GI) complaints (n=76). We excluded children with
a known organic gastrointestinal disease or genetic/metabolic abnormality. Most
of the children had been referred to the Autonomic Clinic by their pediatric
gastroenterologist or general pediatricians for evaluation of dysautonomia as a
possible cause of their gastrointestinal complaints.


## 2.2. Testing

All patients underwent 4 tests of
autonomic function including 3 tests of cardiovascular function (the
cardiovascular responses to deep breathing, to the Valsalva maneuver, and to
tilt table testing) and one test of sweating, the sudomotor axon reflex
response. The patients stopped any medications that could affect autonomic
function for 5 half-lives prior to testing, such as beta-blockers, caffeine,
anticholinergic medications, and so forth.TTT consisted
of 20-minute supine rest on a motorized tilt table prior to an upright tilt to70°.  Continuous BP and HR were monitored
noninvasively in the supine position for 3 minutes, and upright for 10 to 40
minutes.  The diastolic BP normally decreases
less than 10 mmHg, and the systolic BP, less than 20 mmHg, and HR should
increase less than 30 bpm [9].Deep breathing consists of 6 deep
breaths per minute, with the HR variation calculated from the best
6 of 12 cycles (normal values in this age group > 22 bpm [11]). Results are reported as the
average difference between inspiration and expiration of the 5 best breaths.
For the Valsalva maneuver, the subject maintains a 40 mmHg pressure gradient
with an open glottis for 15 seconds, while HR and blood pressure (BP) are
continuously monitored. The Valsalva ratio consists of the fastest HR during
pressure exertion (termed phase II, sympathetically mediated) divided by the
lowest HR after pressure release (termed phase IV, parasympathetically
mediated). Normal values depend on age [11].Sudomotor axon reflex response to
the iontophoresis of acetylcholine (10% with a 2 mA current for 5 minutes,
recording sweat output for 10 minutes, “QSART”) across the skin of the feet,
calves, hands and upper arms, was measured by standard methods [12].  Normal values vary by body site and gender,
and were not considered abnormal unless abnormal axon reflex response found in 2
sites were outside of the range of normal, defining the presence of an
autonomic neuropathy.


## 2.3. Data Analysis

Patients were divided into two
groups on the basis of their symptoms during the TTT: patients with
reproducible GI complaints (RGI) and those without (NRGI). The response to
treatment was scored from 1 to 5 with 1 “much worse,” 2 “little worse” 3 “neither
better nor worse,” 4 “somewhat better” and 5 “much better.”  The score of 5 was reserved for patients whose
symptoms resolved completely. For
analysis purposes, subjects with a “somewhat better” response (rating of 4) and
those with a “much better” (response rating of 5) were collapsed into a single
group and compared to all others. Thus a favorable treatment response was≥ 4 out of 5 on the  symptom response scale.Three orthostatic disorders were
defined for this group of patients: POTS required an increase in (HR) of
greater or equal to 30 bpm in the first 10 minutes of upright position during
tilt test associated with symptoms, and without a drop in blood pressure.  While the adult definition also accepts an
absolute heart rate of 120 bpm we did not include this criterion in this
population, since 120 bpm may be represent a normal (HR) in younger
children. Reflex syncope required an abrupt drop in blood pressure and often
(HR) (over 3 minutes or less) leading to syncope or pre-syncope. OH was defined by a
sustained drop in blood pressure or≥20 mmHg systolic or ≥10 mmHg
diastolic in the first 3 minutes of the tilt study. Patients with an orthostatic disorder who
also had syncope were classified in the group with the orthostatic disorder, as
this was considered to be the underlying process.  For example, if a patient had POTS and
syncope, they were placed in the POTS group.The study population was
described overall and by group.  Nominal
variables were described by frequencies and percents.  Continuous variables were described using the
appropriate measures of central tendency and dispersion.  Groups were compared using two-sample tests
of significance.  Nominal variables were
compared using Fisher’s exact test, and continuous variables were compared
using either a two-sidedt test, or Wilcoxon rank sum test, depending on the
distribution.  All analyses were done
using SAS, v 9.1 (the SAS Institute, Carey, NC).  The level of significance was set at 0.05.


## 3. Results

Of the 76 children
included in the study, 51 were females with a mean age of13.4±3.6 years.
In 32 out of 76 children the tilt table test replicated their GI complaints (RGI) while in 44 it did not (NRGI). Table 1 characterizes the two
groups and Figure 1 describes the results of autonomic testing.
The RGI group
was younger and had a shorter duration of symptoms.  Abdominal pain was the most frequent chief
complaint in the RGI group, though some subjects had more than one chief
complaint.  The predominant complaints in
each group are summarized in Table 2, with no difference between groups (P=.17).Table 1
Summary of demographic
characteristics and results of autonomic testing in each group.
OverallN=76RGIn=32NRGIn=44P valueMean age (years) ± SD13.4 years ± 3.6 yrs12.6±3.314.1±3.70.08Male gender25/76 (32%)9 /32 (28%)16/44 (36%).46Median duration of symptoms
(range in months)41.5±24.029.3±30.951 ± 45.6.0424(1-156)18(2-120)35(1-156)Abnormal Valsalva Ratio
(no. subjects)8/76 (10%)1/32 (3%)7/44 (15%).13Abnormal Deep Breathing (no. subjects)7/76 (9%)2/32 (6%)5/44 (11%).69Either DB and Valsalva ratio abnormal15/76 (20%)3/32 (9%)12/44 (27%).13Abnormal Axon-Reflex Response23/76 (30%)10/32 (31%)13/44 (29%).81POTS on TTT59/76 (77%)28/32 (87%)31/44 (70%).09Patients on Fludrocortisone23/76 (30%)15/32 (46%)8/44 (18%).01No. Patients with≥4/5
Treatment response to Fludrocortisone13/76 (17%)11/32 (34%)2/44 (4%).09Table 2
Summary of the most common
symptoms in each group.
SymptomOveralln=76RGIn=32NRGIn=44Abdominal pain43/76 (56%)23/32 (71%)20/44 (45%)nausea8/76 (10%)5/32 (15%)3/44 (6%)dizziness13/76 (17%)3/32 (9%)10/44 (22%)vomiting13/76 (17%)4/32 (12%)9/44 (20%)syncope6/76 (7%)2/32 (6%)4/44 (9%)fatigue2/76 (2%)1/32 (3%)1/44 (2%)diarrhea5/76 (6%)1/32 (3%)4/44 (9%)headache5/76 (6%)1/32 (3%)4/44 (9%)Figure 1
Result of Autonomic testing.
OI: orthostatic intolerance, DB: Deep breathing, and OH:
orthostatic hypotension.The symptom
replicated during tilt was abdominal pain in 28/32 (87%) of the RGI group, nausea
2/32 (6%) and vomiting in 2/32 (6%). By definition, symptoms were not
replicated in the NRGI group (Figure3). The RGI group had a greater frequency
of POTS than the NRGI group (88%) 28/32 versus (70%) 31/44 (p=0.09, Table 1). Many patients with POTS also had reflex syncope, present in 18/32 (56%) in the RGI
group and 10/44 (23%) in the NRGI group. OH occurred in 1 subject in each
group. Abnormal cardiac reflexes (abnormal Valsalva maneuver or abnormal deep
breathing) were more common in the NRGI group, though this did not reach
statistical significance. In the NRGI group, 8/44 children had normal tilt
testing test (18%), whereas only 1 patient had normal testing in the RGI group.
All but one patient on TTT in the RGI group showed some form of orthostatic
intolerance with patients having POTS, syncope, OH or both POTS and syncope.
The distribution of abnormalities is rendered algorhythmically in Figure 1. There
was no significant difference between quantitative sudomotor axon reflex
findings in the two groups (an indicator of autonomic neuropathy).Treatment was not standardized and generally
selected based on symptoms and results of the autonomic nervous system testing,
often with more than one agent (Table3). In addition, all patients were asked
to supplement salt and fluids to their diet, and increase their physical
activity.  Not surprisingly, patients in the RGI group were more often treated with fludrocortisone
15/32 (46%) aimed at their orthostatic symptoms (mainly POTS) compared to the
NRGI group where only 8/44 (18%) received fludrocortisone P=.01. Of patients
receiving fludrocortisone, patients in the RGI group tended to benefit more,
with 11/15 (73%) reporting an improvement in their symptoms versus 2/8 (25%)  in the NRGI group (Figure 2).Table 3
Treatment choices in both groups.
Treatment groupOverallRGIn=32NRGIn=44Volume expansion/
Fludrocortisone23/76 (30%)15/32 (47%)8/44 (18%)Tricyclic antidepressant9/76 (12%)6/32 (19%)3/44 (7%)Beta-blockers25/76 (32%)10/32 (31%)15/44 (34%)Cyproheptadine3/76 (4%)2/32 (6%)1/44 (2%)SSRI’s18/76 (23%)10/32 (31%)8/44 (18%)Antiepileptic5/76 (6%)2/32 (6%)3/44 (7%)Proamatine9/76 (12%)5/32 (16%)4/44 (9%)Neurontin2/76 (2%)1/32 (3%)1/44 (2%)Mestinon1/76 (1%)1/32 (3%)0/44 (0%)No Treatment17/76 (22%)3/32 (9%)14/44 (31%)Figure 2
Fludrocortisone treatment
effect.Figure 3
Gastrointestinal (GI)
Symptom profile of patients who underwent autonomic testing.


## 4. Discussion

This study divided
patients with functional abdominal pain into a subgroup whose symptoms were
replicated during the upright portion of the tilt table study (RGI) and a subgroup
where this did not occur (NRGI).  The
results suggest that this classification may make sense from both a physiologic
and an outcome perspective.  The RGI group
tended to be younger, with a shorter duration of symptoms, a preponderance of
abdominal pain, and a higher incidence of POTS.
These children appeared to respond better when treated for their
orthostatic symptoms with fludrocortisone. In contrast, the older NRGI subgroup
had less POTS, and most of the abnormal autonomic reflexes in the entire cohort
were found in this subgroup.  From an
autonomic perspective, the RGI group was quite homogeneous, as nearly all
patients had some form of orthostatic intolerance on TTT (POTS, Syncope, and OH).
On the other hand, the NRGI group appears more heterogeneous, with some
subjects entirely normal, some with the same findings as the RGI group, and
some even more abnormal with abnormal cardiovascular reflexes such as a reduced
response to deep breathing or reduced Valsalva ratio. Such a discrepancy
between the two groups further suggests that symptom replication by tilt study may
be physiologically important.One could imagine several
explanations for the difference between these groups.   Both
sets of children could be suffering from the same disorder, but the RGI group
in whom abdominal pain predominated may have harbored more bothersome symptoms,
resulting in an earlier presentation.
According to this hypothesis, the disorder might evolve through a phase
in which symptoms are more variable depending on patient activity, diet, position,
and so forth, (represented by the RGI group in this study) to a final stage in which symptoms
become “hard-wired,” here represented by the NRGI group.  Support for this notion can be drawn from the
chronic pain literature, where such a progression is well recognized, for
example, in complex regional pain syndrome, and in chronic failed back syndrome [13, 14].Alternatively, our
findings could reflect 3 physiologically distinct groups of children with
functional abdominal pain.  The first
group (the entire RGI cohort) has symptom replication on tilt table testing,
owing to some type of dynamic alteration in gastrointestinal blood flow during
orthostatic challenge, an abnormality that is more responsive to medical
management, with consequent better outcome.
This group might correspond to
the term “gastrointestinal vasomotor dysautonomia.”  A second group, perhaps termed
“gastrointestinal neuropathic dysautonomia” would constitute the NRGI subgroup
with abnormal autonomic testing, reflecting a static abnormality of autonomic
innervation to the gut, perhaps resulting in abnormal motility, and less
responsiveness to treatment.  The third
group, “gastrointestinal nonautonomic dysfunction” would comprise the NRGI
subgroup with entirely normal autonomic testing, in whom there is neither a
dynamic blood flow abnormality, nor a static loss of innervation with
dysmotility, and where the abdominal pain appears to bear no relation to any
autonomic abnormality.The concept of a
gastrointestinal vasomotor disturbance accounting for symptomology in the RGI
group dovetails well with some recent POTS investigations, emphasizing
mesenteric hyperemia as a major finding in certain POTS subgroups [15].
As postulated by Stewart et al. the mechanism of this hyperemia could include a
focal denervation, or more likely, local neuroendocrine factors in the enteric
nervous system, such as nitric oxide or vasoactive intestinal peptide resulting
in inappropriate vasodilation.  Other
considerations might include abnormal autonomic-enteric influences, or even central nervous
system alterations, as postulated in abdominal migraine.  Serotonergic pathways could play a role here,
since both POTS [16] and functional abdominal
disorders (e.g., IBS [17])
have demonstrated serotonergic abnormalities.
Future studies could determine whether there is an association between
splanchnic hyperemia and the presence of tilt-induced gastrointestinal symptoms
and the potential role of gastrointestinal motility.Clinically, the
classification into 3 groups may have some utility.  The “gastrointestinal vasomotor dysautonomia”
subgroup is slightly younger, have had symptoms for less time, and respond
better to treatment.  The
“gastrointestinal neuropathic dysautonomia” and “gastrointestinal non-autonomic
dysfunction” groups, both contained in the NRGI group in this study, may well
differ in characteristics, but will require a larger prospectively gathered
cohort for a better comparison of their features and outcomes.  Utilizing this putative classification to
classify patients prospectively will also likely determine which treatment
modalities provide optimal benefit in each group, and further delineate the
phenotype of these children.A majority of
patients, regardless of subgroup, demonstrated POTS
as the primary abnormality on autonomic testing.  The pathophysiology underlying this disorder
remains elusive to-date, although, akin to the proposed classification above
for functional gastrointestinal disorders, one can group patients into those
who have abnormal autonomic reflexes and those who do not [5].  POTS represents a form of nonspecific
autonomic dysregulation, which may be classified as resulting from either a
peripheral or a central autonomic nervous system etiology, based on the axon
reflex response [5].  Interestingly, those with a presumed
peripheral cause in this particular study had a greater frequency of migraine
headache and gastrointestinal symptoms. However, in the present study we did
not find a difference in axon reflex responses, and thus no suggestion that a
peripheral autonomic process is more likely in one dysautonomic group than in
the other.  This could, however, relate
to the lack of power in the present study to detect such a difference.This study has
several additional limitations. The large number of children with functional
abdominal pain who had POTS (77%, Table1) could result from a referral bias,
since many patients were sent for evaluation of dysautonomia.  A randomly selected population of patients
with functional gastrointestinal disorders may harbor less POTS.  Secondly, since children are being treated clinically
without a standardized care-path, treatment benefit is difficult to assess
objectively, and we do not truly know the number of patients who improved with
medications targeted at various putative mechanisms.  For the same reasons, we do not know how many
patients benefited from physical activity and other forms of conditioning,
which we commonly prescribe.  Thirdly, we
do not have adequate information about puberty and menstrual status in our
patients, to know the significance of this factor in the subgroups.  Finally, the study is retrospective, and
subject to well-known biases of such a design, as already alluded to earlier in
the discussion. Nonetheless, it is fair to summarize by stating that autonomic
testing reveals different and interesting subpopulations of patients with
functional abdominal disorders, which may harbor physiologic importance, and
ultimately lead to a better understanding of the mechanism of these symptoms
and their treatment.



---

*Source: 868496-2009-05-05.xml*