Objectives: Cystic fibrosis patients have a wide spectrum of gastrointestinal disorders. The aim of this study was to investigate the function of gastroenteric neuromusculature and its response to a prokinetic.
Methods: 14 CF children aged 8.6 + 1.3 years were studied by electrogastrography and compared to 10 age-matched controls. A second recording was performed in CF patients after administration of cisapride (0.3 mg/kg). Parameters analyzed were percentage of normal gastric rhythm (2.0 to 4.0 cpm), percentage of tachygastria (4.0 to 9.0 cpm), dominant frequency instability coefficient and power ratio.
Results: CF and control groups were not different in age, height or weight. A significant post-prandial increase in percentage of tachygastria (26.7 + 4.5 versus 12.4 + 2.6; P < 0.05) was seen in CF patients, which was not corrected by cisapride. The power ratio showed a statistical increase in 3 cpm (3.7 + 0.8 versus 1.6 + 0.3; P < 0.05) and in tachygastria (5.3 + 1.2 versus 1.7 + 0.4; P < 0.03) in CF compared with controls. Cisapride had an effect on tachygastria power ratio (3.0 + 0.5; P < 0.04). Analysis of normal rhythm and the dominant frequency instability coefficient were not statistically different in CF and controls.
Conclusion: This study provides evidence of gastric dysmotility in CF patients.
*Department of Pediatrics, †Division of Pneumology, HUG, Faculty of Medicine, Geneva; and ‡Department of Pediatrics, CHUV, Faculty of Medicine, Lausanne, Switzerland.
Received March 3, 2004; accepted April 19, 2004.
Address correspondence and reprint requests to Dominique C. Belli, Pediatrics Gastroenterology Unit, Clinique Universitaire de Pédiatrie, 6, rue Willy-Donzé, 1211 Geneva 14 /Switzerland (e-mail:firstname.lastname@example.org).
Cystic fibrosis (CF) is a multisystemic disease, although clinical symptoms affecting the pulmonary and gastrointestinal (GI) systems predominate. Increasing attention has been given to abnormalities in GI motility in CF, as these patients have many symptoms suggesting either dysmotility or intestinal obstructive phenomena. The source of altered GI motility in CF is unclear. The traditional explanation that it is the result of abnormal secretions on duodenal receptors, which are sensitive to acid, osmolarity and fatty acids (1), seems unlikely. Abnormality of nutrient sensing might however result in a delay in gastric emptying by inhibiting the tonic contraction of the fundus.
Surface electrogastrography (EGG) is a technique which measures gastric myoelectrical activity non-invasively from electrodes on the abdominal skin. EGG was first used in 1922 (2) and further developed during the 1980s (3). This technique has been validated by comparisons between serosal and cutaneous measurements in animals and humans. Gastric slow waves, originating in the pacemaker region on the greater curvature near the junction of the gastric fundus and proximal corpus, are propagated toward the pylorus at a rate of one wave front every 20 seconds in humans. EGG represents the frequency of gastric slow waves (4), and its dominant frequency seems to be associated with gastric motility (5). The normal spectrum is between 2.0 and 4.0 cpm, and is expressed as the proportion of time spent in normal rhythm (6,7). The dominant frequency reflects the frequency at which the power peaks (8). The power reflects the contractility of the stomach and represents the contribution of a given frequency. It increases when more of a specific frequency is recorded and therefore usually increases after a meal. It seems to predict gastric emptying in that 3 cpm waves are essential in normal subjects and lost or decreased in patients with delayed gastric emptying (9). The exact relationship between gastric emptying and EGG variables is still a matter of debate (10). Dysrhythmias include bradygastria when the spectrum has a dominant peak in the 0.5 cpm to 2.0 cpm range and tachygastria if the dominant peak is in the 4.0 cpm to 9.0 cpm range. The dominant frequency instability coefficient (DFIC), indicates more subtle changes in the dominant frequency over time and is calculated as the ratio between the standard deviation and the mean. It represents instability of the myoelectrical frequency and is thus often analyzed in EGG studies (11,12). The aim of our study was to investigate the function of gastroenteric neuromusculature by EGG in CF children and its response to a prokinetic drug.
SUBJECTS AND METHODS
Fourteen children with cystic fibrosis (CF Group) were compared with 10 controls (C Group) (Table 1). Ethical approval for the study was obtained from the local Research Ethical Committee and informed written consent was obtained from parents. The study did not provide direct benefit to CF or control children.
CF patients and controls were studied by EGG as previously described (3,13) after fasting overnight. They were positioned comfortably in the supine position as calm as possible to reduce recording interference. The skin was cleaned and slightly abraded. Two Ag/AgCl electrodes were placed over the stomach. The first was positioned below the left costal margin (fundus area) and the second midway between the xiphoid and umbilicus (antrum area). A third electrode for reference was placed below the right costal margin at the level of the antrum electrode. Ultrasound was used to check the exact position of electrodes on both corpus and antrum.
Subjects were studied in the morning and the EGG test was composed of three parts:
1. a preprandial recording period of 35 minutes.
2. the ingestion of a mixed solid-liquid meal which was standardized for energy and macronutrients (500 kcal/1.73 m2; 15% protein, 35% fat, 50% carbohydrate) and which corresponded to a usual meal for each patient. The patients took their usual dose of pancreatic enzyme supplementation before the meal.
3. a postprandial recording period of 35 minutes.
CF patients underwent two EGGs on separate days without (CF Group) or with (CF+C Group) the addition of a single dose of cisapride of 0.3 mg/kg body weight 30 minutes before the meal.
EGG is a multicomponent recording, which includes signal and noise; only its dominant component represents the gastric signal. Consequently, the frequency of gastric origin at which the power has a peak value is called the dominant frequency, which alone was considered in this study. The signal was recorded by a Digitrapper EGG (Synectics®, Middlesex, UK), which was connected to a personal computer, allowing real-time visual analysis throughout the recording.
By Digitrapper EGG, the signal was amplified in the preamplifier and filtered by a bandpass filter with cutoff frequencies of 0.02 Hz to 0.20 Hz, then digitized using a built-in 8-bit analog-to-digital converter and stored. As the raw signal is difficult to assess virtually, the frequency analysis of EGG is an indispensable tool. The method of frequency analysis applied in this study was the fast-Fourier transform (14), whereas power was analyzed by running spectral analysis, as recommended. EGG analysis was made using software (ElectroGastroGram®, Gastrosoft Inc, TX) that displayed on the computer screen the recorded signal and the dominant mode pseudo three-dimensional running spectrum graph and also performed the spectral analysis. The spectrum was defined in cycles per minute (cpm) as bradygastria if the spectrum had a dominant peak <2.0 cpm, 3 cpm, between 2.0 and 4.0 cpm and tachygastria for >4.0 cpm. The proportion of time spent in normal and aberrant rhythms was determined and percentage of bradygastria, 3 cpm and tachygastria calculated. The instability coefficient (DFIC) and power ratio were also analyzed, the latter being defined as the postprandial divided by the preprandial value of power in both normal and tachygastria periods.
Values are reported as mean ± SEM. Before comparison, the homogeneity of variance was checked by the Bartlett test. All parametric data were compared by analysis of variance for repeated measures or parallel groups when appropriate. The level of significance of the type I error was fixed a priori at 0.05.
Fourteen children with cystic fibrosis (CF Group), eight boys and six girls aged 0.9 to 16.2 years (8.6 ± 1.3 yrs), were compared to 10 controls (C Group), three boys and seven girls aged 2.1 to 11.1 years (7.2 ± 2.3 years). CF and control groups were not different in age, height (125.4 ± 7.6 versus 124.3 ± 5.6 cm) or weight (35.1 ± 8.7 versus 25.8 ± 2.5Kg) CF patients were under regular supervision at our CF clinic and all had been diagnosed by repeated chloride sweat values above 80 mEq/L. Five of the 14 had previously had meconium ileus, five had experienced one or more episodes of distal intestinal obstruction syndrome and two had had clinical signs compatible with gastric dysmotility. They were studied at the time of stable gastrointestinal and pulmonary status when there were no signs of intestinal obstruction or bronchial exacerbation. Their pulmonary function tests, expressed as percentage of predicted values, were FEV-1 (forced expiratory volume in one second) of 73.7% ± 6.9% and FVC (forced vital capacity) of 89.5% ± 4.8%. The healthy control subjects had no gastrointestinal symptoms. The results of the frequencies in fasting and postprandial activity are demonstrated in Table 2. The table shows that preprandially the control group had a proportion of time spent in normal rhythm activity, in bradygastria and in tachygastria that was not different from the CF group. In addition, there was no statistical difference in the DFIC between patients and controls. Postprandially the percentage of tachygastria increased in the CF patients and decreased in the controls, although these changes were statistically insignificant. Consequently, the percentage of tachygastria was significantly different between CF and C groups in the postprandial period. The administration of cisapride had no effect on the frequencies in any period.
Analysis of the power ratio (Fig. 1) shows a statistically significant difference not only in the tachygastria percentage but also in the percentage of 3 cpm between control and CF groups. Cisapride caused a slight, non-significant, decrease in 3 cpm power ratio, whereas it had a significant effect on the tachygastria power ratio, leading to a non-different power ratio between the CF + C group and control group. Consequently the power ratio of CF group was statistically different of both C Gr (P < 0.02) and CF + C Gr during tachygastria (P < 0.04).
This study provides evidence of foregut dysmotility in CF patients. The dysmotility is only partly corrected by cisapride, a prokinetic agent known to accelerate gastric emptying. EGG is a reflection of gastric electrical activities and of mechanical activities of gastric smooth muscle. EGG was first described in 1922 (2) and received more and more attention during the last decade in both physiological and pathophysiological studies of the stomach. Indeed, EGG correlates with gastric motility, as gastric slow waves control the frequency and propagation of the gastric contractions. In patients with delayed gastric emptying, electrical dysrhythmias have been demonstrated (9). EGG has been used to evaluate children with chronic intestinal pseudo-obstruction (15), in central nervous system-associated vomiting, in cow’s milk protein allergy and in non-ulcer dyspepsia (16) and only recently in cystic fibrosis (17).
Cystic fibrosis is not infrequently associated with gastrointestinal dysmotility syndromes related to both foregut and hindgut (gastroesophageal reflux, distal intestinal obstruction syndrome, chronic constipation) (18). It is possible that all these entities are manifestations of a generalised gastrointestinal dysmotility syndrome in CF. Gastroesophageal reflux is common in CF, reported to occur in up to 25% of patients (19). Studies of gastric emptying in CF have provided conflicting results. Several reports have reported that gastric emptying is normal (20,21). Others using different methodologies have shown that gastric emptying is delayed in CF patients (22,23). One EGG manifestation of gastric retention might be an increase in power ratio owing to an increase in contractility. This would explain our observation of a two-fold increase in the power ratio in CF patients compared with controls in both normal rhythm and tachygastria, changes that were not found in a previous study in which symptomatic and asymptomatic patients were compared (17). CF patients also manifest evidence of a GI dysrhythmia shown by an increase in percentage post-prandial tachygastria. This is in keeping with Aktay et al.’s study (17). We would expect these changes to result in delayed gastric emptying. There is good evidence that tachygastria correlates with an absence of gastric contractions (8,24,25).
Our finding of postprandial tachygastria in CF patients is likely to be reflected in postprandial gastric hypomotility. These data correlate well with those of Cucchiara et al., who measured gastric emptying by real-time ultrasonography and demonstrated that gastric motor abnormalities predominate during postprandial period (16). Cisapride is a prokinetic agent that stimulates and restores motility throughout the GI tract through its action as a TH2 agonist (26). It is known to improve digestive and interdigestive antroduodenal motility in humans (27). We have shown cisapride to reduce the increase in tachygastria’s power ratio seen in CF patients, a change expected to correlate with an improvement in foregut motility. However, cisapride remained without effect on the 3 cpm power ratio and frequency. The incomplete correction of the motility disturbance by cisapride is in keeping with Cucchiara et al.’s study, which demonstrated that delayed gastric emptying was unchanged by cisapride (22). These data suggest that suppression of antral motility and increased pyloric activity are only partially reversed by the use of cisapride in CF.
We provide further evidence of an intrinsic disturbance in gastrointestinal motor activity in patients with cystic fibrosis. These adverse effects on gastric emptying are likely to aggravate any tendency to GOR, interfere with delivery of pancreatic exocrine supplements to the duodenum and promote a state of anorexia.
The authors thank Dr. Keith Lindley for reviewing the manuscript and Miss Uta Müller for expert technical assistance. This work was supported by grant-in-aid of the Geneva Section of the Swiss Society for Cystic Fibrosis.
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