PATIENTS AND METHODS
Eight children with GERD, between 2 months and 16 years (median age, 3 years), were studied. GERD was diagnosed when the total time of pH less than 4.0 in the distal esophagus was greater than 4.0% in 24-hour esophageal monitoring. All subjects had serious neurologic impairment with increased muscular tone and were confined to bed. Their characteristics are detailed in Table 1. The associated diseases were cerebral palsy with spastic quadriplegia in four patients, West syndrome in three, and Brachmann-de Lange syndrome in one. The chief complaints were frequent emesis in five patients, repeated pneumonia in two, and wheezing in one. An upper gastrointestinal series showed no hiatus hernia. Gastroesophageal reflux of barium was seen in two patients, which was graded I and III reflux by the classification of McCauley et al. (11). The total time of esophageal pH <4.0 ranged between 11% and 42% (median, 17%). No patients had a history of surgery that might possibly influence gastrointestinal motility. Seven patients were taking enteral formula via nasogastric tube, and the remaining patient was nourished orally. Ethical approval was obtained from the departmental committee, and informed consent was obtained from each patient's parents.
Administration of prokinetic agents was stopped at least 2 days before the study, and administration of H2-blockers or proton pump inhibitors was stopped 3 days before the study (12). The study was performed during an inpatient hospital admission. The frequency of emesis, muscular tone, duration of sleeping, mood, and heart rate were recorded daily before and during baclofen therapy. Chest x-ray examinations, blood examinations, and 24-hour esophageal pH monitoring were performed on the day before the commencement of baclofen therapy and on the seventh day of therapy. Blood examinations, including white blood cell count, red blood cell count, platelet count, and the levels of hemoglobin, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine were measured. Twenty-four–hour esophageal pH monitoring was performed with the Medtronics MK III equipment (Medtronics, Shoreview, MN). A pH electrode was inserted via the nose. The location of the antimony pH sensor was 3 cm above the gastroesophageal junction with position confirmed by fluoroscopy. Baclofen was administered at a dose of 0.7 mg/kg/day via nasogastric tube or orally in three divided doses 30 minutes before meals for 7 days.
The frequency of emesis assigned a score as follows: 1 - less than twice per week; 2 - more than twice per week; 3 - once per day; 4 - more than twice per day; 5 - after almost every meal. The clinical effect of baclofen on GERD was evaluated by comparing the emesis scores before baclofen therapy with those during therapy. To assess adverse effects of baclofen therapy, clinical symptoms including muscle tone, prolonged duration of sleeping, irritability, and tachycardia were recorded during baclofen therapy.
Esophageal pH Study
Analysis of esophageal pH data was performed with EsopHgram software, version 2.01 (Medtronics). Esophageal acid reflux was defined as a pH drop in the distal esophagus from >4.0 to <4.0. The end of a reflux episode occurred when esophageal pH returned to >4.0. Standard esophageal pH study parameters, including the total number of acid refluxes, the percentage total time esophageal pH was <4.0, the number of long acid refluxes, and the duration of the longest acid reflux were scored (13), and esophageal acid clearance time was determined in each patient both during the 24-hour period and during the postprandial period. Long acid refluxes were defined as episodes greater than 5 minutes. Esophageal acid clearance time was defined as the median value of the durations of all acid reflux episodes in each subject. The postprandial period was defined as the 2-hour period after all meals. Changes in esophageal pH parameters were determined in each subject by comparing the values on the seventh day of baclofen therapy with those on the day before the commencement of the therapy.
The emesis score, the biochemical and hematologic examinations, and esophageal pH parameters were obtained in all patients. The exact values and percentage decrease of esophageal pH parameters were expressed as medians (interquartile range). The data before baclofen therapy and those during the therapy were compared statistically with the Wilcoxon signed rank test. Statistical significance was accepted with a P value of less than 0.05.
The study protocol was completed successfully in all subjects. The emesis score decreased in six (75%) and did not change in two (Fig. 1). The score was significantly decreased from 4 (range, 3–4) to 1 (range, 1–3) (P = 0.03). No adverse effects were noted, except for a slight reduction in muscle tone in one patient.
Chest Radiograph and Blood Examinations
Signs of respiratory infection were not observed in the chest radiograph in any patients during the study period. The blood examinations did not show any significant change (Table 2).
Esophageal pH Study
The details of each parameter of esophageal pH monitoring are shown in Table 3. Total postprandial time evaluated on the day before the commencement of baclofen therapy raged from 7.1 to 12.1 hours (median, 10.0 hours) and was not significantly different from that on the seventh day of the therapy, 7.5 to 12.0 hours (median, 9.9 hours) (P = 0.67).
The total number of acid refluxes was significantly decreased during the entire 24-hour period (P = 0.01) and during the postprandial period (P = 0.049) (Fig. 2). The number of long acid refluxes was significantly decreased during the 24-hour period (P = 0.02) (Fig. 3), whereas there was no significant change during the postprandial period. The percentage total time with esophageal pH <4.0, the duration of the longest acid reflux, and esophageal acid clearance time (Fig. 4) showed no significant change with therapy either during the 24-hour period or during the postprandial period.
Acid suppressors and prokinetic agents have been used in the medical treatment of GERD. Although histamine-2 receptor antagonists and proton pump inhibitors prevent the esophagus from being exposed to refluxed gastric acid, they do not prevent reflux of gastric contents into the esophagus. Prokinetic agents have been used to improve the contractility of the esophageal body and to promote gastric emptying and result in a reduction of acid exposure to the esophagus. However, the efficacy of prokinetic agents for GERD has been confirmed only for cisapride (14), which is not currently in wide use because of concerns about adverse cardiac effects (15). It is recognized that transient LES relaxations are the predominant mechanism of reflux in adult and pediatric patients with GERD (3,4,16). Therefore, the blockade of transient LES relaxations appears an attractive means to reduce reflux. We previously reported that Nissen fundoplication had a significant impact on transient LES relaxation by reducing its frequency and increasing the nadir pressure during transient LES relaxation (17). Mittal et al. (18) demonstrated for the first time that pharmacologic control of reflux through control of transient LES relaxations was possible with atropine. Lidums et al. (19) reported that atropine inhibited reflux in patients with GERD largely by inhibition of transient LES relaxations and swallow-induced LES relaxations. Since then, several pharmacologic agents, such as cholecystokinin antagonists (20), morphine (21), and inhibitors of nitric oxide synthase (22) have been reported to reduce transient LES relaxation frequency. However, these agents have not been applicable to the treatment of GERD because of their adverse effects (23).
Lehmann et al. (24) and Lidums et al. (25) reported that baclofen reduced frequency of transient LES relaxations in dogs and in healthy volunteers, respectively. Zhang et al. (7) reported that a single 40 mg oral dose baclofen significantly reduced the total number of acid refluxes in adult patients by the reduction of transient LES relaxations, but the percentage of total time that esophageal pH was less than 4.0 did not change. Cange et al. (8) and Van Herwaarden et al. (9) reported that a single 40-mg oral dose of baclofen had a significant effect both on the total number of acid refluxes and the percentage of total time the esophageal pH was <4.0. These studies were conducted in adult patients with GERD. The current study is the first trial to clarify the effects of the regular administration of baclofen on GERD in the pediatric population. We found a significant reduction in the total number of acid refluxes after 1 week of baclofen therapy. However, baclofen did not significantly reduce the percentage of total time the esophageal pH was <4.0. A possible mechanism for these findings is that baclofen decreases reflux frequency but simultaneously increases the duration of esophageal acid clearance by reducing swallowing and secondary peristalsis (23). In the current study, the number of acid refluxes longer than 5 minutes was significantly reduced during the 24-hour period, and we noted no significant increase in esophageal acid clearance time. These data are inconsistent with the possibility that baclofen impairs esophageal clearance. Increased gastric acid secretion by baclofen is also a possible cause of the lack of baclofen effect on total esophageal acid exposure (23). Finally, the difference in effects of baclofen on the esophageal acid exposure time among the studies might be attributable to the variable clinical conditions of the experimental subjects, the small number of subjects, and differences in individual study protocols.
Van Herwaarden et al. (9) investigated the effect of baclofen on heartburn, fullness, and regurgitation in adult patients and reported that a single 40-mg dose of baclofen was no different from placebo. They suggested that the baseline symptom scores of the patients studied were too low to show significant improvement. In the current study, the frequency of emesis was chosen to evaluate the effects of baclofen on GERD because emesis is such an important symptom in pediatric patients. Baclofen therapy reduced the frequency of emesis in six of eight (75%) patients, and the change was statistically significant. In one of the two patients who did not experience response to baclofen therapy, surgery for GERD was subsequently performed.
Baclofen has been used to reduce spasticity. Forty milligrams of baclofen is the usual daily dose in adult patients with spasticity (26). In previous studies in adults, baclofen was administered in a single daily dose of 40 mg (7–9). In the current study, the dose of baclofen was determined by referring to the dose commonly used for spasticity in pediatric patients. The dose of baclofen in the current study was considered optimal because significant clinical effects on GERD were noted without serious adverse effects. Measurement of serum baclofen concentrations and comparative studies to determine the optimal dose for GERD are needed in pediatric patients.
Previous studies have investigated the adverse effects of a single 40-mg dose of baclofen (7–9,25). Lidums et al. (25) found no significant difference in symptom scores between patients treated with baclofen and those treated with placebo, but reported two females of 20 healthy volunteers who experienced lethargy for almost 24 hours after the administration of baclofen. Zhang et al. (7) reported no significant difference in the complications reported with baclofen and placebo. Cange et al. (8) reported a more frequent association of tiredness or mild vertigo in patients treated with baclofen than in those treated with placebo. Van Herwaarden et al. (9) also reported more frequent mental/neurologic symptoms, such as dizziness, sleepiness, tiredness, vertigo, and accommodation disorder in patients treated with baclofen compared with those taking placebo. The current study showed no adverse effects, except for a slight reduction in muscle tone in one subject. Unfortunately, in our subjects, the only objective symptoms we were able to investigate were muscle tone, prolonged duration of sleeping, irritability, and tachycardia. Because baclofen tends to be used at gradually increasing doses in patients with spasticity, a step-by-step increment of baclofen dose might be helpful to reduce its adverse effects.
Neurologically impaired children with GERD are currently the major targets of laparoscopic fundoplication in the pediatric population. The postoperative problems and the incidence of recurrent reflux are not insignificant in such patients (10). Medical therapy would be attractive in the care of these patients if it could control reflux and the related symptoms in even a small subset of affected children. Baclofen could be effective for GERD in neurologically normal pediatric patients. However, neurologically normal children may have more or different adverse symptoms because their expectations and activities are so markedly different from the subjects of the current study.
In conclusion, 1-week baclofen therapy given three times daily had significant effects on GERD in neurologically impaired children. Because therapeutic options for these patients are limited, medical treatment with agents such as baclofen that reduce transient LES relaxations may be promising. Additional studies are required to determine the indication of baclofen therapy and to establish an adequate regimen for its clinical application to GERD.
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