The lower esophageal sphincter zone seems to exist from birth
C. Di Lorenzo (Pittsburgh)
Approximately 40% of normal term infants regurgitate at least once every day [1]. In most cases, evaluation of these infants reveals no definable anatomic, metabolic, infectious, or neurologic etiology, and gastroesophageal reflux (GER) resolves spontaneously after few months. However, in some preterm infants and in a subgroup of term infants, GER may cause significative morbidity and mortality. Because of the scope of this problem there has been great interest in trying to clarify the maturation of the gastroesophageal junction. Unfortunately, several studies using different animal models and, more recently, investigations in human infants have produced somewhat controversial results and current knowledge is still fragmentary.
Anatomy
Although the majority of research studies have focused on the maturation of the gastroesophageal sphincter, it is now clear that other factors, such as the intra-abdominal portion of the esophagus, the esophago-gastric angle, and the crural diaphragm may play an important role in the function of the gastroesophageal junction.
The length of the lower esophageal pressure zone increases from an average of 0.6 cm at 27 weeks gestation to 1 cm at term [2]. The presence of an intra-abdominal esophagus is vital to ensure an antireflux barrier. Because of the maturational changes occurring during gestation, the intra-abdominal portion of the esophagus is very short in the term infant but may be much more prominent in the preterm infant. In the 8 weeks fetus, the abdominal esophagus is as wide and large as the stomach. Gradually it shortens so that at birth it is only few millimeters long [3]. As the infant grows, the abdominal esophagus increases again in length, so that in few years it is 1.5 cm long.
The gastroesophageal angle is variable. In the empty stomach, in most cases it is more than 90°. When food and gas are present, the fundus rises higher and bulges medially so that the angle becomes more acute, making reflux of gastric contents more difficult [4]. The gastroesophageal angle seems to be more obtuse in infants than in adults [5].
There is evidence that the crural fibers of the diaphragm are extremely important in generating the lower esophageal pressure zone. The diaphragm can produce occlusion of the esophageal lumen independently from the esophageal sphincter by a so-called pinchcock mechanism [6]. With each inspiration the diaphragm contracts, at times when reflux would be facilitated by the decrease in intrathoracic and the simultaneous increase in abdominal pressure. This diaphragmatic crura also contracts in response to increased intra-abdominal pressure. This is an important defense mechanism, especially during some common forms of sustained abdominal straining, such as crying or bending. The diaphragm fits tightly around the esophagus creating a localized area of esophageal constriction [4]. In newborns, the crural muscles are thick and provide an oblique hiatal tunnel which encircles the lower esophagus. The hiatal tunnel is less evident in the older child.
A phreno-esophageal membrane, composed of two layers, holds in place the fundus and the lower esophagus. This structure is not a ligament. It is a fibroelastic membrane specially designed to tolerate the continuous movement of the hiatus during diaphragmatic contractions throughout life. The collagenous and elastic elements of the phreno-esophageal membrane increase with fetal age. This membrane constitutes the only fixation of the esophagus to the diaphragmatic hiatus. The fixation is much more firm in infants than in children or adults [4], because, due to the respiratory movements, the layers of the membrane slowly become more stretched [7].
Function
Early studies reported that the lower esophageal sphincter (LES) pressure is decreased in human infant [5, 8]. Recently, other investigators have shown that, from the first day of life, the LES pressure in the pre-term and term infants is similar to the pressure found in adults [9]. The use of different investigative techniques represent a possible cause for this difference. It has been demonstrated that within the same sphincter catheters with different diameters measure variable values of intraluminal pressure [10]. The recorded pressure can change by more than 50% by increasing the amount of stretch induced by a different catheter. Thus, studies using different measuring devices in infants of similar size are impossible to compare. Similarly, the different size of the esophagus in infants and adults makes it difficult to compare studies done using similar manometric techniques in the two age groups.
Animal studies
The LES pressure in the newborn opossum, a very immature species at birth, is quite low and it increases with age. The LES pressure in the newborn opossum was associated with a smaller LES muscle mass and a reduced responsiveness to gastrin [11]. Similar findings have been reported in kittens and neonatal beagle puppies. In the kitten LES, there was an increase in pressure throughout the first 6 weeks of life, at which time the pressure was approximately one half that of the adult cat [12]. To determine whether the reduction of in vivo kitten LES pressure was the result of reduced forces, stresses, or mechanical disadvantages from anatomic differences in the amount of muscle, Hillemeier et al. isolated and tested esophageal rings from the site of the manometric sphincter [12]. Muscle rings from adult cats generated greater forces and kitten rings had less muscle. However, when the force per unit of muscle area was calculated, the kitten muscle generated greater force per unit of mass. Nevertheless, although the muscle is capable of generating larger amount of force, there is simply not enough muscle in the kitten LES to overcome the mechanical disadvantages of the reduced thickness. The kitten LES was also less sensitive to myogenic and neurogenic muscarinic stimulation and to relaxation induced by electrical field stimulation than the adult LES [13]. In normally developing beagle puppies, there is an increase in LES-gastric fundus pressure gradient during the first two postnatal weeks. Such maturational process appears to proceed initially independently of gastrin. After the second week of life, higher endogenous gastrin levels and changes in the LES and fundic sensitivity to gastrin may contribute to the increase of the LES-gastric fundus gradient [14]. The findings that newborn LES muscle generates increased force per unit of mass relative to adult animals has not been confirmed by the study of other muscle groups. Cardiac muscle in lambs generates as much force in newborn as in adults [15] and ureteral muscle generates more force in the adult compared to the newborn guinea pig [16].
Human studies
The relative scarcity of data in term and preterm human newborn is mainly due to the lack of suitable measurement techniques. Commonly used esophageal manometry catheters have outside diameters and require perfusion rates too high to be safely used in neonatal studies. Only recently there has been the development of perfusion catheters with an outside diameter of 2 mm or less (similar to a standard gavage tube) and up to 9 recording lumina with diameters of 0.35 mm each. Perfusion rates as low as 0.05 ml/min have now been shown to provide acceptable fidelity and pressure increase rates. It is now possible to incorporate in such miniaturized catheters a sleeve sensor for monitoring LES motility [9].
Some of the first studies of the LES pressure were performed by Gryboski [8, 17] using a non perfused manometric system. The impaired pressure response of such a system may explain the very low LES pressures noted in preterm and term infants. She also reported that there was a slight LES pressure increase with maturity. Boix-Ochoa and Canals [5] used a perfused side hole pull-through technique to perform 4028 manometric studies of the LES in infants from 34 weeks gestation to term. They found that the LES pressure was low in premature infants (0-6 mmHg) and it increased with post-natal age independently of gestation age. More recently, Newell et al. demonstrated that the LES pressure increased from 3.8 mmHg at 29 weeks gestation to 19.1 at term [3]. In their study, the sphincter pressure increased with post-conceptional age and was not primarily determined by post-natal age. In other studies, LES pressure was found to be high in newborn infants (mean LES pressure: 42 mmHg) and to decline during the first year of life [2, 18].
The pull-through technique has the disadvantage of providing a sample of LES pressure that is unreliable because of the well known changes in LES pressure over time [19]. Unlike side holes, sleeve sensors allow accurate monitoring of LES pressure for prolonged time. Such technique also overcomes the problem of displacing the side hole sensor during the movement of the esophagus associated with swallowing. By using a sleeve sensor, Omari et al. demonstrated that in premature infants, with a post-conceptual age ranging between 33 and 38 weeks, the mean LES pressure was 20.5 mmHg before and 13.7 mmHg after feeding [9]. They recorded instances of LES relaxation in response to swallowing, with a timing similar to that found in adults. There were also some LES relaxation independent from swallowing suggesting that the mechanisms of gastroesophageal reflux in preterm infants could be similar to those demonstrated in older children.
References
5. Boix-Ochoa J, Canals J. Maturation of the lower esophagus. J Ped Surg 1976;11:749-756.
17. Gryboski JD. Suck and swallow in the premature infant. Pediatrics 1969;43:96-102.