Characterization of esophageal motor activity, gastroesophageal reflux, and evaluation of prokinetic effectiveness in mechanically ventilated critically ill patients: a high-resolution impedance manometry study

Dysfunction of the upper gastrointestinal tract (UGIT) leads to deterioration in the patient’s nutritional status, bacterial colonization, and increased risks of reflux esophagitis, and aspiration [1]. Unfortunately, there is very little quantitative and qualitative data regarding esophageal motility functions in mechanically ventilated critically ill patients. Kölbel et al. performed a pilot study of 15 mechanically ventilated patients, which revealed that they had decreased propulsive esophageal motility that was further impaired by any kind of sedation [2]. Nind et al. also evaluated 15 mechanically ventilated patients and reported that gastroesophageal reflux was predominantly related to low or absent lower esophageal sphincter (LES) pressure, which often coexisted with cough or straining [3]. However, those studies evaluated esophageal motility using conventional manometry, where the sensors are spaced at 3–5-cm intervals.

Unlike conventional manometry, high-resolution impedance manometry (HRIM) measures esophageal pressures with 423 sensors distributed longitudinally and radially in the esophagus, along with esophageal impedance monitoring (18 sensors), thus allowing for a very detailed evaluations of esophageal pressures, peristalsis, sphincter functions, and reflux [4]. It might, therefore, identify relevant abnormalities not detected by conventional manometry. Among critically ill patients, pharyngeal HRIM has only recently been used in a study of post-extubation dysphagia [5]. Persson et al. used HRM to evaluate factors affecting esophageal pressures during changes in ventilator settings [6]. Ahlstrand et al. showed that muscle relaxation with rocuronium does not decrease the barrier pressure during anesthesia induction [7]. We believe that HRIM has great potential to improve our understanding of esophageal functions in critically ill patients. In particular, deeper insights into the complex relationships between esophageal motility patterns, antireflux barrier, and gastric emptying may pave way for more effective and safe treatment options and patient care. Therefore, the present mechanistic study used HRIM to characterize the features of esophageal motility in ventilated patients who were receiving intensive care, and evaluated the esophageal physiology and occurrence of reflux depending on the gastric nutritional tolerance. In addition, the effects of metoclopramide were evaluated and related to the esophageal motility patterns.

Demographic and clinical characteristics are presented in Table 2. The main diagnoses were septic shock (5 patients in the LGV and 7 patients in the HGV group), COPD exacerbation (2 patients in the LGV group), cardiogenic shock (1 patient in the LGV group), and aspiration pneumonia (1 patient in the HGV group). Major pathological motility patterns were observed in all patients (Table 3). Esophageal motility abnormalities included both disturbances of contraction vigor, contraction and pressurization patterns and EGJ functions.

This is the first study to use HRIM to characterize esophageal motor activity, reflux mechanisms, and response to metoclopramide in mechanically ventilated critically ill patients during their early recovery phase. The most common patterns were hypercontractility with premature contractions, ineffective propulsive force, and panesophageal pressurization. Gastroesophageal reflux predominantly occurred due to TLESR that was often preceded by panesophageal secondary peristalsis, and reflux was only associated with the absence of LES tone and episodes of straining in a minority of patients. In addition, although all patients had major abnormalities in their contraction vigor and contraction patterns, their characteristics varied according to gastric nutritional tolerance, which is a surrogate parameter for gastrointestinal dysfunction. For example, the LGV group was more likely to have the hypercontractile pattern with panesophageal pressurization, EGJ outflow obstruction, and more frequent reflux. In contrast, delayed gastric emptying was associated with the normal contraction vigor, failed peristalsis, reduced LES tone, and paradoxically fewer reflux episodes. In addition, metoclopramide had opposite effects on the EGJ barrier function in the LGV and HGV groups, but failed to alter the number of reflux episodes in either group.

Very few studies have evaluated quantitative and qualitative physiological parameters of esophageal motility in critically ill [2, 3, 5], and none of those studies have used HRIM in mechanically ventilated patients. The introduction of HRIM in the field of gastroenterology led to the development of novel objective metrics and patterns for describing esophageal motility functions [9]. Hypercontractility with panesophageal pressurization was the most common motor abnormality in our patients, although we observed a very complex spectrum of altered esophageal physiologies. In this context, our study is markedly different from the study performed by Kölbel et al., who used conventional manometry and reported that considerable esophageal hyporeactivity was characterized by reduced propulsive motility, in terms of both the frequency and amplitude of contractions [2]. The difference between their findings and ours might be related to the more intensive analgosedation protocol that they used. Our findings also provide a strong physiological explanation for the negative results of a recent study, which revealed that esophageal electrical stimulation failed to prevent regurgitation and enhance feeding [10].

Another major feature of this study is the evaluation of esophageal physiology in two different gastric motility states. We observed that the LGV group had significantly more esophageal activities than the HGV group, which were associated with greater contraction vigor, more double-peaked waves, and premature and rapid contractions. These factors all reflect spastic peristalsis. Interestingly, a substantial proportion of patients exhibited extremely vigorous peristalsis, which is a pattern that resembles jackhammer (hypercontractile) esophagus [8]. The hyperreactive pattern that was more common in the LGV group was also associated with signs of EGJ outflow obstruction, while ineffective esophageal motility with reduced LES tone was only observed in the HGV group. These intergroup differences may have several explanations. First, the HGV group tended to have higher SOFA scores on the day of measurement and more severe acute kidney injury, which both suggests more severe illness. Furthermore, more frequent use of analgosedation could negatively affect gastrointestinal motility and enteral feeding tolerance in the HGV group [11], whereas the less frequent use of propofol and sufentanil could make the LGV patients more sensitive to irritation caused by the endotracheal and/or nasogastric tubes. Nevertheless, that reasoning is speculative, as the analgosedation was titrated to target the same Richmond Agitation Sedation Score in both groups. Our results may also reflect a physiological connection between esophageal and gastric motility patterns. Indeed, the greater motility in the UGIT of patients in the LGV group might be associated with very good gastric feeding tolerance. However, it was also accompanied by esophageal hypercontractility and EGJ outflow obstruction. The clinical significance of this pattern remains unclear and is it not necessarily indicative of an underlying pathology.

Abnormal esophagus motility disorders in mechanically ventilated patients could be associated with significant clinical consequences, which are related to gastroesophageal reflux and pulmonary aspiration [1]. In this context, low LES pressure and weak or even absent esophageal peristalsis has been traditionally considered crucial for the development of gastroesophageal reflux in critically ill patients [2]. For example, Nind et al. reported that low or absent LES pressure and inadequate esophageal propulsive forces led to poor acid clearance, which was considered the most common mechanism associated with reflux [3]. However, our data suggest that maintaining rest LES tone may not be essential for preventing reflux, as almost 70% of the reflux episodes we observed occurred due to TLESR. Although TLESR may be a normal physiological motor event in healthy subjects [12], previous studies have proven that TLESR plays a crucial role in the occurrence of gastroesophageal reflux disease [13]. It appears that the major mechanisms of reflux in our cohort of patients recovering from critical illness and receiving minimal sedation are similar to non-ventilated patients. By contrast, a notable feature of esophageal activity that often preceded TLESR was panesophageal secondary peristalsis, an abnormality never seen in healthy subjects [12]. It remains unclear, whether this secondary peristalsis is itself a trigger of TLESR. Of note, the absence of LES tone was associated with only a small minority of reflux episodes (18%), and this situation was only observed in patients with HGV. Furthermore, high residual gastric volumes are commonly thought to increase the risk of gastroesophageal reflux [14]. Interestingly, patients in the LGV group had substantially better gastric emptying but also more reflux episodes than patients in the HGV group. Our observations are corroborated by the findings reported by McClave et al., who were unable to identify a threshold for residual gastric volumes that was associated with increased risks of aspiration and pneumonia [15]. Thus, it appears that reflux disease cannot be excluded based on the presence of well-preserved gastric emptying, maintained LES tone, and well-preserved EGJ barrier function in critically ill patients.

Metoclopramide is frequently used to promote motility in the UGIT. However, its beneficial effects remain unclear in critically ill patients [16], and we are not aware of any comprehensive studies regarding the effects of metoclopramide on esophageal physiology and EGJ function. We observed that metoclopramide did not substantially reduce the number of reflux episodes in either group of critically ill patients. In addition, its effects on esophageal functions are noticeably different in the healthy volunteers, where it markedly increases the contraction vigor [15]. Across the observed spectrum of abnormal motility patterns, metoclopramide also paradoxically decreased the number of esophageal events and even tended to weaken the strength of contractions, especially in the LGV group. The mechanisms underlying these unexpected effects remain unclear. In addition, metoclopramide did not substantially influence failed esophageal peristalsis, esophageal pressurization, or EGJ-related parameters. Thus, HRIM does not appear to be able to clinically identify critically ill patients who are likely to benefit from prokinetic stimulation.

This study has several limitations. First, the small sample size may preclude generalization of the results because of selection bias, although this study was only designed as an exploratory physiological study. Focusing on population with “normal” and “delayed” gastric emptying, we studied only patients with two pre-defined, well-separated thresholds for gastric residuals. Hence, the results might not be valid for a wider spectrum of gastric feeding tolerance. Likewise, the observed relationships between reflux and different esophageal patterns should be interpreted with caution as they may be influenced by a correlation within a small number of patients. Second, critical illness is a dynamic process and analyses from a single timepoint only provide a limited perspective regarding these patients. Thus, we suggest that further studies are needed to assess the dynamic long-term implications of our HRIM findings. Third, the definition of abnormalities described in the Chicago classification is based on the analysis of ten 5-ml swallows in patients suffering from dysphagia and/or chest pain and therefore may not necessarily apply to the manometric analysis in ICU patients, in whom dry swallows or spontaneous secondary peristalsis were studied. Finally, all our critically ill patients received anti-ulcer prophylaxis and pH monitoring was not performed for various reasons, including the technical complexity of introducing a pH-meter catheter to the nasogastric tube and HRIM catheter.

In conclusion, this study revealed that HRIM was useful for clarifying the complex esophageal physiology in critically ill patients. HRIM testing in critically ill patients has been found safe and feasible. The results revealed marked heterogeneity in the esophageal motor dysfunctions, as well as links between gastric emptying, esophageal motor patterns, and gastroesophageal reflux. Our study also provides valuable insights into the physiological effects of metoclopramide in this population. Nevertheless, additional studies are needed to better understand the clinical relevance and implications of our findings.