Selective dysfunction of the crural diaphragm in patients with chronic restrictive and obstructive lung disease

Abstract

Background:

Gastroesophageal reflux (GER) is known to be associated with chronic lung diseases. The driving force of GER is the transdiaphragmatic pressure (Pdi) generated mainly by costal and crural diaphragm contraction. The latter also enhances the esophagogastric junction (EGJ) pressure to guard against GER.

Methods:

The relationship between Pdi and EGJ pressure was determined using high resolution esophageal manometry in patients with interstitial lung disease (ILD, n = 26), obstructive lung disease (OLD, n- = 24), and healthy subjects (n = 20).

Key Results:

The patient groups did not differ with respect to age, gender, BMI, and pulmonary rehabilitation history. Patients with ILD had significantly higher Pdi but lower EGJ pressures as compared to controls and OLD patients (p < 0.001). In control subjects, the increase in EGJ pressure at all-time points during inspiration was greater than Pdi. In contrast, the EGJ pressure during inspiration was less than Pdi in 14 patients with ILD and 7 patients with OLD. The drop in EGJ pressure was usually seen after the peak Pdi in ILD group (p < 0.0001) and before the peak Pdi in OLD group, (p = 0.08). Nine patients in the ILD group had sliding hiatus hernia, compared to none in control subjects (p = 0.003) and two patients in the OLD, (p = 0.04).

Conclusions and Inferences:

A higher Pdi and low EGJ pressure, and dissociation between Pdi and EGJ pressure temporal relationship suggests selective dysfunction of the crural diaphragm in patients with chronic lung diseases and may explain the higher prevalence of GERD in ILD as seen in previous studies.

1 ∣. INTRODUCTION

There is a strong association between gastroesophageal reflux disease (GERD) and chronic lung diseases (CLD), seen in up to 90% of patients with interstitial lung disease (ILD), 20%–40% of patients with chronic obstructive lung disease (COPD), and many patients with asthma.^1-5 GERD is also associated with cough, shortness of breath, deterioration of lung function, and increased frequency of respiratory exacerbations in patients with chronic lung disease.⁴ Post-lung transplant, persistent GERD is often thought to be the cause of rejection of transplanted lung.⁶ Regarding the mechanism of association between GERD and chronic lung disease, arguments exist on both sides; lung disease may cause GERD, or the latter may cause lung disease. With regards to GERD causing lung disease, two possibilities have been proposed, (1) acid reflux into the esophagus may induce bronchospasm through a vagovagal reflex pathway,⁷ and (2) micro-aspiration of refluxed material into the lung may cause chronic lung disease such as ILD.^8,9 On the contrary, with regards to lung disease causing GERD, it is suggested that the gastroesophageal pressure gradient, which is same as the transdiaphragmatic pressure (Pdi), is higher than normal in chronic lung disease, which predisposes patients to GERD.^10,11

There are two major types of ventilatory defects, restrictive and obstructive. In obstructive lung disease (OLD) like COPD/emphysema, because of hyper-inflated lung, the diaphragm is “flat” that is, in the descended position.^12-14 On the contrary, in restrictive lung disease like ILD, the diaphragm is in ascended position.¹⁵ The position of the diaphragm determines its length, which is an important determinant of its function as per the length-tension principle of muscles.^16-18 Previous studies in COPD have shown that there are chronic adaptations in the diaphragm muscle fibers that partly preserve its force generating capacity during tidal breathing despite the shortened length.^16,19,20

The diaphragm has three components, costal, sternal and crural (right and left crus), and they arise from the ribs, the xiphoid process and the lumbar spine respectively.²¹ Electrical stimulation of costal as well as crural diaphragm leads to an increase in the Pdi,²² a driving force for the GER.²³ On the contrary, isolated electrical stimulation of the crural diaphragm also results in an increase in the esophagogastric junction (EGJ) pressure, an anti-reflux barrier function.^5,24-27 Under normal conditions, with each inspiration, the costal and crural diaphragm contract together, the latter a few milliseconds earlier than the former and the EGJ pressure is always greater than the Pdi. Studies show a strong linear correlation between the Pdi and EGJ pressure during diaphragmatic contraction in normal healthy subjects.²⁵ Alteration in the length of the costal and crural diaphragm muscle in ILD and OLD disease may affect the relationship between Pdi and EGJ pressure in such a way that may predispose to GER.

The goal of our study was to determine the Pdi and EGJ pressure during diaphragmatic contraction in three groups of subjects, (1) normal healthy asymptomatic subjects, (2) patients with chronic restrictive lung disease, and (3) chronic obstructive lung disease (OLD).

2 ∣. MATERIALS AND METHODS

2.1 ∣. Subjects

We retrieved data from patients with ILD (26 subjects) and patients with OLD like COPD, chronic bronchitis, and bronchiectasis (24 subjects) who had undergone high resolution esophageal manometry (HRM) and pulmonary function tests (PFTs), as a part of their routine clinical care at the University of California San Diego (UCSD), between April 2018 and March 2022. Patients with incomplete data, scleroderma related esophageal dysmotility, mixed obstructive and restrictive ventilatory defect on PFT, prior foregut surgery or primary esophageal motility disorders were excluded from the study. The HRM studies of 20 healthy control subjects with no pulmonary/esophageal symptoms, who had participated in prior esophageal research studies in the laboratory of senior author at UCSD were also scored. Data including demographics, history of GERD, smoking and pulmonary rehabilitation, type of lung disease and PFTs test were retrieved from the chart review of all patients. The HRM studies were scored by two independent observers and then reviewed by the senior author for data accuracy.

2.2 ∣. High resolution esophageal manometry (HRM)

The HRM catheter contains 36 solid-state pressure sensors, spaced 1 cm apart, on a 4.2 mm diameter catheter (Medtronics Inc).^28,29 The pressure from each sensor is displayed as a heat map along the entire length of the catheter (from pharynx to stomach). Using the smart mouse function of the Manoview software (Medtronics Inc), esophageal manometry studies were analyzed to obtain esophageal, EGJ and stomach pressures. In the absence of hiatus hernia, the lower esophageal sphincter (LES) and crural diaphragm are anatomically superimposed on each other and are collectively referred to as the EGJ pressure. The end expiratory EGJ pressure is due to the smooth muscle LES and the increase in pressure with inspiration is due to the skeletal muscle crural diaphragm contraction.^25,30 In hiatus hernia patients, the LES and crural diaphragm are anatomically separate and therefore one records two separate high pressure zone, LES and crural diaphragm.^5,27 The esophageal pressure represented an average pressure between upper esophageal sphincter and EGJ, (5 cm below lower border of upper esophageal sphincter and 5 cm above the upper border of the EGJ). The stomach pressure was measured at 2 cm below the EGJ, (Figure 1). The Pdi was the difference between gastric and esophageal pressure. In patients with no hiatus hernia, the EGJ pressure was calculated by drawing a box around the EGJ and average pressure inside the box was noted. On the contrary, in patients with hiatus hernia, the box was drawn on the crural diaphragm component of the EGJ. The above measurements were obtained during expiration and inspiration phases of the respiratory cycle, during five tidal breaths and three deep breaths, and an average value was determined for tidal inspiration and forced inspiration.

FIGURE 1.

(A), Schematic diagram showing position of the manometer catheter in the GI tract with sensors at 1 cm intervals. (B), Manometry recording showing pressure changes (mmHg) in the esophagus, stomach, and EGJ during tidal and deep breathing in a control subject. The pressure from each sensor is displayed as heat map along the entire length of the catheter. Pressure in the esophagus drops during inspiration and increases during expiration while pressure in the EGJ and stomach increases during inspiration and decreases during expiration. The white boxes represent the areas selected to measure mean pressures in the three compartments in this study. EGJ, esophago-gastric junction; GI, gastrointestinal.

The temporal relationship between Pdi and EGJ pressure during each inspiration was plotted graphically using a custom-built software. The difference in peak pressures of EGJ and Pdi pressure curve and time lag between the two peaks were calculated for each group and compared.

Hiatus hernia was identified in the HRM recordings when there was a separation of >2 cm at expiration between the high-pressure zones of the LES and crural diaphragm.³¹ The length of esophagus was measured between the lower border of upper esophageal sphincter and upper border of EGJ.

2.3 ∣. Statistical analysis

Data are presented as mean±SD. Analysis of Variance method was used to compare the differences between the groups for each continuous outcome and Fisher's exact test for comparing the differences between groups for each binary outcome. Statistical significance was adjusted for multiple comparisons based on Bonferroni correction. A p < 0.05 was considered statistically significant.

2.4 ∣. Ethics

The authors had no conflict of interest. All authors contributed sufficiently and are responsible for the manuscript. No professional or ghost writer was hired to write this manuscript. The study protocol was approved by the local ethics committee (protocol # 202106).

3 ∣. RESULTS

3.1 ∣. Patient characteristics

The demographic data are shown in Table 1. The ILD and OLD groups did not differ with regard to age (p = 0.249), body mass index (p = 0.208), gender (p = 0.387), or history of pulmonary rehabilitation (p = 0.762). GERD symptoms were reported by 76% patients in the ILD group and 55% in the OLD group, the difference between the two was not significant (p = 0.14). The rate of cigarette smoking was higher in the OLD group (p = 0.009). Pulmonary function testing showed significantly lower FVC and higher FEV1/FVC ratio in patients with ILD compared to patients with OLD, consistent with restrictive and obstructive defects, respectively (p < 0.001). The etiology of ILD and OLD are described in Table 1.

TABLE 1.

Patient characteristics.

				p-Value
	Control	Interstitial lung disease	Obstructive lung disease	Ctrl vs. ILD	Ctrl vs. OLD	ILD vs. OLD
N	20	26	25
Age, Mean (SD)	27.47 (8.14)	62.8 (11.7)	60.0 (8.72)	<0.001	< 0.001	0.249
BMI, Mean (SD)	26.31 (6.33)	27.5 (4.5)	27.3 (8.6)	0.5	0.7	0.208
Female (%)	53	46	36	0.318	0.751	0.399
Smoking (%)	-	38	83			0.009
Type of lung disease		Idiopathic pulmonary fibrosis (10)	Emphysema (19)
		Hypersensitivity pneumonitis (9)	Chronic bronchitis (3)
		Connective tissue disease-ILD (1)	Bronchiectasis (3)
		Idiopathic NSIP (1)
		Sarcoidosis (1)
		Organizing pneumonia (1)
		Unclassifiable (3)
History of GERD (%)		73	56			0.140
Pulmonary rehabilitation (%)		56.3	43.8			0.762
		PFT Data, Mean (SD)
FVC, % predicted		46.9 (13.9)	67.2 (15.7)			<0.001
FEV1, % predicted		50.7 (13.7)	38.4 (19.6)			0.019
FEV1/FVC		86.1 (7.1)	43.8 (13.7)			<0.001

Abbreviations: FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GERD, gastro-esophageal reflux disease; ILD, interstitial lung disease; NSIP, nonspecific interstitial pneumonitis; PFT, pulmonary function test.

3.2 ∣. High resolution manometry data

Figure 2 and Table 2 show the changes in esophageal, EGJ and stomach pressure during tidal and deep breaths in healthy control subjects, patients with ILD and OLD. The esophagus length was shorter in the ILD and longer in OLD patients compared to controls, consistent with hypo-inflated and hyper-inflated lungs, respectively (p < 0.001).

FIGURE 2.

Representative manometry recordings showing changes in the esophageal, EGJ and stomach pressure during tidal and deep breaths in a healthy control, a patient with ILD and a patient with OLD. (A, B), In normal subject, the esophageal pressure falls, EGJ pressure increases, and stomach pressure increases during inspiration. (C, D) In patient with ILD, the breaths are deeper and faster. The fall in esophageal pressure is greater and EGJ pressure increase is relatively smaller causing higher Pdi and lower pressure difference between Pdi and EGJ pressure. (E, F) The changes in esophageal, EGJ and stomach pressure in patient with OLD are similar to normal subject. EGJ, esophago-gastric junction; ILD, interstitial lung disease; OLD, obstructive lung disease; Pdi, transdiaphragmatic pressure gradient.

TABLE 2.

Manometry findings.

				p-value
	Controls	ILD	OLD	Ctrl vs. ILD	Ctrl vs. OLD	ILD vs. OLD
N	20	26	24\
Mean esophagus length (cm)	22.2 (2.5)	21.4 (1.9)	24.8 (2.1)	0.237	< 0.001	< 0.001
Manometry Data (mmHg) in Mean (SD)
Deep inspiration esophageal pressure	−4.41 (3.2)	−23.32 (7.1)	−9.28 (5.2)	< 0.001	< 0.001	< 0.001
Deep inspiration gastric pressure	17.09 (6.4)	15.57 (9.8)	19.52 (11.4)	0.529	0.378	0.196
Deep Inspiration Pdi	26.5 (8.6)	38.9 (12.1)	28.3 (13.8)	< 0.001	0.6	0.005
Deep Inspiration LES Pressure	72.2 (12.9)	56.2 (19.4)	82.0 (30.1)	0.002	0.2	< 0.001
Tidal inspiration esophageal pressure	0.65 (3.8)	−10.75 (3.7)	−4.47 (3.6)	< 0.001	< 0.001	< 0.001
Tidal inspiration gastric pressure	11.92 (5.2)	9.59 (4.2)	10.29 (3.8)	0.11	0.253	0.542
Tidal Inspiration Pdi	11.3 (5.2)	20.3 (5.8)	14.6 (5.2)	< 0.001	0.04	< 0.001
Tidal Inspiration LES Pressure	41.5 (11.2)	32.2 (11.3)	44.5 (17.3)	0.008	0.5	0.005
Pressure diff of Pdi vs EGJ peak	98.45	60.57	106.92	< 0.001	0.665	< 0.001
Pdi vs EGJ peak time lag (ms)	−0.355	−0.099	0.258	0.616	< 0.001	< 0.001

Abbreviations: EGJ, esophago-gastric junction; ILD, interstitial lung disease; LES, lower esophageal sphincter; OLD, obstructive lung disease; Pdi, transdiaphragmatic pressure gradient.

The ILD patients had rapid and deeper breaths during spontaneous tidal breathing as compared to controls and patients with OLD. In control subjects, with each tidal and forced inspiration, the esophageal pressure fell, EGJ pressure increased, and stomach pressure increased. The above pressure changes were larger with forced inspirations as compared to tidal inspirations. Patients with ILD had significantly greater negative esophageal pressure during tidal and forced inspiration which led to higher Pdi as compared to controls and patients with OLD (p < 0.001). The increase in EGJ pressure was smaller in patients with ILD as compared to controls (p = 0.002). On the contrary, the changes in esophageal, EGJ and stomach pressure in patients with OLD were similar to normal subjects.

The change in EGJ pressure over time, during forced inspiration is shown in Figure 3. In control subjects, the increase in EGJ pressure lasted for the duration of inspiration, i.e., negative esophageal pressure and increase in Pdi. In patients with ILD, the EGJ pressure increased at the beginning of inspiration but did not last during the entire period of inspiration, it started to fall before the end of negative pressure wave in the esophagus. In patients with OLD, the EGJ pressure started lower and continued to increase throughout the course of the inspiratory effort.

FIGURE 3.

(A), Representative image of a control subject showing the EGJ pressure during a deep breath. (B), The increase in EGJ pressure during inspiration lasts for the duration of inspiration and remains higher than the Pdi throughout inspiration. (D, E), In patient with ILD the fall in esophageal pressure is greater leading to higher Pdi. The EGJ pressure increase is smaller causing the Pdi and EGJ waveforms to intersect during inspiration. In addition, the EGJ pressure increase does not last during the entire period of inspiration, it starts to fall before the end of negative pressure wave in the esophagus. (G, H) In patients with OLD, the EGJ pressure increases higher than the Pdi and lasts throughout the duration of inspiration. (C, F, I), The graphs show the Pdi and EGJ pressure in each individual subject at the peak of forced inspiration in three groups respectively. Patients with ILD generate lower EGJ pressure and higher Pdi values as compared to normal subjects and patient with OLD. EGJ, esophago-gastric junction; ILD, interstitial lung disease; OLD, obstructive lung disease; Pdi, transdiaphragmatic pressure gradient.

The temporal relationship between EGJ pressure and Pdi is shown in Figure 4. In control subjects, the increase in EGJ pressure at all-time points during the entire inspiration period was larger than Pdi, and the two waveforms never intersected at any time point, (Figure 4A). In contrast, the above was not the case in all patients with ILD and OLD. The EGJ pressure dropped below Pdi in 14 patients with ILD compared to none of the controls and 7 patients with OLD. Thirteen out of the 14 patients with ILD had intersections in the descending limb of the waveforms (after the peak Pdi pressure was reached; p < 0.0001) confirming the weakening of the EGJ towards the latter part of inspiration (Figure 4C, D). All the intersections in the OLD group were seen in the ascending limb of the pressure waveform (before the peak Pdi pressure was reached; Figure 4B; p = 0.08). Patients with OLD had later peak in their EGJ in relation to Pdi, compared to controls and ILD (p < 0.001). The difference in peak pressures of EGJ and Pdi pressure curve was significantly lower in patients with ILD compared to controls and OLD (p < 0.001).

FIGURE 4.

(A–D), Simultaneous pressure waveforms of Pdi and EGJ pressure during deep inspiration showing four types of intersections: (A). No intersections, (B), EGJ pressure drops before the peak of Pdi waveform (ascending limb). (C), EGJ pressure drops below the Pdi after the peak of Pdi waveform (descending limb), (D), EGJ pressure drops below Pdi before and after the peak of Pdi waveform (both limbs). (E). Graph showing the number of patients in each group with each type of EGJ-Pdi waveform intersection. EGJ, esophago-gastric junction; Pdi, transdiaphragmatic pressure gradient.

Nine patients in the ILD group revealed presence of sliding hiatus hernia on manometry recording, as compared to none in control subjects and two patients with OLD, and this difference was statistically significant, (p = 0.003 and p = 0.04, respectively).

4 ∣. DISCUSSION

In summary, important findings of our study are as follows: (1) patients with ILD generate higher Pdi and lower EGJ pressure during tidal inspiration and forced inspiration, as compared to normal healthy subjects and patients with OLD, (2) the temporal correlation between the Pdi and EGJ pressure indicates that they are affected differently in patients with ILD and OLD; unlike normal subjects, the increase in EGJ pressure is not sustained during the entire period of inspiration, (3) the EGJ pressure falls below Pdi during different phases of inspiration in patients with ILD and OLD; while it remains higher than the Pdi at all times in control subjects, and (4) A greater number of patients with ILD had evidence of sliding hiatus hernia as compared to control subjects and OLD patients. Above differences between ILD and OLD patients may explain the higher incidence/prevalence of gastroesophageal reflux disease in patients with ILD as described in previous studies. An altered relationship between the Pdi and EGJ pressure during breathing in patients with chronic lung disease may also indicate selective dysfunction of the crural diaphragm.

A higher Pdi in patients with restrictive lung disease as compared to normal subjects, as a possible mechanism of GERD has been described by other investigators.^32,33 However, increase in the Pdi if associated with appropriate increase in the EGJ pressure, as seen in normal subjects during forced breathing and Muller maneuvers,²⁵ and in patients with sleep apnea and other obstructed breathing disorders does not cause reflux.³⁴ The novel aspect of our study is that along with Pdi, we measured the LES/EGJ pressure during tidal and forced inspiration. Even though others have measured Pdi and resting EGJ pressure (at end-expiration) in patients with chronic lung diseases,^32,33 those indices do not reflect the crural diaphragm function. At end-expiration the Pdi is only 6–10 mmHg and the smooth muscle LES portion of the EGJ with a pressure of 10–30 mm can be an effective anti-reflux barrier. On the contrary, with inspiration, as the diaphragm contracts, there is a large increase in the Pdi (50 mmHg or more) and it is during these times that the crural diaphragm contraction which increases EGJ pressure (100 mmHg or more) is relevant for the prevention of reflux.^25,35,36 We measured Pdi and EGJ pressure during forced and tidal inspiration and found that the peak increase in Pdi does not coincide with the increase in EGJ pressure in patients with ILD. The peak Pdi is greater and EGJ pressure smaller in ILD patients as compared to normal subjects. Furthermore, the temporal relationship between Pdi and EGJ pressure is altered in both ILD and OLD. In normal subjects, the EGJ pressure always remains higher than Pdi, which is not the case in patients. Both abnormalities are conducive to reflux events as proven by a recent study, which found that the Botox injected into the EGJ of patients with esophageal motility disorders paralyzes the crural diaphragm and it results in disassociation between the changes in Pdi and EGJ pressure during inspiratory efforts, which results in reflux events during forced inspiration.³⁷

With regards to the cause of dysfunction of crus muscle, we can only speculate at this juncture. Changes in the shape, contractile strength, mobility and functional length of the diaphragm muscle along with the extent of excursion of the diaphragm due to changes in lung volumes, may explain higher Pdi in ILD and lower Pdi in OLD.^{12,15,16,38-42} Our study suggests that diaphragmatic dysfunction in the ILD and OLD may affect costal and crural muscle differentially resulting in selectively affecting one muscle more than the other. To the best of our knowledge, none of the studies have looked at the length-tension relationship of the costal and crural diaphragm function simultaneously in the setting of hyper and hypo-inflated lungs. We speculate that mechanical stretching/disruption of the crus muscle or changes in its length due to changes in lung volumes may explain the weakness of the crus muscle in patients with ILD.

There is a strong association between sliding hiatus hernia and GERD. It is well known that severe reflux disease including Barrett's esophagus is seen only in patients with sliding hiatus hernia.^43,44 Our finding that the patients with ILD had higher prevalence of hiatus hernia also adds to the existing evidence that reflux disease may be quite prevalent in patients with ILD.^11,45 With regards to the genesis of sliding hiatus hernia, degeneration of muscle, atrophy and fatty deposition in the crus muscle has been observed in patients with sliding hiatus hernia.^46-48 Our findings of selective dysfunction of crus muscle, in addition to the more negative intrathoracic pressures during inspiration in patients with ILD, may explain why these patients have a higher prevalence of sliding hiatus hernia.

There are several limitations of our study. It is retrospective in nature; prospective studies are needed to validate the direction of causality between chronic lung disease and GERD. The sample size was small; however, differences between groups were highly significant, which allows us to make inferences using a small sample size. Most importantly, we did not monitor reflux by pH monitoring in all patients to determine if patients with dysfunction of crus diaphragm have higher prevalence of GERD. Prospective studies are needed to delineate selective dysfunction of crural diaphragm in the ILD and OLD patients, and its relevance in the development of GERD.

5 ∣. CONCLUSION

Patients with ILD generate higher Pdi and lower EGJ pressure during inspiration compared to normal healthy subjects and patients with OLD. They also have higher incidence of hiatal hernia. These factors are conducive to higher incidence of GER in patients with ILD. The temporal relationship between Pdi and EGJ pressure during inspiration is altered in patients with ILD and OLD; unlike normal subjects, the increase in EGJ pressure is not sustained during the period of inspiration and falls below the Pdi. Our findings indicate selective dysfunction of the crus of diaphragm in patients with chronic lung disease.

Practitioner Points.

1. This study compares the relationship between trans-diaphragmatic pressure gradient (Pdi), a driver of GER and the EGJ pressure (anti-reflux barrier) in patients with interstitial lung disease (ILD), obstructive lung disease (OLD) and healthy subjects.

2. Patients with ILD and OLD were found to have multiple factors conducive for GERD related to altered diaphragm mechanics:

   1. Patients with ILD generate higher Pdi and lower EGJ pressure during tidal inspiration and forced inspiration, as compared to normal healthy subjects and patients with OLD.
   2. The temporal correlation between the Pdi and EGJ pressure indicates that they are affected differently in patients with ILD and OLD; unlike normal subjects, the increase in EGJ pressure is not sustained during the entire period of inspiration.
   3. The EGJ pressure falls below Pdi during different phases of inspiration in patients with ILD and OLD, while it remains higher than the Pdi at all times in control subjects.
   4. A greater number of patients with ILD had sliding hiatus hernia as compared to control subjects and OLD patients in our cohort.

3. The altered temporal relationship between Pdi and EGJ pressure during inspiration suggests selective dysfunction of the crural diaphragm in these patients.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.