Reverse triggering in patients with acute brain injury undergoing controlled ventilation

Introduction

Background

Reverse triggering (RT) is a form of ventilatory asynchrony in which the patient’s inspiratory effort is triggered by ventilator insufflation in a repetitive pattern (1). Notably, RT has been observed in deeply sedated patients with acute respiratory distress syndrome (ARDS), anesthetized patients, and even healthy individuals (1-3). However, the pathophysiological mechanisms of RT are not well-understood. The prevailing hypothesis suggests that RT involves the entrainment of the patient’s respiratory rhythm to periodic ventilator insufflation. This phenomenon is thought to engage mechanisms such as the Hering-Breuer reflex mediated by vagal afferents, intercostal-to-phrenic reflexes, and both cortical and subcortical influences (2,4). Furthermore, occurrences of RT in brain-dead patients implies a potential role for spinal reflexes (5). Recent research proposes five distinct phenotypes of RT, classified by their timing in the respiratory cycle and the presence or absence of breath stacking (BD) (6). When inspiratory effort occurs during the inspiratory phase, it may inadvertently increase tidal volume (V_T) and transpulmonary pressure, potentially exacerbating lung injury (7). Conversely, inspiratory effort occurring during the expiratory phase might prevent lung collapse and preserve functional residual capacity but could lead to eccentric contraction of the diaphragm, resulting in muscle injury (8). The ultimate impact of RT is contingent upon its timing, the magnitude of inspiratory effort, the prevailing lung conditions, and the duration of RT. The likelihood of RT may be influenced by factors such as ventilator settings, the use of opioids and sedatives, and the patient’s overall condition (7,9,10).

Rationale and knowledge gap

Patients with acute brain injury are particularly susceptible to asynchrony due to potential injuries to the respiratory center (11). Despite this, there remains a significant gap in knowledge regarding RT in this patient group.

Objective

This retrospective study aims to elucidate the incidence and contributing factors of RT among patients with acute brain injury undergoing controlled ventilation, utilizing esophageal pressure (Pes) monitoring to identify RT across different respiratory phases. This manuscript was written in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-694/rc).

Methods

Study population

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study conducted a secondary analysis of data derived from a prospective observational study on patient-ventilator asynchrony in patients with acute brain injury at the intensive care unit (ICU) of Beijing Tiantan Hospital, affiliated with Capital Medical University (ClinicalTrials.gov identifier: NCT03212482). The cohort comprised adult patients diagnosed with acute brain injury who were receiving controlled mechanical ventilation. Exclusion criteria included: (I) mechanical ventilation duration of less than 24 hours; (II) presence of epilepsy; (III) agitation; (IV) contraindications to esophageal balloon catheter insertion; (V) evidence of an active air leak from the lung, including conditions such as bronchopleural fistula, pneumothorax, pneumomediastinum, or the presence of a chest tube; and (VI) absence of spontaneous breathing.

The use of anonymized data was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (approval No. KY 2017-028-02) and the informed consent was waived due to the retrospective nature of this study.

Data collection

Demographic and clinical data were collected at ICU admission and included the classification of acute brain injury, Glasgow Coma Scale (GCS) score, comorbidities, and the Acute Physiology and Chronic Health Evaluation (APACHE) II score. Additional data included the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂ ratio), and the duration of mechanical ventilation.

Patients were ventilated using an AVEA ventilator (CareFusion Co., Ltd., Illinois, USA) equipped with Pes monitoring (SmartCath-G catheter: LOT 7003300; CareFusion Co., Ltd.). The optimal position of the esophageal balloon was verified using Baydur’s occlusion test for patients with spontaneous breathing (12) or the positive pressure occlusion test for those without spontaneous breathing (13). Airway pressure (Paw), flow, and Pes waveforms were collected through a dedicated acquisition system (VOXP Research Data Collector 3.2; Applied Biosignals GmbH, Weener, Germany) at a frequency of 100 Hz. Recordings were taken four times daily, each lasting 15 minutes, and were compiled into waveform datasets. Data collection spanned 3 days or until the patient was separated from the ventilator. End-expiratory occlusion tests were performed at the end of each recording session. In patients with spontaneous breathing, the pressure of occlusion at 0.1 seconds (P_0.1) was measured and averaged across 5 occlusions to assess respiratory drive (14).

The ventilatory modes and settings, respiratory parameters [peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), and Pes], and the usage of opioids or sedatives were documented for each recording session. The Sedation-Agitation Scale (SAS) score was evaluated following waveform data collection. Arterial blood gas measurements were recorded at least once daily. The investigators were not involved in the clinical management of the patients, and the ICU physicians were responsible for determining ventilatory settings, as well as the administration of opioids or sedatives, which remained constant during the recording periods.

Definition of RT

RT was defined as an inspiratory effort, indicated by a negative fluctuation of Pes, occurring after a mandatory insufflation in a repetitive and stable manner (1,15). The entrainment ratio for RT was determined by the count of RT breaths for each ventilator breath. A 1:1 ratio required presence in at least three or more consecutive cycles, and for a 1:2 ratio or other ratios, presence in at least six cycles was necessary (16). RT phenotypes were classified based on the respiratory phase at which the inspiratory effort commenced and where the maximum inspiratory effort occurred. Classes included “Early RT with early relaxation”, “Early RT with delayed relaxation”, “Mid-cycle RT”, “Late RT”, and “RT with breath staking” (6). To differentiate from ineffective efforts during expiration, Late RT was defined as the contraction of the respiratory muscles occurred during the early expiration, in which the maximal Pes deflection occurred less than 1.5 s after the machine insufflation beginning (17). The incidence of RT was calculated as the ratio of the number of RT breaths to the total number of breaths (9,17). The level of inspiratory effort originated from an RT was assessed by the change in Pes (ΔPes) (18). For each RT phenotype, the average Pes values for the first, last and middle events in each waveform dataset were utilized (19). Each breath was independently evaluated and diagnosed by two investigators (X.Y.L. and Y.M.Z.). Consensus was required for a diagnosis, and discrepancies were resolved through discussion among a review panel (H.L.L., Y.L.Y., and J.X.Z.).

Statistical analysis

Continuous variables were reported as medians and interquartile ranges (IQRs) and were compared between groups using the Mann-Whitney U test or Kruskal-Wallis analysis-of-variance test, with Bonferroni correction applied for multiple comparisons. Categorical variables were presented as proportions and analyzed using the Chi-squared test or Fisher’s exact test. Inter-rater agreement between investigators in classifying RT was assessed by Kappa statistics. The predictive capacity of P_0.1 for BD was assessed by calculating the area under the receiver operating characteristic (ROC) curve. The correlation between P_0.1 (patient triggered breath) and ΔPes (inspiratory effort originated from an RT) was assessed by Pearson correlation. Logistic regression was used to determine factors associated with BD. All statistical analyses were performed using SPSS version 21.0 (IBM Corp., Armonk, NY, USA). P values less than 0.05 were considered to be statistically significant.

Results

Demographic and clinical characteristics of patients

From June 2017 to July 2019, 264 patients diagnosed with acute brain injury and undergoing mechanical ventilation were screened. Of these patients, a total of 211 were excluded for the following reasons: age under 18 years (104 patients), epilepsy (25 patients), mechanical ventilation for less than 24 hours (32 patients), contraindications to esophageal balloon catheter insertion (3 patients), absence of spontaneous breathing (6 patients), and use of pressure support ventilation during the recording period (41 patients). The final cohort consisted of 53 patients, for whom 334 waveform datasets were generated from 92,013 ventilator breaths. The diagnoses for the cohort included stroke (41.5%), post craniotomy for brain tumor (30.2%), and traumatic brain injury (TBI; 28.3%). The median APACHE II score at ICU admission was 18 (IQR, 14–22). Among these patients, 12 (22.6%) were diagnosed with ARDS, presenting a median PaO₂/FiO₂ ratio of 171.3 (IQR, 107.1–222.7) mmHg. The characteristics of this cohort are presented in Table 1. Of the 334 waveform datasets analyzed, 166 (49.7%) were on pressure assist/control ventilation (PACV), 110 (32.9%) on pressure-preset synchronized intermittent mandatory ventilation (P-SIMV), and 58 (17.4%) on volume assist/control ventilation (VACV).

Incidence and distribution of RT

A total of 7,724 RT breaths (8.4%) were detected across 59 datasets (17.7%). The median incidence of RT in datasets that showed RT was 43.1% (IQR, 20.2–65.8%). Sixteen patients (30.2%) experienced at least one RT event. RT occurrence was more frequent in the stroke and TBI groups compared to the post-craniotomy for brain tumor group (10.3% vs. 8.8% vs. 4.7%, P<0.001). Patients with ARDS exhibited a higher frequency of RT breaths compared to those without ARDS (18.4% vs. 4.8%, P<0.001).

Four phenotypes of RT were detected (Figure 1). The Kappa index was 0.752 [95% confidence interval (CI): 0.740–0.764, P<0.001] between investigators in classifying RT (Table S1). Most disagreements in reads occurred between “Early RT with early relaxation” and “Early RT with delayed relaxation” (Figure S1), as well as “Mid-cycle RT” and “Late RT” (Figure S2). Mid-cycle RT was the most prevalent, accounting for 61.1% of all cases of RT, followed by BD at 16.6%. Late RT typically occurred during the transition from the ventilator-inspired phase to the expired phase. Among the patients, 11 (20.8%) experienced at least one BD event, affecting 36 waveform datasets (10.8%). Among these patients, the median incidence of BD was 8.7% (IQR, 1.7–21.6%), with a higher proportion observed in patients without ARDS (Figure 2).

Figure 1 Four phenotypes of RT. Arrows indicate the patient’s inspiratory effort occurring after the start of a mandatory insufflation in a repetitive and stable manner. (A) Early RT with early expiratory relaxation during VACV: the patient’s inspiratory effort (the red line) and the max effort (the blue line) occurred during the inflation phase. (B) Mid-cycle RT during PACV: the patient’s inspiratory effort (the red line) started during the inflation phase and the max effort (the blue line) occurred during the deflation phase. (C) Late RT during VACV: the patient’s inspiratory effort (the red line) and the max effort (the blue line) both occurred during the deflation phase. (D) RT with breath stacking during PACV: the patient’s inspiratory effort (the red line) triggered a second ventilator inflation. Paw, airway pressure; Pes, esophageal pressure; RT, reverse triggering; VACV, volume assist/control ventilation; PACV, pressure assist/control ventilation.

Figure 2 The distribution of RT phenotypes was different between patients with and without ARDS (P<0.001). The proportion of breath stacking was higher in patients without ARDS. RT, reverse triggering; ARDS, acute respiratory distress syndrome.

Factors associated with RT

Analgesia/sedation strategy

Patients were categorized into four groups based on their receipt of opioids/sedatives. Patients in the opioids-plus-sedatives group exhibited a higher incidence of RT and higher P_0.1 compared to those in the opioids-only, sedatives-only, and no-drug groups. Additionally, this group demonstrated lower PaO₂/FiO₂ ratios than both the opioids-only and no-drugs groups (Figure 3). The SAS scores were similar among the opioids-plus-sedatives, opioids-only, and no-drug groups, but were significantly lower compared to the sedatives-only group [3 (IQR, 1–3) vs. 2 (IQR, 2–4) vs. 3 (IQR, 2–4) vs. 4 (IQR, 3–4), P<0.001]. Moreover, patients in the TBI and stroke groups received more frequent administration of opioids/sedatives, particularly the combination of opioids-plus-sedatives, and had lower SAS scores [2 (IQR, 2–3) vs. 2 (IQR, 2–4) vs. 4 (IQR, 3–4), P<0.001], when compared with those in the post craniotomy for brain tumor groups (P<0.001) (Figure 4).

Figure 3 Comparison of RT rate, P_0.1, and PaO₂/FiO₂ ratios among different analgesia/sedation strategies. The opioids-plus-sedatives group exhibited a higher incidence of RT (A) and higher P_0.1 (B) compared with the opioids-only, sedatives-only, and no-drugs groups, even after Bonferroni correction. They also demonstrated lower PaO₂/FiO₂ ratios (C) than both the opioids-only and no-drugs groups. RT, reverse triggering; P_0.1, pressure of occlusion at 0.1 second; PaO₂, partial pressure of oxygen; FiO₂, fraction of inspired oxygen.

Figure 4 The proportion of sedatives-only, opioids-only, sedatives-plus-opioids, and no-drugs administration among the TBI, stroke, and post-craniotomy for brain tumor groups. Patients in the TBI and stroke groups received more opioids/sedatives administration, especially opioids-plus-sedatives, compared with the post-craniotomy for brain tumor group (69% vs. 46.9% vs. 41.8%, 30% vs. 18.2% vs. 5.5%, P<0.001). TBI, traumatic brain injury.

Respiratory parameters

Waveform datasets featuring RT were characterized by higher P_0.1 values, smaller differences between the set respiratory rate (RR_set) and the actual respiratory rate (RR_act), and lower PaO₂/FiO₂ ratios compared to waveform datasets without RT [2.1 (IQR, 1.3–3.1) vs. 1.3 (IQR, 1.0–1.8) cmH₂O, P=0.01; 0 (IQR, 0–0) vs. 0 (IQR, 0–2), P=0.001; 220.4 (IQR, 130.7–336.9) vs. 275.0 (IQR, 196.0–352.8) mmHg, P=0.06, respectively]. There were no statistically significant differences in V_T and delta airway pressure (PIP-PEEP) between the two groups [8.0 (IQR, 7.4–9.5) vs. 7.9 (IQR, 7.1–8.8) mL/kg, P=0.16; 12 (IQR, 10–15) vs. 12 (IQR, 12–14) cmH₂O, P=0.24, respectively].

For patients with ARDS, waveform datasets with RT showed lower V_T, lower PaO₂/FiO₂ ratios, and a trend towards higher PIP-PEEP compared to those without RT (Figure 5). The differences between RR_act and RR_set were similar between these groups [0 (IQR, 0–2) vs. 0 (IQR, 0–2), P=0.34]. Conversely, among patients without ARDS, datasets with RT had larger V_T, similar PaO₂/FiO₂ ratios, and lower PIP-PEEP compared to those without RT (Figure 5). The difference between RR_set and RR_act in the RT group was smaller than in the no-RT group [0 (IQR, 0–0) vs. 0 (IQR, 0–2), P=0.002].

Figure 5 Comparison of respiratory parameters between datasets with RT and those without. For patients with ARDS, datasets with RT exhibited lower V_T, lower PaO₂/FiO₂ ratios, and a trend towards higher PIP-PEEP than those without RT (upper panel). Conversely, among patients without ARDS, datasets with RT had higher V_T, similar PaO₂/FiO₂ ratios, and lower PIP-PEEP than those without RT (lower panel). RT, reverse triggering; PaO₂, partial pressure of oxygen; FiO₂, fraction of inspired oxygen; PIP, peak inspiratory pressure; PEEP, positive end-expiratory pressure; ARDS, acute respiratory distress syndrome; V_T, tidal volume.

After adjusting for classification of brain injury, P_0.1, V_T, and PaO₂/FiO₂ ratio, the use of opioids-plus-sedatives, lower SAS scores, lower PIP-PEEP, and a smaller difference between RR_set and RR_act were independently associated with RT (Table 2).

BD

Waveform datasets with BD had higher P_0.1 values and lower PaO₂/FiO₂ ratios compared to those without BD [2.1 (IQR, 1.7–3.3) vs. 1.3 (IQR, 1.0–2.0) cmH₂O, P<0.001; 178.0 (IQR, 90.0–275.0) vs. 273.8 (IQR, 195.0–365.0) mmHg, P=0.003, respectively]. The difference between RR_set and RR_act was smaller in datasets with BD [0 (IQR, 0–0) vs. 0 (IQR, 0–2), P=0.007]. Furthermore, patients with BD received more opioids-plus-sedatives administration, although the SAS scores were comparable between the groups [58.3% vs. 16.4%, P<0.001; 3 (IQR, 2–3) vs. 3 (IQR, 2–4), P=0.56, respectively]. Moreover, P_0.1 demonstrated robust predictive ability for BD occurrence, with the area under the curve (AUC) being 0.72 (95% CI: 0.64–0.80, P<0.001). The optimal cutoff value was determined to be 1.69 cmH₂O, achieving 83.3% sensitivity and 67.1% specificity.

ΔPes originated from RT breaths was higher in BD than in other phenotypes [7.2 (IQR, 5.6–11.4) vs. 3.7 (IQR, 2.3–6.0) cmH₂O, P<0.001]. However, the correlation between ΔPes of RT and P_0.1 and was poor (r=0.003, P=0.98).

RT and outcomes

No significant differences were observed in ICU mortality, in-hospital mortality, duration of mechanical ventilation, or weaning rate between patients with and without RT. However, among patients who survived to hospital discharge, those with RT had a shorter ICU stay (Table 1). Among patients who survived to hospital discharge, those with RT exhibited a trend towards shorter duration of mechanical ventilation, shorter ICU stay, and shorter hospital stay [6 (IQR, 5–14) vs. 8 (IQR, 5–19) days, P=0.37; 9 (IQR, 7–20) vs. 19 (IQR, 10–30) days, P=0.049; 19 (IQR, 11–30) vs. 37 (IQR, 27–48) days, P=0.11, respectively]. Similar results were noted between patients with and without BD (Table S2). Among patients who survived to hospital discharge, those with BD exhibited shorter ICU stay [9 (IQR, 7–20) vs. 18 (IQR, 10–30) days, P=0.03].

Discussion

The main observations of this study can be summarized as follows: (I) RT was prevalent among patients with acute brain injury and who were undergoing controlled ventilation. (II) The use of opioids-plus-sedatives, lower SAS scores, lower PIP-PEEP, and a smaller difference between RR_set and RR_act were independently associated with RT. (III) Respiratory drive, as indicated by the P_0.1 value, showed significant predictive ability for the development of BD.

Incidence of RT and associated factors

The incidence of RT in this study was 8.4% of total breaths, which with the lower range of 2.4% to 24% of all mechanical insufflations reported in previous studies (10,16,17). Sixteen patients (30.2%) experienced at least one RT event, a proportion consistent with previous findings ranging from 30% to 66.7% (4,20). An automated algorithm based on Paw and flow waveforms could detect more RT breaths than visual inspection of ventilator waveforms used in the present study (17). Furthermore, most of the previous studies were conducted among patients with ARDS, who seemed have higher incidence of RT than those without (1,4,6,7). However, only 12 (22.6%) patients were diagnosed with ARDS in the present study. Both V_T and set respiratory rate could influence RT (1,16,20). Previous studies have reported mixed results regarding V_T and RT. For instance, Damiani et al. found that lower V_T was associated with RT in experimental pigs (7), while Rodriguez et al. reported that lower V_T increased the incidence of RT in the early phase of ARDS (9). In contrast, Shimatani et al. identified that large V_T was independently associated with RT in pediatric ARDS (10). In our study, datasets with RT demonstrated lower V_T in patients with ARDS, but the opposite was true in patients without ARDS. After adjusting for confounding factors, V_T was no longer associated with RT. Moreover, lower PIP-PEEP and a smaller difference between RR_set and RR_act were also associated with RT, similar to findings in Shimatani’s study of pediatric patients with ARDS (10). Periodic mechanical insufflations may synchronize the patient’s intrinsic respiratory rhythm with the ventilator, thereby facilitating patient-ventilator interaction (2,16). Decreasing the respiratory rate below the patient’s intrinsic neural rate may reduce RT breaths (1,9,21), although some studies have reported contrary findings (16,22).

The pathophysiological mechanisms of RT are not fully understood, but the predominant hypothesis is respiratory entrainment or respiratory phase locking. This involves the Hering-Breuer reflexes mediated by slowly adapting receptors, the intercostal-to-phrenic reflex, and both cortical and subcortical influences (2,4,5). The Hering-Breuer reflex may be activated during mechanical inflation to shorten the neural inspiratory time and protect the lungs from overinflation, or during the patient’s neural expiratory phase to prolong expiratory time (4). RT has frequently been reported in deeply sedated patients (1,9,17), as deep sedation may alter cortical modulation of the respiratory control center in the brainstem, increasing susceptibility to entrainment by mechanical insufflations (2,4,20). However, deep sedation was uncommon in the present study, with a median SAS score of 3 (IQR, 2–4). Patients in the stroke and TBI groups exhibited higher incidences of RT compared to those in the post craniotomy for brain tumor group (Figure 4). These groups were given more opioids-plus-sedatives and had lower SAS scores, which were independently associated with RT.

BD occurred in 16.6% of RT breaths, which is lower than reported in previous studies (10,16,17). BD was more likely to occur when the inspiratory effort generated was sufficiently large. We found that having a P_0.1 ≥1.69 cmH₂O was strong predictive of BD occurrence. However, patients with acute brain injury exhibited relatively low respiratory drive, as indicated by a median P_0.1 of 1.4 (IQR, 1.0–2.1) cmH₂O, which may explain the lower incidence of BD in our study.

Reverser triggering and outcomes

Patients with RT exhibited a trend towards shorter duration of mechanical ventilation and a reduced lengths of stay in the ICU, possibly attributable to their relatively higher P_0.1 values. Respiratory drive and rhythm are controlled by neurons in the brain stem, including the rhythmicity center in the medulla and the pontine pneumotaxic center, which adjusts the rate and depth of respiration (23). Patients with acute brain injuries, especially those with infratentorial lesions, are more susceptible to impairments of the respiratory center. Approximately 43.4% of the patients in this study had infratentorial lesions, and decreased respiratory drive was a primary reason for prolonged mechanical ventilation in this population (24). Mellado Artigas et al. enrolled 39 patients with 56% having a pulmonary cause of admission but not necessarily ARDS and analyzed a 1-h recording obtained after 24 h after intubation. They reported that patients exhibiting more RT were more likely to be extubated within the next 24 hours, proposing that RT might indicate the recovery of spontaneous breathing (16). Rodriguez et al. found RT was associated with reduced hospital mortality (9). However, our study did not find significant differences in mortality between patients with and without RT. The clinical effects of RT may depend on several factors, such as phenotypes, the magnitude of inspiratory effort, lung condition, and duration of RT, all of which deserve further investigation.

Limitations

There are some limitations in this study. First, as a single-center study, the clinical procedures employed here might differ from those in other settings, potentially limiting the generalizability of our findings. Second, we analyzed only a brief period in the early phase of mechanical ventilation; thus, the short observation period may underestimate the incidence of RT. Continuous monitoring of asynchrony manually throughout the entire ventilation phase is challenging, and automatic software and algorithms could provide more precise data. Third, inspiratory efforts that occurred after the initiation of ventilator insufflation but did not follow a repetitive pattern were not identified as RT. There was no clear definition of irregular RT, which does not require a fixed repetitive pattern. Due to the retrospective nature of this study, we could not perform an expiratory occlusion to verify the association between these irregular inspiratory efforts and ventilator insufflations, potentially underestimating the incidence of RT. Finally, given the small sample size, definitive conclusions about the associations between RT and clinical outcomes remain elusive, highlighting the need for further research.

Conclusions

RT is frequently observed in patients with acute brain injury and who are undergoing controlled ventilation. The most prevalent phenotype of RT is mid-cycle RT, followed by BD. Factors such as deep sedation, lower airway delta pressure, and a closely matched respiratory rate between the ventilator and the patient are associated with the occurrence of RT. Additionally, respiratory drive, as indicated by P_0.1, demonstrated robust predictive ability for the occurrence of BD.

Acknowledgments

Funding: This work was supported by a grant from the Beijing Municipal Science and Technology Commission (No. Z161100000116081). The sponsor had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-694/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-694/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-694/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-694/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The use of anonymized data was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (approval No. KY 2017-028-02) and the informed consent was waived due to the retrospective nature of this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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