Third space endoscopy pulmonary complications and chylothorax post peroral endoscopic myotomy

Abstract

Third-space endoscopy (TSE) has emerged as an effective treatment modality for various gastrointestinal motility diseases and gastrointestinal tumors. TSE is based on the concept of working in the submucosa using a mucosal flap valve technique, which is the underlying premise for all TSE procedures; thus, some complications are shared across the spectrum of TSE procedures. Despite the high safety profiles of most TSE procedures, studies have reported various adverse events, including insufflation-related complications, bleeding, perforation, and infection. Although the occurrence rate of those complications is not very high, they sometimes result in critical conditions. No reports of chylous effusion following TSE procedures, particularly per-oral endoscopic myotomy, have been documented previously. We are presenting the first reported case of chylous pleural effusion after per-oral endoscopic myotomy. Additionally, we aim to present a comprehensive overview, discuss the existing data, and provide insights into pulmonary post-endoscopic complications in light of recent advancements in endoscopic procedures, especially TSE.

Key Words: Endoscopy; Third-space endoscopy; Submucosal endoscopy; Per oral endoscopic myotomy; Endoscopic submucosal dissection; Pulmonary complications; Chylothorax; Pleural effusion

Core Tip: In this review, we discuss a case of post-per oral endoscopic myotomy chylothorax, focusing on its management, which was carried out with the assistance of other specialties through a multidisciplinary team including a cardiothoracic surgeon, nutritionist, anesthesiologist, and, of course, gastroenterologists. We also provide a brief review of the current known data in the literature regarding post-endoscopic pulmonary complications, especially in relation to third-space endoscopic procedures such as per oral endoscopic myotomy.

INTRODUCTION

Third-space endoscopy (TSE), or submucosal endoscopy, is an interventional endoscopic technique that reaches the submucosa and beyond under direct visualization accomplished via fluid injection and expansion of the submucosal space. As shown by Sumiyama et al[1], the peritoneal cavity and mediastinum could be accessed safely via a submucosal tunnel secured by a mucosal flap valve, thus minimizing the risk of contamination and leakage after secure mucosal incision closure[1,2]. TSE uses the submucosal space as the default working space to treat various gastrointestinal (GI) diseases or to endoscopically resect early GI tumors as an alternative to surgery.

TSE is now the primary treatment for several GI disorders. For example, peroral endoscopic myotomy has been suggested as an alternative to surgery for achalasia. It has since become the preferred method of managing achalasia after proving to be effective and safe in long-term follow-up studies. Multiple subsidiary procedures have been introduced using the same concept, such as gastric-per oral endoscopic myotomy (POEM)[3] to treat gastroparesis, diverticular-POEM for epiphrenic diverticulum (pulsion diverticulum)[4], Zenker-POEM for Zenker’s (hypopharyngeal) diverticulum[5]. Recently, peroral endoscopic fundoplication has been introduced to treat post-POEM gastroesophageal reflux, considered a pure natural orifice transluminal endoscopic surgery procedure[6]. In terms of managing early GI tumors, this began with advances in techniques such as endoscopic mucosal resection and endoscopic submucosal dissection (ESD), submucosal endoscopic tumoral resection and now includes more invasive techniques such as endoscopic full-thickness resection.

The typical steps of POEM involve submucosal injection of fluid, allowing the endoscopist to make a tunnel in the submucosa, followed by myotomy and, lastly, the closure of the mucosa, which stands as the only barrier between the esophageal lumen and the mediastinum[7]. ESD shares with POEM the concept of working in the third space/submucosa, but instead of myotomy, mucosectomy will be done to resect the tumor[8]. Due to the quite invasive nature of those procedures compared to luminal endoscopy, there are expected to be several complications not reported during and after luminal endoscopy[9]. This review will focus on pulmonary complications of these procedures, which most commonly are aspiration pneumonia, pulmonary embolism, and gas-related complications like retroperitoneal air, pneumoperitoneum, pneumothorax, and pneumomediastinum. Although studies have recognized pleural effusion as a possible post-POEM complication, no reports of post-POEM chylothorax have been published so far[10,11]. Therefore, we are also reporting a rare case of chylothorax as an adverse event after POEM and presenting the outlines of management of such cases using the help of similar cases after cardiothoracic surgeries.

OVERVIEW OF THE COMPLICATIONS

In most luminal endoscopic procedures (first space endoscopy), the type of anesthesia is usually conscious sedation using midazolam and/or propofol. Generally, cardiopulmonary complications represent nearly 60% of the total adverse events that happen during or after all types of endoscopic procedures. The most common type of complication that could happen is hypoxia, which could happen in as low as 1.5% and up to 70% of patients, especially in patients undergoing endoscopic variceal ligation[12]. However, this is usually reversible within a few minutes after proper management and usually has no future morbidity. Prevention of such complications could be done by proper assessment, patient selection, tailored anesthesia according to each case, and continuous monitoring of vital signs during the procedure. Management requires early detection of the adverse event, reporting, and a multidisciplinary approach[13]. Advanced endoscopic techniques such as TSE are usually associated with a higher incidence of complications, which tend to be more severe pulmonary complications.

In a prospective post-POEM computed tomography (CT) esophagram cohort that included 84 patients who underwent POEM for achalasia. The CT revealed that nearly 86% of patients had pneumomediastinum, 67% had pneumoperitoneum, 52% had subcutaneous emphysema, and 46% had pleural effusion[14]. Other findings that had lower frequencies in their cohort included retroperitoneal air in 38% of patients, pneumothorax in 19%, atelectasis in 14%, intramural air in 13%, pericardial effusion in 2%, and pneumopericardium in 2%. Despite the high incidence rates of post-POEM pulmonary events, only 6% (5 patients, 4 with pneumonia and 1 with leak) of patients in the total cohort required an intervention based on that imaging. The authors concluded that an early post-POEM CT could help detect complications before symptoms appear. Chartier et al[15] also studied this, where the early CT post-POEM detected adverse events that required intervention in 14% of their cohort. However, the authors concluded that follow-up using CT without symptoms remains questionable. Multiple grading systems have been introduced to assess the severity of surgical complications, for example the Clavien-Dindo classification, originally used for surgical adverse events but then adapted to include endoscopic adverse events[16]. New grading systems have been originally designated to evaluate the adverse events of endoscopic procedures. Nass et al[17] introduced the adverse events in GI endoscopy classification (Table 1). Another proposed classification was proposed by Chavan et al[18], divided into 4 classes (not an adverse event, mild, moderate, and severe) (Table 2).

Table 1 The adverse events in gastrointestinal endoscopy classification.

Grading	Definition
No adverse event	A telephone contact with the general practitioner, outpatient clinic, or endoscopy service without any intervention or extended observation of the patient after the procedure, < 3 hours, without any intervention
Grade I	Adverse events with any deviation of the standard postprocedural course, without the need for pharmacologic treatment or endoscopic, radiologic, or surgical interventions
	Presentation at the emergency ward, without any intervention
	Hospital admission (< 24 hours), without any intervention
	Allowed therapeutic regimens are drugs as antiemetics, antipyretics, analgesics, and electrolytes
	Allowed diagnostic tests: Radiology and laboratory tests
Grade II	Adverse events requiring pharmacologic treatment with drugs other than those allowed for grade I adverse events (i.e., antibiotics, antithrombotics, etc.)
	Blood or blood product transfusions
	Hospital admission for more than 24 hours
Grade III	Adverse events requiring endoscopic, radiologic, or surgical intervention
Grade IIIa	Endoscopic or radiologic intervention
Grade IIIb	Surgical intervention
Grade IV	Adverse events requiring intensive care unit/critical care unit admission
Grade IVa	Single-organ dysfunction (including dialysis)
Grade IVb	Multiorgan dysfunction
Grade V	Death

Definition of adverse event: All negative outcomes for a patient that prevent completion of the planned procedure or cause any deviation from the standard postprocedural course.

Table 2 Classification of adverse events of third space endoscopy[18].

Category	Type of adverse event
Severe	Any events requiring prolongation of hospital for > 10 days and ICU admission > 1 night
	Insufflation related events
	Causing hemodynamic instability
	Requiring premature termination of procedure ± drainage
	Mucosal injury (during or after)
	Requiring special closure techniques (stenting/sponge/surgery/drainage)
	Bleeding (during or after)
	Requiring blood transfusion
	Causing hemodynamic instability
	Endoscopic reintervention or surgery
	Post procedure leak
	Requiring endoscopic reintervention, drainage or surgery
	Cardiopulmonary events
	Causing hemodynamic instability
	Requiring premature termination of procedure
	Infection
	Causing hemodynamic instability requiring antibiotics ± drainage or surgery
Moderate	Any events requiring prolongation of hospital for 4-10 days and ICU admission for 1 day
	Insufflation related events with high probability of hemodynamic compromise requiring prolonged withholding of procedure (15 minutes) ± immediate drainage
	Capno-pericardium
	Mediastinal emphysema
	Tension pneumothorax
	Pleural effusion (during or after)
	Requiring drainage ± antibiotics
Mild	Insufflation related events requiring temporary withholding of procedure ± drainage
	Retroperitoneum
	Pneumothora
	Capno-peritoneum
	Mucosal injury (during or after) which can closed endoscopically
	Bleeding (during or after) not requiring blood transfusion or additional endoscopic intervention
	Infection requiring prolonged antibiotics
Not an adverse event	Insufflation related events not requiring any measures and accidently detected during fluoroscopy
	Small pneumothorax
	Small pneumoperitoneum
	Retroperitoneum
	Mild mediastinal emphysema
	Subcutaneous emphysema

Citation: Chavan R, Nabi Z, Reddy DN. Adverse events associated with third space endoscopy: Diagnosis and management. Int J Gastrointest Interv 2020; 9: 86-97. Copyright © International Journal of Gastrointestinal Intervention. Published by The Society of Gastrointestinal Intervention. Powered by INFOrang Co., Ltd. ICU: Intensive care unit.

COMPLICATIONS HIGHLY ASSOCIATED WITH TSE

Insufflation-related complications

The definition of insufflation-related complications needs a consensus from experts worldwide before it can be validated. However, it was suggested that it should only be defined as a complication if the insufflation-related events required an intervention[19]. The rate of insufflation-related events usually depends on multiple factors, including the definition of complication, the type of gas used (air or CO₂), the nature and duration of the procedure, and the method of diagnosis[15]. Most pulmonary complications are reported after POEM compared to other endoscopic procedures; this could be explained by the anatomy of the esophagus, where after myotomy, the mucosa will be the only barrier with the mediastinum[19]. The most common respiratory complications with POEM are insufflation-related complications. These include subcutaneous emphysema (7.5%) and pneumoperitoneum (6.8%). pneumothorax (1.2%), and pneumomediastinum (1.1%)[20].

The use of CO₂ instead of air has been associated with low insufflation-related complications; this is because CO₂ has a higher diffusion capacity and quicker absorption than air[21,22]. Cai et al[22] reported a study where room air was used in 52% of patients, and insufflation-related complications included pneumomediastinum (48%), pneumoperitoneum (37%), subcutaneous emphysema (28%), and pneumothorax (17%). In contrast, Zhang et al[23] reported a decrease in the incidence rate of insufflation-related complications from 3.3% to 1.9% after switching to CO₂. The previous results highlight the most important preventive measure to decrease the incidence of insufflation-related complications: Using CO₂ instead of room air. Other measures that could help include positive pressure ventilation, using the low-flow gas tube, and dissecting a wider submucosal tunnel[24-27]. However, all these measures cannot completely prevent complications related to insufflation.

The diagnosis of insufflation-related complications should be done as early as possible to prevent irreversible damage. This could be done by clinical examination and other investigations, including monitoring the end-tidal CO₂ and peak airway pressure. Fluoroscopy could help differentiate between capnoperitoneum and retroperitoneal CO₂[28].

In the Nabi et al[19] review article, where the authors discussed the insufflation-related complications of POEM, they suggested a 4-pronged approach to be applied to manage such complications. The approach includes: (1) Gastric decompression through suctioning; (2) Temporary pausing of the procedure to allow CO₂ absorption; (3) Subtle changes in ventilator settings to increase minute ventilation and augment CO₂ washout; and (4) Lastly, needle decompression[19,29]. However, we would like to add a fifth point to this approach that we believe should be number one: Good communication between the endoscopist and the anesthesiologist before, during, and after the procedure. Since POEM is a procedure that causes an increase in the peak inspiratory pressure and means arterial pressure with a lot of CO₂ insufflation leading to systemic absorption[30], this will not be possible to be controlled only by an anesthesiologist. Thus, endoscopists should also be involved in the management of such situations.

Subcutaneous emphysema could happen in TSE procedures as an insufflation-related complication with a potential risk of airway obstruction. It has been found that 60% of the instances of raised end-tidal CO₂ > 50 mmHg are associated with subcutaneous emphysema[31]. Therefore, general anesthesia with intubation is necessary to allow the regulation of ventilation volume. The uptake of CO₂ produced by the insufflation could be resolved through hyperventilation. While mild cases can be treated with hyperventilation, this may not be sufficient to maintain normocapnia in more severe cases where subcutaneous emphysema has occurred and requires needle drainage[31]. A meta-analysis study reported that the incidence rate of pneumothorax during or after POEM is 1.2%[20]. In most cases, pneumothorax can be treated conservatively or by needle decompression. On the other hand, post-POEM tension pneumothorax, as reported by Kang et al[32] and Rajmohan et al[33] requires a chest tube insertion and could be a life-threatening condition.

Although pneumoperitoneum is not a direct pulmonary complication, its incidence could result in severe lung injury. This happens due to either gastric distention or pneumoperitoneum due to continuous insufflation, eventually leading to an increase in the peak inspiratory pressure and lung injury. To decrease the peak inspiratory pressure, the anesthesiologist usually decreases the tidal volume and increases the respiratory rate to keep ventilation. If these measures fail, the anesthesiologist could ask the endoscopist to start gastric decompression, decrease the amount of CO₂ insufflation, and percutaneous abdominal needle decompression (the 5-pronged approach)[30]. However, Inoue et al[7] recommended keeping the positive pressure ventilation above the levels produced by the CO₂ insufflation by the endoscopist, believing this could be a protective measure against emphysema and embolism. The disagreement regarding the limitation of peak inspiratory pressure during POEM has persisted. However, we recommend keeping peak inspiratory pressure under 30 cmH₂O is best.

Empyema, pneumonia, and mediastinitis

Since the peritoneal and mediastinal cavities are exposed in POEM, it is postulated that contamination of these spaces could lead to infection-related complications[34,35]. Contamination and sepsis are frequently seen following dehiscence of mucosal entry or delayed mucosal perforations, leading to mucosal barrier failure[10,23]. Zhang et al[23] reported 13 cases of delayed mucosal barrier failure leading to infection. To prevent such complications, prophylactic antibiotics are routinely administered before POEM and for a few days postoperatively[36]. Post-operative infections can be managed by antibiotics only in mild cases. Significant infections usually require drainage or surgery along with a prolonged course of antibiotics[10]. Delayed mucosal barrier failure requires nil per os, nasogastric/naso-jejunal feeds, and intravenous antibiotics.

Aspiration pneumonia

The incidence of aspiration pneumonia in POEM is very low > 0.1%[36-38]. As most patients lie in a left lateral decubitus position during endoscopy, when aspiration pneumonia happens, it is usually in the left lung. Aspiration pneumonia is mainly diagnosed clinically with fever, cough, and sputum symptoms. A chest X-ray or a CT scan can also detect the radiographic signs of pneumonia. White blood cell count, C-reactive protein level, and body temperature are reported to be significantly higher in patients with aspiration pneumonia than in those without aspiration pneumonia[39]. Preventive measures include a clear liquid diet for at least 24 hours preoperative, adequate suction of the oral cavity to remove saliva, esophageal content aspiration, if present, before induction of anesthesia, and rapid sequence intubation with cricoid pressure in a semi-reclining position[37,40,41]. If the patient develops post-POEM aspiration pneumonia, antibiotics should be administered to avoid prolonged hospital stays[39].

Pulmonary embolism

Pulmonary embolism is a rare complication; however, it could be fatal if not discovered early. Khashab et al[42] reported an event of pulmonary embolism managed with as a possible complication of POEM. The source of the embolism could be either a venous thromboembolism (VTE) or an air embolism. The risk of VTE is increased because of prolonged recumbency during TSE and after the procedure because of the intravenous sedation. Kusunoki et al[43] reported an overall frequency of asymptomatic VTE after ESD of 10%. To prevent VTE, it is recommended to use mechanical prophylactic measures such as changing the posture right after the procedure, massaging the lower limbs, and wearing elastic stockings. Early detection of VTE is important to minimize the risk of pulmonary embolism; thus, the D-dimer level on the day after ESD, particularly, could be valuable. It is reported to be potentially associated with the risk for VTE in ESD patients[43]. Air embolism is a very rare insufflation-related complication. The main problem is that it can be difficult to notice because it mimics sedation-related problems. Therefore, it should be considered with prolonged altered mental status, anisocoria, tachycardia, tachypnea, dyspnea, or ST-T changes in the electrocardiogram. The only proven method to reduce the incidence of air embolism is by using CO₂ instead of room air[44].

Hemothorax

Hemothorax is another post-POEM adverse event where earlier detection is important. Werner et al[10] reported a delayed bleeding event causing hemothorax. The event required surgery for definitive treatment.

Pleural effusion

Pleural effusion that requires drainage is a rare complication of POEM. According to some reports, it only occurs in 0.2% of patients who undergo POEM[10]. Several studies examined the rate of post-POEM pleural effusion. Werner et al[10] reported that, up to 2017, data from literature studying post-POEM complications recruited 4117 patients; of those who underwent POEM, 11.7% developed pleural effusion, and only 0.2% of patients required drainage. Another multicentric study recruited 1826 patients and reported that only 0.2% of patients developed pleural effusion post-POEM. However, in most cases, the pleural effusion spontaneously resolved[35]. In a recent Korean cohort, the data of 328 patients were collected retrospectively, showing that the frequency of pleural effusion post-POEM was 0.9%[11]. Based on the above-mentioned studies, the frequency of developing pleural effusion after POEM ranged from 0.2% to 11.7%, with a small number of reported cases of pulmonary embolism.

PREVENTION OF PULMONARY COMPLICATIONS

To reduce pulmonary complications in TSE and POEM it is recommended to follow the following recommendations.

Preoperative preparation

Preoperative prevention strategies include keeping the patient on clear liquids for at least 24 hours before the procedure, aspirating the esophageal contents before induction of anesthesia and rapid sequence intubation with cricoid pressure, starting induction/intubation with the patient in a semi-reclining position, and giving antibiotic prophylaxis to reduce postoperative infections.

Intraoperative technical optimization

Intraoperative prevention strategies include the use of CO₂ instead of room air, avoidance of full-thickness myotomy, and avoidance of over-insufflation when full-thickness myotomies have been recognized. These strategies will reduce insufflation-related complications and pneumothorax. Frequent abdominal palpation could help in the early detection of tense pneumoperitoneum. Inadvertent entry in the mediastinum should be promptly recognized as it could lead to pneumoperitoneum and pneumopericardium. In cases where clinical instability is thought to be due to pneumopericardium or pneumothorax, it is recommended to briefly interrupt the procedure without insufflation to reestablish clinical stability and continue the procedure. In cases with cardiac arrest, bilateral chest tubes and subxiphoid pericardial windows can be lifesaving.

Postoperative monitoring strategies

Thorough postoperative monitoring is recommended to early detect and manage postoperative complications.

FUTURE RESEARCH DIRECTIONS

Investigating the underlying mechanisms of pulmonary complications associated with TSE, particularly the impact of insufflation techniques, will enrich our understanding of how these complications develop and how they could be further prevented. Moreover, exploring advancements in surgical techniques aimed at minimizing the risk of such complications would be valuable.

CASE REPORT

To our knowledge, no cases of chylothorax have been reported post-POEM. However, we report a post-POEM chylothorax in a 58-year-old female patient without notable medical history apart from suffering from type II achalasia for which she underwent an open Heller’s myotomy 20 years ago. With an Eckardt score of 11, the patient presented with recurring dysphagia, vomiting, and significant weight loss. Esophagoscopy revealed a dilated esophagus, and esophageal manometry confirmed the recurrence of type II achalasia. An 8-cm tunnel was started above the cardia and extended for 3 cm on the gastric side. We were driven to use a higher current due to the severe submucosal fibrosis (forced coagulation effect 2 at 60 watts). Myotomy was performed successfully without intraprocedural complications.

36 hours later, the patient started a clear fluid diet without developing complications and was discharged a day later. On post-procedural day 4, the patient presented with severe dyspnea. Chest examination revealed absent breath sounds on the right side. The patient was readmitted to the hospital, and a chest X-ray revealed a massive right pleural effusion with a left mediastinal shift. A pigtail catheter was inserted (Figure 1A), which drained a white milky effusion (Figure 1B), and the patient was kept nil per os. The diagnosis of empyema was excluded based on the absence of fever, normal C-reactive protein, and total leucocytic count. Fluid analysis revealed high triglycerides; otherwise, the patient had normal biochemical parameters in her effusion sample. After three days of drainage, the catheter evacuated most of the fluid, leaving a scant amount of drained serous fluid with a normal triglycerides level on fluid analysis.

Figure 1 Case report. A: Chylous pleural effusion with pigtail inserted; B: Syringes showing the aspirated white pleural fluid “chylous effusion”; C: X-ray showing the total resolution of the previous chylothorax after our management plan; D: Flowchart showing the management of post-peroral endoscopic myotomy chylothorax. POEM: Peroral endoscopic myotomy; CRP: C-reactive protein; TLC: Total leukocyte count.

A CT of the chest with oral and intravenous contrast confirmed the diagnosis of pulmonary embolism and also confirmed the absence of any esophageal leaks or esophageal-pleural fistulas. The patient was kept on anticoagulation for pulmonary embolism. After a trial to restart the clear fluid diet, the patient developed chylothorax again despite the absence of an esophageal leak. A thoracic duct leak was excluded using lymphoscintigraphy. The high morbidity and mortality of thoracic duct ligation pushed us to apply the algorithmic approach described by Chalret du Rieu et al[45] in 2011 in order to manage post-operative chylothorax based on when the chylothorax formed and how the drainage flowed. Upon applying the algorithm, the decision was for a conservative treatment. The patient was kept on exclusive parenteral nutrition, and based on our nutritionist’s recommendations, total elimination of fats was applied. Two weeks later, the patient started an oral diet with the elimination of all fats except for medium-chain triglycerides to reduce the risk of bacterial translocation, which was of beneficial value. During the following week, the patient became symptom-free, and the effusion resolved, which was confirmed using imaging (Figure 1C), leading to the removal of the pigtail catheter. The patient was discharged safely and was advised to continue a fat-free diet supplemented with medium-chain triglycerides for another 3 months.

During the subsequent follow-up visits, there was a significant improvement in pre-POEM symptoms, especially dysphagia. In addition, the patient gained nearly 25 kg, and her Eckardt score dropped to 2. Regarding the effusion, the patient remained asymptomatic without any evidence of chylothorax recurrence to date (1 year). The management of such a post-POEM chylothorax was challenging, especially after the exclusion of a thoracic duct injury and the presence of any esophageal leaks or fistulas. Based on our experience and after reviewing the literature, we suggest the following algorithm for the management of post-POEM chylothorax (Figure 1D)[45,46]. This includes conservative treatment in the form of diminution of chyle flow, efficient drainage of the pleural cavity, nutritional support for the prevention of chronic adverse events, and the avoidance of septic consequences; regular chest X-rays; total cessation of oral or enteral fat consumption at the time of chylothorax diagnosis which can reduce chyle flow by a factor of 10[46]. Surgery and radiographic embolization should be considered if conservative measures fail to treat chylothorax.

CONCLUSION

TSE has transformed the field of GI endoscopy, making it possible to replace surgery with minimally invasive procedures either in some diseases such as achalasia, gastroparesis, or to resect early GI tumors. Under the umbrella of TSE, many procedures have been developed, including POEM, submucosal tunnelling endoscopic resection, Zenker-POEM, gastric-POEM, diverticular-POEM, and peroral endoscopic fundoplication. Although TSE is technically challenging, major complications are rarely reported; however, once they occur, they require careful observation and prompt management. In this review, we aimed to spotlight the pulmonary complications of TSE, especially POEM. We could summarize the management of these complications in the sentence, “working as a team”. The management could never be done by an anesthesiologist or the endoscopist alone; instead, it requires a team effort. However, the main steps are the 4-pronged approach that includes gastric decompression, temporary holding of the procedure, increasing the minute ventilation, and needle decompression.

Also, we are reporting the first case of chylothorax after POEM. We faced challenges in managing such cases because of the lack of similarly reported cases and, thus, the absence of guidelines for managing this complication. We overcame this obstacle by consulting our colleagues in the cardiothoracic surgery specialties, which allowed us to successfully manage this case and develop an algorithm of management for similar cases after POEM. However, further studies and research are needed to validate the use of this algorithm on a larger number of patients.