Percutaneous Transhepatic Flexible Ureteroscope-Guided Frequency-Doubled Dual Pulse ND:YAG Laser Lithotripsy for Refractory Choledocholithiasis


 ObjectivesTo evaluate the safety and efficiency of percutaneous transhepatic flexible ureteroscope-guided frequency-doubled dual pulse ND:YAG laser lithotripsy (PTFU-FREDDY) for refractory choledocholithiasis.MethodsFrom December 2017 to October 2018, 24 refractory choledocholithiasis patients with large common bile duct stones, anatomic variations, multiple stones or stones at difficult locations (impacted, above a biliary stricture) were admitted to two centers. Four patients were considered intolerant to surgery or endoscopic retrograde cholangiopancreatography (ERCP), and 2 had ERCP failure, the others refused. All patients underwent PTFU-FREDDY. Clinical success rate, recurrence of calculus, laser safety, and related complications, such as fever, haematoma, and local thermal damage were recorded. ResultsPatients’ mean age was 66.0±12.1 (43-89) years. Sex ratio was 1:1.2 (male: female). The mean diameter of stones was 21.8±2.4 mm. All stones were successfully broken and pushed into the duodenum. The mean lithotripsy frequency and procedure time of Bilirubin stones was higher than cholesterol stones, and the mixed were in middle，P<0.01. One patient（4.2%）had haemobilia, requiring immediate transarterial embolisation with 100mg 300-500um gelatin sponge particles. No pancreatitis, sepsis, or serious local thermal damage, such as bile duct perforation, was observed. The rates of Grade A/B of fever, abdominal pain, nausea, and vomiting were 12.5%, 12.5%, 8.3%, and 4.2% during follow-up, respectively. The recurrence was none at the endpoint of 12 months.Conclusion PTFU-FREDDY is a safe and effective alternative treatment for refractory choledocholithiasis, especially when traditional treatments fail or are difficult to perform.


Introduction
The common bile duct stones (CBDS) are present in 10%-20% of individuals with symptomatic cholecystolithiasis 1 . Clinical presentations that warrant investigation for CBDS include right upper quadrant or epigastric pain, especially if accompanied with jaundice and/or fever. In patients with acute pancreatitis, CBDS should also be considered, because gallstones or intrahepatic stones also move to the CBD 2 . Laparoscopic duct exploration 3 and ERCP 1 , supplemented by endoscopic papillary balloon dilation with prior sphincterotomy 4 , mechanical lithotripsy or cholangioscopy 5 , are considered to be the rst-line treatments with high success rates in moving CBDS. In patients in whom the previously described techniques failed or are di cult, percutaneous transhepatic balloon dilation (PTPBD) 6 or combination with basket retrieval 7 is considered an alternative. Regardless of the type of method, the procedure may be di cult to perform in patients with large CBDS, anatomic variation, multiple stones, and stones at di cult locations (impacted, above a biliary stricture) 8 . With the widespread use of laser lithotripsy for urinary calculus 9 , Himanshu Verma et al. rst reported a novel technical method, exible ureteroscope-guided laser lithotripsy to successfully remove the CBDS after other methods failed 10 . The present study rst tried to combine PTPBD with novel laser lithotripsy-frequency-doubled dual pulse ND:YAG laser lithotripsy (FREDDY) 11 to manage these complicated cases, considering that it could shorten lithotripsy time, improve stone removal rate, and help avoid unnecessary surgeries. This study aimed to evaluate the e cacy and safety of PTPBD combined with FREDDY, which were renamed as percutaneous transhepatic exible ureteroscope-guided frequency-doubled dual pulse ND:YAG laser lithotripsy (PTFU-FREDDY), for removal of refractory CBDS in patients with large CBDS(>15mm), anatomic variations, multiple stones, and lesions at di cult locations (impacted, above a biliary stricture).

Patients
This retrospective observational study was approved by the ethics committee of the Second Hospital of Shandong University. At the beginning of this retrospective analysis, the patients who could be contacted provided written informed consent; patients who could not provide informed consent were excluded from the study.
The inclusion criteria were as follows: trans-abdominal ultrasound combined with enhanced computed tomography (CT) or magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS)-con rmed CBDS (Fig 1); refractory CBDS including large CBDS, anatomic variations, multiple stones or stones at di cult locations (impacted, above a biliary stricture); patients between 18 and 90 years old; the Karnofsky performance score is no less than 70.
Exclusion criteria were severe as follows: coagulation disorder (prothrombin time prolonged more than 6s) that was di cult to correct; cachexia or other serious organ disorders with life expectancy of <3 months; concurrent multiple intrahepatic calculi; pregnancy or Breast-Feeding Women.
The study analysed a total of 106 patients with CBDS who were admitted to two centers from December 2017 to October 2018. Refractory CBDS was detected in 30 patients, of these, 5 patients concurrent multiple intrahepatic calculi. Of the residual 25 patients, one was diagnosed with local advanced gastric carcinoma whose life expectancy was considered to be less than 3 months who accepted biliary drainage alone. Therefore, there were 24 eligible patients.

PTFU-FREDDY
Pre-procedural preparations included the administration of sensitive antibiotics (levo oxacin or cephalosporin) and intravenous anaesthesia (dexmedetomidine or fentanyl). Percutaneous transhepatic biliary access was obtained, preferably through right-sided access, and a 12Fr sheath (Olympus, Japan) was used with a safety wire through the ampulla (Fig 2A). After dilation of the papilla with a 40mm x 10mm balloon(Blat, France), the 9.8Fr exible ureteroscope (Olympus, Japan) with an U100plus laser ber (W.O.M, German) in its biopsy hole was inserted into the bile duct tree through the 12-F sheath( Fig 2B). The exible ureteroscope was maneuvered until its terminal end was against the CBDS ( Fig 2C). Laser lithotripsy at 120 mJ single pulse and 5 Hz was chosen to break the stone under the scope, although the setting of 160 mJ and 10 Hz was more e cient for stiff and large stones( Fig 2D). During laser lithotripsy, the bile was replaced by a saline solution, because uid was required for the generation of shock waves, and plasma was formed by the 532-nm laser ( Fig 2E). Repeat lithotripsy was performed until all fragments were small enough (mostly <6 mm) to get through the papilla. The access site was ushed again through the sheath to ensure all small fragments owed to the duodenum. Repeat scope check and cholangiography were performed to ensure all stones were pushed into the duodenum and no residual calculi were left. A 10.2-F external drainage catheter was placed into the CBD through the existing access to prevent pancreatitis and reserve a channel for repeat PTPBD when residual calculi occurred, and was removed if no residual calculi were observed during the repeat cholangiography 1 week later( Fig 2F).

Concurrent gallbladder stones
For concurrent gallbladder stones, patients were treated with routine PTFU-FREDDY to deal with CBD stones, followed by a 1 week later percutaneous transcyst access PTFU-FREDDY, which was performed as before.

Stone analysis
The diameter of stone was determained according to the cholangiography imaging, combined with contrast CT or MRCP when di cult. Stone chemical and structural analyses were performed using the Attenuated Total internal Re ectance Fourier Transform Infrared spectroscopy (ATR-FTIR, Spectrum 100 equipped with an attenuated total re ection sampling universal accessory, Perkin-Elmer, USA). The re ectance mode was selected.
Post-procedural management Liver-protecting drugs and the second generation cephalosporin antibiotics, might be changed according to susceptibility testing, were administered for 1 week. Oral ursodeoxycholic acid (250 mg, Losan Pharma GmbH, Germany) was recommended for all patients after the procedure. The prescribed dose was 250 mg three times a day 6 . Routine analysis of blood, liver function, and serum amylase was performed. One week after the procedure, repeat cholangiography via the existing drainage catheter was performed, and the catheter was removed when no residual calculi were present; otherwise, a repeat PTPBD was performed. Somatostatin (3mg q12h) was continually recommended to prevent choleperitonitis for at least 24 hours from 1 h before the drainage catheter was removed 12 . During repeat cholangiography, if the contrast agent over ows to the enterocoelia, access coil embolisation was recommended to prevent choleperitonitis.

Follow-up
All patients were generalizational followed for 1 year at 3-month intervals and underwent clinical assessment, physical examination, laboratory test, and imaging evaluation (Fig 3). For pure cholesterol stones, ultrasound was the rst choice, and MRCP was recommended. Complete absence of CBDS was the optimal result and referred to as technical success, and the secondary result was medical success, which was de ned as the absence of symptoms regardless of the presence or absence of residual stones.

Statistical analysis
All statistical analyses were performed using SPSS Statistics 24×0 (IBM, USA). Categorical variables were presented as number and percentage. The normal distribution of continuous variables was evaluated by Kolmogorov-Smirnov test. Continuous data with normal distribution were expressed as mean±standard deviation; if with non-normal distribution, data were expressed by the median and range. Paired t-tests were used to compare the indices at 1 week and 1 month after PTPBD with those before the procedure. A P-value <0×05 was considered statistically signi cant.

Population information
Among the consecutive 106 patients with CBDS admitted during the study period, 24 patients were included, and the other patients underwent conventional PTPBD, ERCP or laparoscopic common bile duct exploration and stone extraction. Sex ratio was 1:1.2 (male: female), and the mean age was (66.0±12.1, 43-89) years. Among all patients, 4 were considered intolerant to ERCP or surgery because of cardiopulmonary insu ciency, anaesthesia contraindication, upper gastrointestinal stenosis, acute pharyngitis or tonsillitis. Two patients had ERCP failure because of impacted stones with anatomic variation, and the other 18 refused ERCP or surgery. The mean diameter of the biggest stone was (21.8±2.4) mm, which was determined according imaging or cholangiogrphy. The reasons for stones di cult to removal included smaller common bile duct/stone diameter ratio (29.2%), strictures distal to the stones(20.8%), large diameter(20.8%), impacted stone(16.7%) and anatomic variations(12.5%). The demographic and baseline clinical characteristics are presented in Table 1.  Table 2.

Laboratory test changes
The changes in the laboratory data pre-and post-intervention are shown in Table 3. Alanine transaminase, total bilirubin (TBIL), and white blood cell (WBC) count normalised after the procedure. There was no signi cant statistical difference in the serum amylase and haemoglobin levels before and after the procedure (P>0.05).

Complication
All complications details per SIR standards are shown in Table 4. One patient had haemobilia, because of the formation of bile duct and hepatic artery stula during the 12-F 35-cm-long sheath insertion into the intrahepatic bile duct. Immediate transcatheter arterial embolisation was performed with 100mg 300-500um gelatin sponge particles (Gelpart; Nippon Kayaku, Tokyo, Japan). No other major complications, such as bile duct or duodenum perforation and procedure-related perioperative death, occurred.
According to the SIR guidelines, the occurrence rate of Grade A/B complications of fever, abdominal pain, nausea, and vomiting were 12.5% (3/24), 12.5% (3/24), 8.3%(2/24), and 4.2%(1/24), respectively. Pancreatitis severer than Grade C was not observed, and only one patient had increased amylase levels at 3 days after the procedure with normal imaging ndings, which normalised after somatostatin treatment. No cholangitis and stone recurrence was observed at the endpoint of 12 months.

Discussion
Complete stone removal by using traditional, less invasive methods such as endoscopic Retrograde Cholangiopancreatography(ERCP), endoscopic papillary balloon dilation (EPBD), and percutaneous transhepatic balloon dilation (PTPBD) were challenging in refractory choledocholithiasis, especially when CBDS bigger than 15mm was impacted. The authors showed their experiences of the advantages of combination of FREDDY and PTPBD to manage these complicated cases and veri ed its e cacy and safety in the present study.
European Society of Gastrointestinal Endoscopy (ESGE) recommended stone extraction for all patients with CBDS, symptomatic or not, who were t enough to tolerate the intervention 13 . Multiple studies showed that larger stones were inversely correlated with successful biliary clearance during ERCP 14 .
Biliary sphincterotomy with a balloon dilation time of 30 s could signi cantly increase stone extraction and reduce the frequency of post-ERCP pancreatitis 15,16 . Mechanical bile stone lithotripsy on di cult bile duct stones could produce around 90% successful rate with minimal complications. 17,18 But a randomized study showed that Mechanical lithotripsy had a signi cantly lower stone clearance rate in the rst session compared with laser lithotripsy (63% vs. 100%; P < 0.01) 19 . Extra-corporeal shock wave lithotripsy (ESWL) also could be an alternative in di cult common bile duct stones (DCBDS), with a success rate greater than 90%, and a recurrence rate of 20% over a median follow-up of 4 years 20 . stenting for immediate and de nitive stone treatment 21 , papillary large balloon dilation 22 In 1986, Hochberger et al. reported performing the rst successful endoscopic retrograde laser lithotripsy in humans using a ash lamp-pulsed millisecond meodymium:YAG laser. 23 With the development of microsecond-pulsed dye laser systems that allowed the formation of plasma-induced shock waves, laser lithotripsy has become a commonly accepted modality for the treatment of di cult CBDS.
Most studies on laser lithotripsy for CBDS removal involved endoscopic guidance, but sometimes it might be di cult to perform this procedure. Himanshu Verma et al. reported a case of a 91-year-old woman with a medical history of gallstone ileus and prior ERCP who experienced several failed treatments, 10 such as ERCP with spyglass cholangioscopy, Holmium laser lithotripsy, and cholangioscopy with percutaneous transhepatic cholangiography access to help position the stone for laser lithotripsy, for removing large CBDS; nally, the stone was successfully removed through percutaneous transhepatic cholangiography combined with exible ureteroscope-guided laser lithotripsy.
The present study presented experience of percutaneous transhepatic exible ureteroscope-guided FREDDY laser lithotripsy for refractory choledocholithiasis with a technical successful rate of 100%, low incidence of haemobilia which need correction, and absence of other Grade C or severer procedure-related adverse effects, such as perioperative death or intestinal and bile duct perforation.
The percutaneous access to the biliary tree was established by a 12-F 35-cm-long sheath, which was speci cally suitable for the exible ureteroscope to get through. One laser-related instrument complication was ureteroscope damage, which occurred during the initial application of the technique. Accurate positioning, complete view of the working area, and close coordination of ureteroscope and laser were useful to avoid this.
The selected pulse energy usually was 120 mJ, and the pulse frequency was 5 Hz. Higher energy and frequencies could crush the stones more e ciently, but these could shorten the service life. The usual selection was enough, except for stiff cholelithiasis. In addition to impact stones, 24 the composition of choledocholithiasis was another in uencing factor of lithotripsy. In this study, the ratio of bilirubin stones was signi cantly higher than usual, 25 which usually require more lithotripsy frequency or higher energy and pulse frequency because of its rigidity.
For refractory choledocholithiasis, in the present study, none pancreatitis occurred. The main reason for this might be the smaller size of stones after lithotripsy, and a small-sized balloon might be capable of pushing the stones into the duodenum.
Although several studies have shown that endoscopic sphincterotomy plus balloon dilation was safe and effective for large CBDS removal, owing to the improvements of laser technology, more and more endoscopists preferred lithotripsy plus balloon dilation. [26][27][28] Peroral cholangioscopy-guided lithotripsy achieved a technical success rate of 80%-86% in a single procedure, and was signi cantly more likely indicated for stones ≤30 mm in size than for stones with >30 mm in size. 29,30 In the present study, no CBDS had a size of 30 mm, and the technical success rate was 100%. However, there were no cases of recurrence at 1 year, indicating that the PTFU-FREDDY was better than the simple PTPBD procedure we reported before, 31 and ERCP alone, 5 similar to choledochoscopy-guided laser lithotripsy, 32 but with less complications. Digital single-operator cholangioscopy with electrohydraulic and laser lithotripsy is also effective in removing di cult biliary stones, 33 but the procedural injury is larger than that of PTFU-FREDDY. A 10-year retrospective study showed that multiple CBDS (≥2), cholesterol stone, and sharp bile duct angulation (<145°) are associated with recurrent CBDS after cholecystectomy. 34 To prevent recurrence, ursodesoxycholic acid was administered in this study, 6 and a prospective cholelithiasis-related bile acid metabolomics have been initiated in multiple centers.
Large di cult CBDS also can be managed either by open surgery or laparoscopically with comparable and acceptable outcomes and without the need for multiple ERCP sessions due to their related morbidities. 35 Open choledocoscopy was considered to be more suitable for stone clearance than a T-tube. 36 For concurrent gallbladder and CBD stones, Liu et al. introduced a novel technique, which they referred to as sequential percutaneous transhepatic balloon dilation (PTBD) and percutaneous transhepatic extraction and balloon dilation (PTEBD). 37 In the present study, patients were treated with routine PTFU-FREDDY, followed by percutaneous transcyst access PTFU-FREDDY.
Recently, a retrospective analysis study reported the outcomes of percutaneous transhepatic biliary laser lithotripsy for intrahepatic cholelithiasis, 38 which achieved a 100% success rate in fragmenting the target stones. Eleven (92%) out of the 12 patients had successful rst pass extraction of target stone fragments, and two patients (2/12; 17%) required repeat lithotripsy. In this study, the authors exclude the CBDS with concurrent multiple intrahepatic cholelithiasis, considering that it was di cult to ensure complete intrahepatic calculi fragmentation and discharge. In the following research, these patients would be prioritized for admission and treatment, and a special report would be presented.
The limitation of this study includes its small sample size and retrospective nature. More prospective, multicenter, randomised controlled trials are necessary to con rm the results of this study.
In conclusion, PTFU-FREDDY is a safe and e cient alternative treatment for refractory choledocholithiasis, especially when traditional treatments are di cult to perform or failed.
Declarations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Declarations of interest
The authors who have taken part in this study declare that they do not have anything to disclose regarding con icts of interest concerning this manuscript.