POSTMANIPULATION PANCREATITIS: THE URGENCY OF THE PROBLEM, THE COMPLEXITY OF DIAGNOSIS AND UNRESOLVED PROBLEMS Popova M.A., Leontyev A.S., Korotkevich A.G., Merzlyakov M.V., Shestak I.S.
Kemerovo Regional Clinical Hospital named after S.V. Belyaev, Kemerovo, Russia,
Novokuznetsk State Institute of Postgraduate Medicine,
Novokuznetsk City Clinical Hospital No.29, Novokuznetsk, Russia
Currently, the problem of diagnostics and treatment of pancreatobiliary organs is still actual and debated. So, cholelithiasis is predominant pathology, which is also called “the well-being disease”. According to some expert estimates, the increase in incidence of the disease is expected within 5-10 years, with increasing proportion of young patients [11]. According to World Gastroenterological Association, cholelithiasis occurs in more than 10 % of European population and takes the third place after cardiovascular diseases and diabetes mellitus. The incidence of malignant obstructive lesions of extrahepatic bile passages increases, resulting in increasing number of surgeries in this category of patients and complications in 1-23 %, with increasing period of rehabilitation [27].
Low invasive surgery becomes more advanced. Surgery with flexible videoendoscopic technologies for the major duodenal papilla (MDP) became the main techniques in diagnosis and treatment of pathology of extrahepatic bile ducts. Particularly, endoscopic retrograde cholangiopancreatography (ERCP) is still the gold standard, and endoscopic papillosphincterotomy (EPS) is a surgery of choice in treatment of choledocholithiasis and stenotic changes in MDP, especially in patients with high degree of surgical and anesthesiological risk and in patients with postcholecystectomy syndrome [3, 15]. Such type of surgery has some advantages in incidence of postsurgical complications, unfavorable outcomes and rehabilitation period, with total efficiency up to 98 % [2, 9].
From the first procedure of ERCP performed by W.S. McCune et al. in 1968 and the first endoscopic papillosphincterotomy performed by M. Classen, L. Demling and K. Kawai in 1973, the problem of prevention of complications of transpapillary interventions is still actual. The total amount of complications after EPS reaches 36 % despite of improvement in endoscopic techniques, implementation of new techniques and materials, appearance of new medical agents. It accentuates the importance of further investigation of this issue [9, 15, 24, 25]. The ongoing (more than 20 years) studies by Ì. Freeman (2001), M. Christen (2004), B. J. Elmunzer (2012), J. Buxbauml (2016), Jun-Ho Choi (2017) and others, which are dedicated to the problem of decreasing specific complications of ERCP, have not resolved the problem yet. Despite of evident advantages and high clinical efficiency (87-98 %) (Watanabe H. et al., 2007), the retrograde transcapillary interventions are often accompanied by complications: duodenal perforation in 0.2-1.6 %, cholangitis in 1.7-24 %, recurrent choledocholithiasis in 15 %, bleeding in 1.1-1.7 %. The total amount of complications after EPS reaches 23 %, the mortality – 4 % [6].
Acute postmanipulation pancreatitis (APMP) is the most dangerous and frequent complication of ERCP/EPS. It appears in 25-30 % of the cases and is characterized by fast development and severe course [27. 31]. Currently, the experts accept the fact that introduction of contrast media into the main pancreatic duct during ERCP is the main factor of APMP, with incidence > 15 % in patients with high risk [50]. At the same time, the literature analysis showed that incidence of APMP after ERCP/EPS significantly differs and varies from 1 to 40 %, with the mean value of 5-20 % [17, 23, 36, 39]. APMP develops manly in working age persons (age of 30-50) with severe type of APMP or necrotising pancreatitis. Also complications may appear that cause severe disability [30]. Despite the mild form in most cases (44-60 %), which is quickly corrected with the complex of conservative procedures, the severe forms appear in 2-4.7 %, with mortality of 13 % [10, 15].
Pancreatic necrosis and multiple organ dysfunction appear in approximately 15 % of cases with severe course of APMP. According to the data from different authors, the mortality reaches 15-30 % for sterile pancreatic necrosis, and 85 % for infected forms [5, 17, 43]. Up to 50 % of all complications of ERCP/EPS are associated with APMP, about 40 % of complications cause the death. APMP is the cause of more than 60 % of judgment proceedings after endoscopic treatment [1, 31].
Acute postmanipulation pancreatitis is a serious complication of endoscopic interventions not only in the Russian Federation. So, the annual costs for treating such patients exceed 150 million dollars in USA [17, 36]. The highest incidence of pancreatitis after ERCP is noted in the Northern America (13 %), the lowest one – in Europe (8.4 %), the average incidence – in Asian countries (9.9 %) [19].
The term APMP is known more than 20 years, and, according to the classification by Cotton et al., it presents the clinical manifestation of pancreatitis with more than three-fold increase in amylase level, developing within 24 hours after manipulations with MDP and requiring for hospital follow-up or prolonged hospital stay. Afterwards, Freeman et al. made some amendments in APMP, and defined it as appearing or intensifying abdominal pain with increasing levels (more than three times) of amylase and/or lipase, developing within 24 hours after endoscopic intervention and requiring for hospital admission or its prolongation for 2-3 days [35, 39].
L. Demling analyzed the retrospective ten-year experience in EPS in 1983. He determined the general contraindications for endoscopic interventions for MDP. According to the author’s opinion, the risk factors are presence of big concretion or extensive stenosis, a big tumor, and young age of the patient [15]. According to the data from American Society for Gastrointestinal Endoscopy (ASGE), the incidence of APMP reaches 40 % in patients with at least two risk factors [36]. As Freeman and coauthors showed, the combination of several factors increases the risk of responsive pancreatitis. The risk increases 5-10 times in presence of three and more predisposing factors [29, 40].
There are several groups of risk factors: the patient-related factors, factors relating to a procedure and endoscopist, which are separated into main and possible ones [15, 31]. The main risk factors of the patient include Oddi's sphincter dysfunction, female sex, previous pancreatitis. The possible risk factors of the patient include a known case of APMP, excessive body mass, unchanged vile ducts, absence of history of pancreatitis, absence of bilirubinemia [29, 35, 42].
Difficulties in cannulation of MDP, duration of procedures exceeding 5 minutes, more than 5 attempts of duct catheterization with the guide, use of contrast media, use of solutions below room temperature and fast introduction of contrast media into bile ducts are the main factors predisposing to development of APMP after endoscopic intervention. At the same time, the risk factors of APMP are precut sphincterotomy, isolated dissection of pancreatic duct sphincter, balloon dilatation of MDP, traumatic and long term lithoextraction and intraductal ultrasonic examination [6, 20, 35, 36, 40, 42].
The literature does not mention any uniform opinion on a direct relationship between APMP development and a contrast media type used for choledochography and wirsungographie. Particularly, it is related to necessity for separate realization of the procedures and amount and rate of introduction of contrast media [28]. ASGE recommends using the maximally lowest volume of contrast media [35, 42]. Wirsungographie is one of the main risk factors of APMP, with pancreatitis developing in most cases (up to 84.6 %) [48]. Within 3-4 hours after ERCP, one may observe the transitory increase in amylase, but amylasemia regresses within 24 hours. So, G. Skude et al. report on symptomless hyperamylasemia in 34 % of cases [1, 14, 48].
According to other authors, the risk factors of APMP also include older age, anatomical features (peripapillary diverticula, ulcerous lesions and stenotic changes in MDP, migration of concretion, presence of additional ducts), administration of pancreotoxic agents [7, 15]. In some cases, additional ducts and the papilla have the insufficient size for adequate draining of secretion, or absent anastomosis between the main and additional ducts cause pancreatitis [13, 29, 32].
Some publications show that “alternative anatomy” also has the high risk of APMP, even experienced endoscopists should consider this fact [7, 15, 20, 28]. Therefore, the close attention is given to description of risks for endoscopist in the foreign and domestic literature. The favorable prognosis is execution of at least two ERCP/EPS per week. In this case, the risk of APMP decreases [36]. So, S. Loperfido think that the incidence of postmanipulation complications is 3 times higher in the medical center, which executes less than 200 ERCP/EPS per year as compared to clinics performing higher amount of interventions (7.1 % and 2 % correspondingly). At the same time, these findings have not been proved in other literature sources [6, 15, 34, 50].
Therefore, the absence of the uniform opinion and the universal approach to the risk factors of APMP indicates the need for further analysis of the current situation and opens the perspective for development of the new uniform algorithm for this category of patients.
Quite high incidence of APMP explains the increasing use of less invasive diagnostic techniques of pancreatobiliary organs, particularly, endosonography and magnetic resonance cholangiopancreatography (MRCP) [7]. In this respect, one should note the improvement in quality of diagnostics and the decreasing rate of APMP after wide clinical implementation of these techniques [16, 25].
Endosonography has the high amount of advantages. This low invasive technique shows the sensitivity of 94.7 %, the specificity of 95.2 % and diagnostic efficiency of 99 % in diagnosis of choledocholithiasis. The disadvantage of the technique is low deepness of penetration (10 cm) and impossibility of introduction of the apparatus into the stomach or the duodenal bulb in some anatomical features [10].
MRCP is a safe non-invasive alternative for ERCP. The sensitivity, the specificity and the diagnostic accuracy of ERCP in choledocholithiasis identification is 81–100 %, 84–100 % and 90–96 % correspondingly. The sensitivity of the technique is directly related to the concretion size: for size ≤ 5 mm, MRCP with 90.5 % sensitivity and 87.5 % specificity is comparable to transabdominal ultrasonic examination (sensitivity – 76.6 %, specificity – 86 % correspondingly). For concretion size > 5 mm, the diagnostic accuracy of MRCP achieves 99 %. The study can be conducted without administration of contrast media. Good visualization is based on high level of fluid in biliary tracts. But it is necessary to note that the result of examination without contrast media is often doubtful in case of fluid accumulation and evident inflammatory events in the examined region.
Hydropressive magnetic resonance cholangiopancreatography (HPMRCP) is a relatively new invasive technique of examination of pancreatobiliary organs. Increasing hydraulic pressure in biliary tract with introduction of 7-10 ml with the rate of 0.3 ml/sec of saline through the external opening of cholangiostoma increases the information capacity of visualization of biliary tracts up to 97.1 %, the biliary system of the pancreas – up to 94.8 %. The advantage of the technique is a possibility for detailed imaging of the frame biliary excretion system and the pancreatic biliary system without introduction of aggressive contrast media [21].
HPMRCP allows detailed imaging of segmental and subsegmental intrahepatic biliary ducts that is impossible without standard MRCP [5]. According to many authors, the main advantage of MRCP is non-invasive characteristics of examination and absence of additional radial load. Often the technique does not require for sedation and intravenous administration of contrast media. It has the advantages in more detailed imaging of biliary tracts, especially in estimation of extension of biliary tracts and intraductal formations. MRCP allows precise imaging of extension of the block and topical relationship between formations and big hepatic vessels [4, 12, 18]. As compared to ERCP, the main disadvantages of MRCP are low spatial resolution, impossibility of surgical manipulations during examination, claustrophobia, and presence of cardiostimulators or ferromagnetic implants. Presence of artifacts also impedes the examination: air artefacts occur in 39 %, artefacts from vascular pulsation – 37 %, artefacts from various anatomical features including diverticula, parallel examination of the gallbladder duct, duodenal diverticula, surgical clamps for abdominal organs, application of hollow structures with motionless fluid and others) – in 24 %. Also MRCP cannot give the appropriate estimation of narrowed segmental biliary ducts [4, 22]. MRCP is better to perform in presence of history of gastric resection or gastrectomy and after application of the biliodigestive anastomosis. ERCP is less informative for such cases, and the risk of complications is higher.
In most cases, after confirming diagnostic procedures, it necessary to return to surgical interventions. Despite of multiple studies of increasing safety of ERCP, the problem still exists. The incidence and severity of APMP is still clinically significant [46]. Prevention of pancreatitis is performed with various pharmacological agents: hormones, anti-inflammatory agents, myorelaxants, antioxidants, protease inhibitors. Currently, the analogs of somatostatin show the one of the main roles in prevention of pancreatitis by means of their antisecretory activity and, as result, suppressing influence on pancreatic function [17]. The use of octreotide, which is a synthetic analogue of somatostatin and is often used for treatment of acute pancreatitis, shows the disputable results despite of wide use for therapy and prevention of APMP [19].
A. Andriulli et al. (2000) conducted the metaanalysis of 13 randomized clinical studies (RCS) of somatostatin. Somatostatin showed the high efficiency regardless of the route of administration of the agent: somatostatin was administered with single bolus before ERCP, and intravenously up to 26 hours after the intervention [33]. Two years later, a multi-centered RCS (by the same authors) identified some contradictive results as compared to the previous analysis. The study included 579 patients with high risk of APMP. Somatostatin was introduced one time with dosage of 750 µg 30 minutes before ERCP and with the dosage of 300 µg per hour within 2 hours after it. Pancreatitis developed after administration of somatostatin in 11.5 % and 6.5 % after use of placebo [46]. Afterwards, A. Andriulli et al. reduced the mortality from APMP to 0.36 % and 0.57 % after use of somatostatin and octreotide correspondingly. However octreotide and somatostatin do not decrease the risk of secondary complications, resulting in inevitable surgical intervention [31, 35].
The analysis of several RCS that octreotide for prevention APMP is efficient only with prescription of high dosages (> 0.5 mg) [19]. According to ASGE, introduction of octreotide does not influence on the general incidence of APMP, and prevention with octreotide is not recommended. New studies with new prevention dosages ≥ 0.5 mg are required [42].
The agents influencing on Oddi's sphincter tone are used widely, but they are not recommended by European Society of Gastrointestinal Endoscopy as the routine prevention (lidocaine, adrenaline, nifedipine, botulinum toxin, nitroglycerine); most of them did not prove their efficiency. However some authors insist on efficiency of these agents [1, 7. 8, 26, 41, 45].
The efficiency of transdermal or sublingual nitroglycerine was shown in two RCS [49]. Nitroglycerine decreases the pressure in Oddi’s sphincter and hypertension in the pancreatic duct. 2 mg sublingually immediately before ERCP or transdermal plaster decreased the percentage of pancreatitis in the control group according to the data from M. Moreto et al. However other studies did not show the efficiency. Also administration of nitroglycerine is often accompanied by side-effects in view of headache and transitory hypotonia which significantly limit its use [35, 42, 50].
Non-steroidal anti-inflammatory drugs (NSAIDs) demonstrate the evident anti-inflammatory effect. This group of agents influences on the main link of inflammation pathogenesis – it inhibits cyclo-oxygenase-2 (COX-2), resulting in disordered synthesis of prostaglandins (central mediators of inflammation). It determines the appropriateness of prescription of NSAIDs as the anti-inflammatory agent. In their metaanalysis, X. Ding et al. (2012) compared 10 RCS with ERCP with rectal administration of NSAIDs. The therapy decreased the incidence of acute pancreatitis two times. It is important that NSAIDs decreased the incidence of severe and middle-severe forms of pancreatitis [3, 28, 42]. I. Puig et al. showed other, but the very similar results. They compared the results of 9 RCS with 2,133 patients. The relative risk of APMP decreased two times after prescription of NSAIDs as compared to the placebo group.
In 2014, the results of two independent metaanalysis were published. The researchers based on the study by S. Sethi et al. who analyzed 7 RCS (2,133 patients). The outcomes were estimated in two groups: NSAIDs for prevention of APMP and the group without NSAIDs. The analysis showed that rectal administration of indomethacin and diclofenac before or after ERCP/EPS decreased the incidence of pancreatitis [19]. In other study, in the group of patients with MDP stenosis, the incidence of pancreatitis was 9.2 % after NSAIDs and 16.9 % in the control group. In the patients of high risk, the use of indomethacin without pancreatic duct stenting is also efficient – the risk of pancreatitis decreases from 20.6 % to 6.3 % [31]. The use of NSAIDs before ERCP, and preventive stenting of the main pancreatic duct reduces the incidence of acute pancreatitis 5.5 times [27].
It is very important that NSAIDs reduces the incidence of middle-severe and severe forms of acute pancreatitis [19]. The clinical recommendations ESGE and the Japanese recommendations for treatment of acute pancreatitis (2015) show the obligatory use of 100 mg diclofenac or indomethacine rectally before and after ERCP for all patients without contraindications [42, 45]. It is proved that low dosages of NSAIDs significantly decrease the risk of APMP. The Japanese researchers report that 50 mg rectal diclofenac are efficient for prevention of pancreatitis after manipulations with MDP. Moreover, the patient with body mass < 50 kg received 25 mg of NSAIDs 30 minutes before ERCP. The analysis of the dosages showed that pancreatitis developed in only 3.9 %. It was also found that low dosages of NSAIDs (as well as the standard dose of 100 mg) decreased the risk of APMP and improved the tolerability of the intervention: pain after ERCP/EPS was registered in 7.8 % in the main group and in 37.7 % in the control group.
One should note that rectal NSAIDs are cheap. The analysis of costs and advantages of monotherapy with indomethacin shows the average economy of $1,472 as compared to the stenting [19, 50]. According to the above-mentioned recommendations, intensive hydration with lactated Ringer's (LR) solution is an obligatory component for prevention and treatment of any condition, including APMP. It is believed that hydration prevents a pancreatic injury after microvascular hypoperfusion. Introduction of LR instead of saline can prevent subsequent acidosis, which activates the enzyme activity of the pancreas. The experimental study of 62 patients who received LR with dosage of 3 ml per kg of body mass per hour during the procedure, bolus of 20 ml/kg immediately after it, and 3 ml/kg/h for 8 hours thereafter showed the significant decrease in APMP (0 % in LR group as compared to 17 % for common hydration).
Although some specialists beware of intensive intravenous infusions for patients with concurrent cardiovascular pathology, the studies show that intensive hydration do not cause such unacceptable complication as overloaded volume [35, 36, 42, 45]. Another approach to prevention of APMP is prescription of anti-inflammatory therapy. The administration of anti-inflammatory cytokines (interleukins (IL)) is an efficient and perspective preventive measure. J. Deviere et al. showed that a single injection of IL-10 (4 µg or 40 µg/kg, 30 minutes before intervention for MDP) efficiently prevents the pancreatitis in all risk groups. J. Dumont et al. received the similar results: IL-10 showed almost two-fold decrease in the risk of pancreatitis as compared to the placebo group (7.1 % and 13.9 % correspondingly). But owing to high costs, IL is not used widely. The technique has not been studied appropriately. So, further studies are required [37, 38, 50].
CONCLUSION
Therefore, one may conclude that despite of ongoing studies and search for the efficient algorithm for prevention of APMP, the results of studies are contradictable or do not confirm the efficiency. The problem of APMP prevention is difficult and requires for further researching [19].The modern literature shows some discrepancies (sometimes significant) in the model of presurgical preparation for ERCP/EPS, and it gives the foundation for development and research of new preventive procedures. There is not any algorithm for interventions for the major duodenal papilla with formation of the risk groups with various risk factors.
There is not any uniform algorithm for treating patients after interventions for MDP. The domestic recommendations for APMP have not been developed. On the basis of the Russian and foreign publications, one may conclude that the high efficiency and wide experience in use and pharmacological prevention do not allow full control of development and the course of pancreatitis after ERCP, especially in the high risk groups, resulting in increasing mortality in young patients.
There is not any uniform standard of pharmacological prevention. Despite the fact that NSAIDs are widely acknowledged as the most efficient and safe preventive measures for APMP, with actual high efficiency, most studies show that pancreatitis develops in 2 % of patients, with high risk of pancreatic necrosis and lethal outcome. Therefore, one may conclude that along with appropriate identification of risk groups, correct realization of the technique and prescription of obligatory basic pharmacological prevention, it is necessary to develop, to investigate and to implement new agents or techniques for maximally possible decrease in percentage of complications.