The patient is sedated or anaesthetized. Then a flexible camera ( endoscope ) is inserted through the mouth, down the esophagus, into the stomach, through the  pylorus  into the  duodenum  where the  ampulla of Vater  (the union of the common bile duct and pancreatic duct) exists. The  sphincter of Oddi  is a muscular valve that controls the opening to the ampulla. The region can be directly visualized with the endoscopic camera while various procedures are performed. A plastic catheter or  cannula  is inserted through the ampulla, and radiocontrast is injected into the bile ducts and/or pancreatic duct.  Fluoroscopy  is used to look for blockages, or other lesions such as stones. [ 8 ] [ 9 ]


When needed, the sphincters of the ampulla and bile ducts can be enlarged by a cut (sphincterotomy) with an electrified wire called a sphincterotome for access into either so that gallstones may be removed or other therapy performed. [ 10 ]


Other procedures associated with ERCP include the trawling of the common bile duct with a basket or balloon to remove gallstones and the insertion of a plastic  stent  to assist the drainage of bile. [ 11 ]  Also, the pancreatic duct can be cannulated and stents be inserted.


The pancreatic duct requires visualisation in cases of pancreatitis. Ultrasound is frequently the first investigation performed on admission; although it has little value in the diagnosis of pancreatitis or its complications. contrast-enhanced computed tomography (MD-CECT) is the most used imaging technique. However, magnetic resonance imaging (MRI) offers diagnostic capabilities similar to those of CT, with additional intrinsic advantages including lack of ionizing radiation and exquisite soft tissue characterization. [ 12 ]


In specific cases, other specialized or ancillary endoscopes may be used for ERCP. These include mother-baby and SpyGlass cholangioscopes (to help in diagnosis by directly visualizing the duct as opposed to only obtaining X-ray images [ 13 ] [ 14 ] [ 15 ] ) as well as balloon enteroscopes (e.g. in patients that have previously undergone  digestive system surgery  with post- Whipple  or  Roux-en-Y  surgical anatomy). [ 16 ]


One of the most frequent and feared complications after endoscopic retrograde cholangiopancreatography (ERCP) is post-ERCP pancreatitis (PEP). In previous studies, the incidence of PEP has been estimated at 3.5 to 5%. [ 17 ] [ 18 ]  According to Cotton et al., PEP is defined as a "clinical pancreatitis with amylase at least three times the upper limit of normal at more than 24 hours after the procedure requiring hospital admission or prolongation of planned admission". Grading of severity of PEP is mainly based on the length of hospital stay. [ 19 ]


Risk factors for developing PEP include technical matters related to the ERCP procedure and patient-specific ones. The technical factors include manipulation of and injection of contrast into the pancreatic duct, cannulation attempts lasting more than five minutes, and biliary balloon sphincter dilation; among patient-related factors are female gender, younger age, and Sphincter of Oddi dysfunction. [ citation needed ]  A systematic review of clinical trials concluded that a previous history of PEP or pancreatitis significantly increases the risk for PEP to 17.8% and to 5.5% respectively. [ 20 ] [ 21 ]


Intestinal perforation  is a risk of any gastroenterologic endoscopic procedure, and is an additional risk if a  sphincterotomy  is performed. As the second part of the duodenum is anatomically in a  retroperitoneal  location (that is, behind the peritoneal structures of the abdomen), perforations due to sphincterotomies are retroperitoneal. Sphincterotomy is also associated with a risk of bleeding. [ 22 ]  ERCP may provoke hemobilia from trauma to friable hilar tumors or a guide-wire penetrating the bile duct wall, creating a  biliary fistula . Delayed bleeding is a rare but potentially serious complication of sphincterotomy, particularly as many patients are discharged home within hours of ERCP.


There is also a risk associated with the  contrast dye  in patients who are allergic to compounds containing  iodine , which can be very severe, even if the anaphylactoid reactions occur while you are in a hospital. [ 23 ] [ 24 ]


Oversedation can result in dangerously low blood pressure, respiratory depression, nausea, and vomiting. [ citation needed ]


Other complications (less than 1%) may include heart and lung problems, infection in the bile duct called  cholangitis , that can be life-threatening, and is regarded as a medical emergency. Using antibiotics before the procedure shows some benefits to prevent cholangitis and septicaemia. [ 25 ]  In rare cases, ERCP can cause fatal complications. [ 26 ]


Cases of hospital-acquired (i.e., nosocomial) infections with  carbapenem resistant enterobacteriaceae  linked to incompletely disinfected duodenoscopes have occurred in the U.S. since at least 2009 per the  Food and Drug Administration . [ 27 ]  Outbreaks were reported from  Virginia Mason Hospital  in Seattle in 2013,  UCLA Health System  Los Angeles in 2015, Chicago and Pittsburgh. [ 28 ]  The FDA issued a safety communication "Design of ERCP Duodenoscopes May Impede Effective Cleaning" in February 2015, [ 29 ]  which was updated in December 2015, [ 30 ]  and more recently in 2022 which recommended disposable components. [ 31 ]


Prevalence of vitamin K and vitamin D deficiency, [ 32 ]  as bile is to assist in the breakdown and absorption of fat in the intestinal tract; a relative deficiency of bile can lead to fat malabsorption and deficiencies of fat-soluble vitamins.


In  medicine ,  endoscopic sleeve gastroplasty  (ESG) is a minimally-invasive, non-surgical (incisionless), endoscopic weight loss procedure that is part of the  field of endoscopic bariatric therapies. To perform ESG, a physician sutures a patient’s  stomach  into a narrower, smaller tube-like configuration. [ 1 ]  The result is a more restricted stomach that forces patients to feel fuller sooner, eating fewer calories, which facilitates  weight loss  . [ 2 ] [ 3 ] [ 4 ]


Early iterations of endoscopic gastric remodeling for weight loss included the endoluminal vertical gastroplasty, which attempted to mimic the restricted stomach configuration of the vertical sleeve gastrectomy. [ 5 ]  Around the same time, similar endoscopic remodeling along the stomach’s larger curvature was performed through tissue acquisition with a suction-based device, though this was limited by suture loss. [ 6 ] [ 7 ]  In 2012, Dr. Christopher Thompson, a Harvard Medical School professor and later Co-founder of Bariendo, performed the first ESG case in humans. [ 8 ]  This was modified and tissue was acquired with a full-thickness suturing device, which has been the basis of the present ESG procedure. [ 9 ]   In July 2022, the creation of the ESG using the Apollo Overstitch device was authorized by the  United States Food and Drug Administration  for the treatment of  obesity  in patients with a  body mass index  between 30–50 kg/m 2 .


The ESG may be performed with slight variations by different physicians. It most commonly is performed using the Apollo ESG Device (formally Overstitch device). This device fits over a therapeutic double-channel  endoscope  to create a sutured row of stomach tissue. The tissue helix is advanced from the endoscope, put up against stomach tissue, and turned 2-4 rotations to access the gastric muscle layer. The helix is then retracted towards the scope, bringing the full-thickness acquired stomach tissue with it. Using the handle-operated needle driver, a needle attached to the suture wire is passed through the full-thickness tissue to the anchor exchange. This creates a full-thickness plication of stomach tissue. The needle is then passed back from the anchor exchange to the needle driver, and the process is repeated, threading the suture wire through each bite of stomach tissue. When enough full-thickness bites have been taken for a suture row, a cinch is passed through the scope over the suture. Typically, sutures are placed starting at the border of the  antrum  and  gastric body  at the  incisura , then placed proximally up to the border of the  gastric body  and  fundus . Each row of sutures can be a straight line or one of the variety of suture patterns reported in the literature, such as the “M,” “Z,” and “U” pattern as well as other novel patterns; nonetheless, to date, no suture pattern has been proven to be superior for weight loss. [ 10 ] [ 11 ] [ 12 ] [ 13 ]  Regardless of suture pattern, creation of the ESG focuses on tissue imbrication along the greater curvature of the stomach. The  fundus  is typically avoided due to the relatively thinner wall compared to the  gastric body  to avoid complications from the procedure. [ 14 ]


Accredited advanced  fellowship  training programs in ESG and other endoscopic bariatric therapies are currently rare, and competency in ESG is typically achieved through proctoring by experts after completion of an accredited gastroenterology or surgical training program. Studies have reported that efficiency with performance of ESG and improved weight loss outcomes occur after approximately 35-38 cases. [ 15 ] [ 16 ] [ 17 ]  Mastery was reported in one study to occur after 55 cases. [ 15 ]  While early performance of the ESG has traditionally been carried out in university-affiliated/academic centers, ESG has been shown to be feasible and safe when performed in the community setting. [ 18 ]


The primary measures of weight loss outcomes for endoscopic bariatric therapies include total body weight loss (percentage of pre-procedure weight lost by a certain time point) and excess weight loss (percentage of pre-procedure weight above ideal body weight that is lost by a certain time point). The Preservation and Incorporation of Valuable Endoscopic Innovation thresholds is an expert panel with gastroenterologists and surgeons from the  American Society for Gastrointestinal Endoscopy  and  The American Society for Metabolic and Bariatric Surgery , and in 2015, this panel recommended that any new endoscopic therapy for weight loss should have an excess weight loss exceeding 25% and a serious adverse event rate less than 5%. [ 19 ]  Total body weight loss thresholds were not defined but are generally considered meaningful in novel endoscopic bariatric therapies if exceeding 5%. [ 20 ] [ 21 ]  Multiple studies of ESG have shown that this therapy satisfies these criteria, as outlined below.


The recently published MERIT study is the first and only  randomized controlled trial  of the ESG for treatment of obesity and included 209 adult subjects with class I and II obesity ( BMI  30–40 kg/m 2 ). [ 22 ]  It was conducted from Dec. 2017 to Jun. 2019, spanned nine centers in the United States, and comprised 85 adults in the ESG arm and 124 adults in the control arm (lifestyle modification only). Subjects in the ESG arm lost 13.6% of body weight and 49.2% of excess body weight at one year, compared to 0.8% total body weight loss and 3.2% excess weight loss in the control arm at the same time point.


Prior to the MERIT study, numerous meta-analyses of studies on ESG report a total body weight loss of approximately 16% at one year. [ 23 ] [ 24 ] [ 25 ] [ 26 ] [ 27 ]  Excess weight loss was observed to be approximately 60% at one year. [ 23 ] [ 25 ] [ 27 ] [ 28 ]  Weight loss reported from high volume community practices that have both expertise in ESG and robust longitudinal aftercare programs with  dietitians  have shown even greater outcomes, with total body weight loss approaching 30% and excess weight loss of 66% at one year. [ 18 ]


Patient selection is an important consideration for any weight loss therapy. The present published literature shows either no influence or conflicting results for patient age, sex, starting weight/ BMI  on weight loss from ESG. Long-term after care programs have demonstrated benefit for sustained weight loss after ESG, with one study showing that patients who continued after care visits following ESG had 20.5% total body weight loss compared to 16.9% total body weight loss in those who dropped out of long-term follow up programs. [ 29 ]


There are over 200  obesity-related comorbidities , and it has been reported that achieving a total body weight loss of 10% has a significant impact of such conditions. [ 30 ]  Thus, the weight loss outcomes with ESG are unsurprisingly accompanied by an improvement in several  obesity-related comorbidities . Weight loss facilitated by ESG has been observed to bring about benefits in or even cure of  diabetes /insulin sensitivity, [ 31 ] [ 32 ] [ 33 ]   dyslipidemia , [ 31 ] [ 32 ]   blood pressure , [ 31 ]  and  fatty liver disease , [ 31 ] [ 33 ] [ 34 ]  as well as quality of life. [ 35 ] [ 36 ]  The MERIT study showed 80% of patients who underwent ESG had improvement in one or more comorbidities at one year. [ 22 ]


Mid-term durability from ESG appears promising. A total body weight loss of 17% and excess weight loss of between approximately 60-67% was observed to be sustained at 18–24 months. [ 23 ] [ 26 ] [ 28 ]  This was later confirmed in the multicenter, randomized controlled MERIT study, which observed that 68% of subjects who underwent an ESG maintained 25% or more of their excess weight loss at two years. [ 22 ]   As a novel therapy, ESG presently lacks studies assessing long-term durability, though more data on this component of ESG are anticipated as more ESGs are performed over time. One recent study observed at 5 years from ESG that at least 10% total body weight loss was maintained in 90% of patients and at least 15% total body weight loss was maintained in 61% of patients. [ 17 ]


Mild to moderate gastrointestinal side effects (such as nausea, cramping, bloating, and abdominal discomfort) are common after ESG (reported in over 70% of patients), but these are predictable, temporary, and can be managed with medications. [ 25 ]  Most will resolve within one week after ESG. Due to the minimally invasive nature of ESG, serious complications are rare. These include pain or nausea requiring hospitalization (1.08%);  upper gastrointestinal tract bleeding  (0.56%);  peri-gastric leak or infected fluid collection  (0.48%);  pulmonary embolism  (0.06%);  perforation  (0.06%). [ 23 ]  Similar rates of serious adverse events were reported in the multicenter, randomized controlled MERIT study. [ 22 ]  No deaths have been observed in the published ESG literature.


Mechanisms of weight loss from ESG remains an area of active study. There are at least two mechanisms of  peripheral appetite signaling  thought to be mediated by ESG: first, increased sense of fullness during a meal leading to meal termination, potentially a result of the intact gastric fundus that serves as a food reservoir and the restriction to gastric expansion (accommodation) during a meal; [ 2 ] [ 4 ]  and second, from delayed emptying of the stomach, which promotes a prolonged sensation of fullness after a meal. [ 4 ]


Unlike the surgical  sleeve gastrectomy , the ESG does not appear to affect central appetite signaling through the hunger hormone,  ghrelin . [ 29 ]  This is thought to be because the surgical sleeve removes the fundus, the primary site of ghrelin production, and the relatively thinner-walled fundus is avoided in the ESG for safety concerns. Furthermore, in cases where the fundus was sutured in ESG, this did not benefit weight loss outcomes. [ 14 ]


ESG can safely be combined with  weight loss medications  to improve weight loss or prevent weight regain after the procedure. The daily injectable medication  liraglutide  showed greater total body weight loss when combined with ESG compared to ESG alone at 7 months (approximately 25% vs 20% respectively). [ 14 ]  Similar results are anticipated with other  incretin  agents, such as  semaglutide  and  tirzepatide , though no studies have directly assessed these combinations.


Weight regain after surgical sleeve gastrectomy has historically been managed with medications or a more invasive revisional surgery. [ 37 ] [ 38 ] [ 39 ] [ 40 ]  Recent data suggested that an ESG can safely be performed after the  surgical sleeve gastrectomy  (sometimes referred to as a “revisional ESG”), with total body weight loss of approximately 16-18% at 12 months. [ 41 ] [ 42 ]  While weight loss is not thought to be as robust as the initial weight loss surgery, the revisional ESG has an improved safety profile compared to a surgical revision and is therefore hypothesized to have greater patient acceptance. [ 37 ]


Laparoscopic  sleeve gastrectomy  (LSG) is one of the most common bariatric surgeries performed worldwide and shares a similar restricted stomach configuration with the ESG. However, it appears to operate with different weight loss mechanisms from the ESG, as it has been shown to reduce the hunger hormone  ghrelin , [ 29 ] [ 43 ]  as well as accelerate, rather than delay, stomach emptying. [ 3 ]


Large, prospective studies directly comparing LSG to ESG are lacking. Comparison of the two therapies has relied on retrospective analysis and findings are conflicting. In a recent propensity score-matched study, the difference in weight loss for LSG vs ESG was 9.7% at 1 year, 6.0% at 2 years, and 4.8% at 3 years in favor of LSG, though the authors described the ESG as  non-inferior  based on an  a priori  definition of non-inferiority as being within 10% total body weight loss of the surgical arm. [ 44 ]  Advantages of the ESG over LSG include lack of incisions, shorter length of stay (same-day-discharge vs 3 days in hospital); [ 29 ]  less  gastroesophageal reflux  (0-2% vs 15-31%); [ 36 ] [ 45 ]  and lower morbidity and overall adverse event rate (1.9% vs 14.5%), [ 45 ] [ 46 ]  though some studies have presented similar rates of adverse events between ESG and LSG. [ 47 ] [ 48 ]  Despite less weight loss, one study found that patients who had undergone ESG had the same degree of comorbidity resolution and had higher quality of life scores at 6 months compared to those who had undergone LSG. [ 36 ]


EndoStim Electrical Stimulation Therapy  is a form of anti-reflux  surgery , intended to assist in correcting a problem with the muscles at the bottom of the  esophagus  (the tube from the mouth to the stomach). Problems with these muscles allow  gastroesophageal reflux disease  (GERD) to happen. [ 1 ]  The procedure was developed by Endostim, based in  St. Louis ,  Missouri , and  Amsterdam ,  Netherlands . [ 2 ]


EndoStim therapy directly targets the weak  lower esophageal sphincter  (LES) muscle, without altering anatomy or using mechanical constraints. EndoStim's proprietary technology uses  functional electrical stimulation  (a type of  neuromodulation ) to restore esophageal function, thereby reducing GERD symptoms. Tiny pulses of electric current are delivered to the LES without causing any sensation. [ citation needed ]


The implantable pulse generator (IPG) and bipolar lead deliver therapy to the lower esophageal sphincter. The IPG is a small device similar to a  pacemaker  and is implanted under the skin of the  abdomen . The lead connects two electrodes from the IPG to the esophagus. Both the IPG and lead are placed  laparoscopically  through a short,  minimally-invasive procedure  under  general anesthesia . [ citation needed ]


The  implantation  procedure lasts approximately 40 minutes, and involves attaching two small electrodes from the lead to the lower esophagus. The lead is brought out into a small pocket located under the abdominal skin and connected to the stimulation device (IPG). Minimally-invasive procedures have been shown to dramatically reduce healing time as well as reduce procedure risk. [ 3 ]


The first  clinical study  using EndoStim technology was published in 2010, showing that in patients with GERD, electrical stimulation therapy significantly and consistently increased LES pressure.


An  open-label trial  conducted in Chile showed the procedure showed “significant and sustained improvement in GERD symptoms, esophageal pH, and reduction in  proton-pump inhibitor  (PPI) usage without any side effects” in patients. [ 4 ]


Endostim therapy is currently not approved by the U.S.  Food and Drug Administration  (FDA).


The procedure, however, received the  CE mark  allowing implants in Europe. [ 5 ]
Endostim is carried out in Argentina, [ 6 ]  Chile, Colombia, Brazil, [ 7 ]  Hong Kong, India, [ 8 ]  Denmark, Germany, [ 9 ]  Netherlands and Switzerland.


Esophageal dilation  or  oesophageal dilatation  (British English) is a therapeutic  endoscopic  procedure that enlarges the  lumen  of the  esophagus . [ 1 ]


It can be used to treat a number of medical conditions that result in narrowing of the esophageal lumen, or decrease motility in the distal esophagus.  These include the following:


There are three major classes of dilators: [ citation needed ]


Complications of esophageal dilatation include the following: [ citation needed ]


A  gastrostomy  is the creation of an artificial external opening into the stomach for nutritional support or gastric decompression.
Typically this would include an incision in the patient's  epigastrium  as part of a formal operation. When originally devised over a century ago the procedure was completed through open surgery using the Stamm technique. [ 1 ]  It can be performed through surgical approach,  percutaneous  approach by  interventional radiology ,  percutaneous endoscopic gastrostomy  (PEG) or  percutaneous ultrasound gastrostomy  (PUG). [ 2 ]


A gastrostomy may be required due to illness, trauma or disability impacting upon the ability to eat or swallow safely, or conditions causing increased nutritional requirement  [ 3 ]  and once formed (or for some techniques, during formation), a  gastrostomy tube  is inserted.


The  Stamm gastrostomy  is an open technique, [ 4 ]  requiring an upper midline  laparotomy  and gastrotomy, with the catheter brought out in the left  hypochondrium . It was first devised in 1894 by the American Gastric Surgeon, Martin Stamm (1847–1918), who was educated greatly in surgery when he visited Germany. [ 5 ] [ circular reference ]


Over the last three decades less invasive approaches such as percutaneous endoscopic gastrostomy (PEG) and laparoscopic assisted Stamm gastrostomy [ 6 ]  have become increasingly popular. [ 7 ] [ 8 ] [ 9 ]


Conventional PEG involves inserting the primary feeding device through the mouth and extracting it through a small incision formed through the abdomen. [ 10 ]


Apparent benefits of PEG include shorter operative times and reduced financial cost. [ 11 ] [ 12 ] [ 13 ]


Severe complications for gastrostomy formation classify as Clavien-Dindo grade 3 and above, requiring surgical or radiological interventions with potential morbidity and mortality. [ 14 ] [ 15 ]  These complications may occur due to damage to surrounding structures intra-operatively, issues affecting the immature gastrostomy early post-operatively, or be secondary to device or site complications, including: adjacent bowel injury, gastrocolic fistulae, migration of gastrostomy to ribs, and failure for spontaneous closure when gastrostomy no longer needed (persistent gastrocutaneous fistula). [ 16 ]


Impedance–pH monitoring  is a technique used in the diagnosis of  gastroesophageal reflux disease  (GERD), by monitoring both  impedance  and  pH . [ 1 ] [ 2 ]


Patients with ongoing symptoms while on  proton-pump inhibitor (PPI) therapy  are commonly diagnosed with impedance–pH monitoring while continuing their medications. The impedance–pH monitoring diagnostic test determines the frequency of reflux episodes and the time relationship of reflux episodes and symptoms. The impedance–pH monitoring test determines if the patient's symptoms are related to  acid reflux , related to  nonacid reflux , or not related to reflux of any type. A positive GERD diagnosis is made if acid or nonacid reflux precedes symptoms in a statistically meaningful manner. Patients with a positive impedance–pH monitoring test may benefit from acid-reduction therapy such as  fundoplication surgery  or  endoscopic  fundoplication techniques. [ citation needed ]


Intraperitoneal injection  or  IP injection  is the injection of a substance into the  peritoneum  (body cavity). It is more often applied to non-human animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed or when low blood pressure or other problems prevent the use of a suitable blood vessel for  intravenous injection . [ citation needed ]


In humans, the method is widely used to administer  chemotherapy  drugs to treat some  cancers , particularly  ovarian cancer . Although controversial, intraperitoneal use in ovarian cancer has been recommended as a  standard of care . [ 1 ]  Fluids are injected intraperitoneally in infants, also used for  peritoneal dialysis . [ citation needed ]


Intraperitoneal injections are a way to administer therapeutics and drugs through a peritoneal route (body cavity). They are one of the few ways drugs can be administered through injection, and have uses in research involving animals, drug administration to treat ovarian cancers, and much more. Understanding when intraperitoneal injections can be utilized and in what applications is beneficial to advance current drug delivery methods and provide avenues for further research. The benefit of administering drugs intraperitoneally is the ability for the peritoneal cavity to absorb large amounts of a drug quickly. A disadvantage of using intraperitoneal injections is that they can have a large variability in effectiveness and misinjection. [ 2 ]  Intraperitoneal injections can be similar to oral administration in that hepatic metabolism could occur in both.


There are few accounts of the use of intraperitoneal injections prior to 1970. One of the earliest recorded uses of IP injections involved the insemination of a guinea-pig in 1957. [ 3 ]  The study however did not find an increase in conception rate when compared to mating. In that same year, a study injected egg whites intraperitoneally into rats to study changes in "droplet" fractions in kidney cells. The study showed that the number of small droplets decreased after administration of the egg whites, indicating that they have been changed to large droplets. [ 4 ]  In 1964, a study delivered chemical agents such as acetic acid, bradykinin, and kaolin to mice intraperitoneally in order to study a "squirming" response. [ 5 ]  In 1967, the production of amnesia was studied through an injection of physostigmine. [ 6 ]  In 1968, melatonin was delivered to rats intraperitoneally in order to study how brain  serotonin  would be affected in the midbrain. [ 7 ]  In 1969, errors depending on a variety of techniques of administering IP injections were analyzed, and a 12% error in placement was found when using a one-man procedure versus a 1.2% error when using a two-man procedure. [ 8 ]


A good example of how intraperitoneal injections work is depicted through "The distribution of salicylate in mouse tissues after intraperitoneal injection" because it includes information on how a drug can travel to the blood, liver, brain, kidney, heart, spleen, diaphragm, and skeletal muscle once it has been injected intraperitoneally. [ 9 ]


These early uses of Intraperitoneal injections provide good examples of how the delivery method can be used, and provides a base for future studies on how to properly inject mice for research.


Currently, there are a handful of drugs that are delivered through intraperitoneal injection for chemotherapy. They are mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed, and melphalan. [ 10 ]  There needs to be more research done to determine appropriate dosing and combinations of these drugs to advance intraperitoneal drug delivery.


There are few examples of the use of intraperitoneal injections in humans cited in literature because it is mainly used to study the effects of drugs in mice. The few examples that do exist pertain to the treatment of pancreatic/ovarian cancers and injections of other drugs in clinical trials. One study utilized IP injections to study pain in the abdomen after a hysterectomy when administering anesthetic continuously vs patient-controlled. [ 11 ]  The results depicted that ketobemidone consumption was significantly lower when patients controlled anesthetic through IP. This led to the patients being able to be discharged earlier than when anesthesia was administered continuously. These findings could be advanced by studying how the route of injection affects the organs in the peritoneal cavity.


In another Phase I clinical trial, patients with ovarian cancer were injected intraperitoneally with dl1520 in order to study the effects of a replication-competent/-selective virus. [ 12 ]  The effects of this study were the onset of flu-like symptoms, emesis, and abdominal pain. The study overall defines appropriate doses and toxicity levels of dl1520 when injected intraperitoneally.


One study attempted to diagnose  hepatic hydrothorax  with the use of injecting Sonazoid intraperitoneally. Sonazoid was utilized to aid with contrast-enhanced ultrasonography by enhancing the peritoneal and pleural cavities. [ 13 ]  This study demonstrates how intraperitoneal injections can be used to help diagnose diseases by providing direct access to the peritoneal cavity and affecting the organs in the cavity.


In a case of a ruptured hepatocellular carcinoma, it was reported that the patient was treated successfully through the use of an intraperitoneal injection of OK-432, which is an immunomodulatory agent. [ 14 ]  The patient was a 51-year-old male who was hospitalized. The delivery of OK-432 occurred a total of four times in a span of one week. The results of this IP injection were the disappearance of the ascites associated with the rupture. This case is a good example of how IP injections can be used to deliver a drug that can help to treat or cure a medical diagnosis over the use of other routes of delivery. The results set a precedent of how other drugs may be delivered in this way to treat other similar medical issues after further research.


In 2018, a patient with stage IV ovarian cancer and peritoneal metastases was injected intraperitoneally with 12g of mixed cannabinoid before later being hospitalized. [ 15 ]  The symptoms of this included impairment of cognitive and psychomotor abilities. Because of the injection of cannabis, the patient was predicted to have some level of THC in the blood from absorption. This case presents the question of how THC is absorbed in the peritoneal cavity. It also shows how easily substances are absorbed through the peritoneal cavity after an IP injection.


Overall, this section provides a few examples of the effects and uses of intraperitoneal injections in human patients. There are a variety of uses and possibilities for many more in the future with further research and approval.


Intraperitoneal injections are the preferred method of administration in many experimental studies due to the quick onset of effects post injection. This allows researchers to observe the effects of a drug in a shorter period of time, and allows them to study the effects of drugs on multiple organs that are in the peritoneal cavity at once. In order to effectively administer drugs through IP injections, the stomach of the animal is exposed, and the injection is given in the lower abdomen. The most efficient method to inject small animals is a two-person method where one holds the rodent and the other person injects the rodent at about 10 to 20 degrees in mice and 20 to 45 degrees in rats. The holder retains the arms of the animal and tilts the head lower than the abdomen to create optimal space in the peritoneal cavity. [ 2 ]


There has been some debate on whether intraperitoneal injections are the best route of administration for experimental animal studies. It was concluded in a review article that utilizing IP injections to administer drugs to laboratory rodents in experimental studies is acceptable when being applied to proof-of-concept studies. [ 16 ]


A study was conducted to determine the best route of administration to transplant mesenchymal stem cells for colitis. This study compared intraperitoneal injections, intravenous injections, and anal injections. It was concluded that the intraperitoneal injection had the highest survival rate of 87.5%. [ 17 ]  This study shows how intraperitoneal injections can be more effective and beneficial than other traditional routes of administration.


One article reviews the injection of sodium pentobarbital to euthanize rodents intraperitoneally. [ 2 ]  Killing the rodent through an intraperitoneal route was originally recommended over other routes such as inhalants because it was thought to be more efficient and ethical. The article overviews whether IP is the best option for euthanization based on evidence associated with welfare implications. It was concluded that there is evidence that IP may not be the best method of euthenasia due to possibilities of missinjection.


Another example of how intraperitoneal injections are used in studies involving rodents is the use of IP for micro-CT contrast enhanced detection of liver tumors. [ 18 ]   Contrast agents  were administered intraperitoneally instead of intravenously to avoid errors and challenges. It was determined that IP injections are a good option for Fenestra to quantify liver tumors in mice.


An example of how intraperitoneal injections can be optimized is depicted in a study where IP injections are used to deliver anesthesia to mice. This study goes over the dosages, adverse effects, and more of using intraperitoneal injections of anesthesia. [ 19 ]


An example of when intraperitoneal injections are not ideal is given in a study where the best route of administration was determined for cancer biotherapy. [ 20 ]  It was concluded that IP administration should not be used over intravenous therapy due to high radiation absorption in the intestines. This shows an important limitation to the use of IP therapy.


The provided examples show a variety of uses for intraperitoneal injections in animals for in vitro studies. Some of the examples depict situations where IP injections are not ideal, while others prove the advantageous uses if this delivery method. Overall, many studies utilize IP injections to deliver therapeutics to lab animals due to the efficiency of the administration route.


Lithotripsy  is a procedure involving the physical destruction of hardened masses like  kidney stones , [ 1 ]   bezoars [ 2 ]  or  gallstones , which may be done  non-invasively . The term is derived from the  Greek  words meaning "breaking (or pulverizing) stones" ( litho-  +  τρίψω  [tripso]).


Lithotripsy is a  non-invasive procedure  used to break up hardened masses like  kidney stones , [ 1 ]   bezoars [ 2 ]  or  gallstones .


Commonly cited absolute contraindications to shock wave lithotripsy (SWL) include pregnancy,  coagulopathy  or use of  platelet aggregation inhibitors ,  aortic aneurysms , severe untreated  hypertension , and untreated urinary tract infections. [ 3 ]


Surgery was the only method to remove stones too large to pass until  French   surgeon  and  urologist   Jean Civiale  in 1832 invented a  surgical instrument  (the  lithotrite ) to crush stones inside the  urinary bladder  without having to open the  abdomen . To remove a calculus, Civiale inserted his instrument through the  urethra  and bored holes in the stone. Afterwards, he crushed it with the same instrument and aspirated the resulting fragments or let them flow normally with  urine . [ citation needed ]


Lithotripsy replaced using lithotrites as the most common treatment beginning in the mid 1980s.  In extracorporeal shock wave lithotripsy (ESWL), external shockwaves are focused at the stone to pulverize it. [ 6 ]   Ureteroscopic  methods use a rigid or flexible scope to reach the stone and direct mechanical or light energy at it. Endoscopy can use lasers as well as other modes of energy delivery: ultrasound or electrohydraulics. [ citation needed ]


ESWL was first used on kidney stones in 1980. It is also applied to gallstones and pancreatic stones. External shockwaves are focused and pulverize the stone which is located by imaging. The first shockwave lithotriptor approved for human use was the Dornier HM3 (human model 3) derived from a device used for testing aerospace parts. Second generation devices used  piezoelectricity  or  electromagnetism  generators. American Urological Association guidelines consider ESWL a potential primary treatment for stones between 4 mm and 2 cm. [ 6 ]


Electrohydraulic lithotripsy is an industrial technique for fragmenting rocks by using electrodes to create shockwaves. It was applied to bile duct stones in 1975. It can damage tissue and is mostly used in biliary tract specialty centers. Pneumatic mechanical devices have been used with endoscopes, commonly for large and hard stones. [ 7 ]


Laser lithotripsy  was introduced in the 1980s.  Pulsed dye lasers  emit 504 nm ( cyan -colored) light that is delivered to the stone by optical fibers through a scope.  Holmium:YAG  lasers were developed more recently and produce smaller fragments.


Endovascular lithotripsy is an  angioplasty  procedure using a balloon internally fitted with an ultrasound generator. [ 8 ]  It can be used in the reduction of very calcified  coronary arteries , with or without the combined usage of  stents . [ 9 ]


A  liver support system  or  diachysis  is a type of  therapeutic device  to assist in performing the functions of the liver. Such systems focus either on removing the accumulating toxins ( liver dialysis ), or providing additional replacement of the  metabolic  functions of the liver through the inclusion of hepatocytes to the device ( bioartificial liver device ). A diachysis machine is used for acute care i.e. emergency care, as opposed to a  dialysis machine  which are typically used over the longer term. These systems are being trialed to help people with  acute liver failure  (ALF) or acute-on-chronic liver failure. [ 1 ]


The primary functions of the liver include removing toxic substances from the blood, manufacturing  blood proteins , storing energy in the form of  glycogen , and secreting  bile . The  hepatocytes  that perform these tasks can be killed or impaired by disease, resulting in  acute liver failure  (ALF) which can be seen in person with previously diseased liver or a healthy one.


In hyperacute and acute liver failure, the clinical picture develops rapidly with progressive  encephalopathy  and  multiorgan dysfunction  such as  hyperdynamic circulation ,  coagulopathy ,  acute kidney injury  and  respiratory insufficiency , severe metabolic alterations, and  cerebral edema  that can lead to brain death. [ 2 ] [ 3 ]  In these cases the mortality without  liver transplantation  (LTx) ranges between 40-80%. [ 4 ] [ 5 ]  LTx is the only effective treatment for these patients although it requires a precise indication and timing to achieve good results. Nevertheless, due to the scarcity of organs to carry out liver transplantations, it is estimated that one third of patients with ALF die while waiting to be transplanted. [ 6 ]


On the other hand, a patient with a chronic hepatic disease can suffer acute decompensation of liver function following a precipitating event such as variceal bleeding,  sepsis  and excessive alcohol intake among others that can lead to a condition referred to as acute-on-chronic liver failure (ACLF).


Both types of hepatic insufficiency, ALF and ACLF, can potentially be reversible and liver functionality can return to a level similar to that prior to the insult or precipitating event.


LTx has shown an improvement in the prognosis and survival with severe cases of ALF. Nevertheless, cost and donor scarcity have prompted researchers to look for new supportive treatments that can act as “bridge” to the transplant procedure. By stabilizing the patient's clinical state, or by creating the right conditions that could allow the recovery of native liver functions, both detoxification and synthesis can improve, after an episode of ALF or ACLF. [ 7 ]


Three different types of supportive therapies have been developed: bio-artificial, artificial and hybrid liver support systems (Table 2).


Extracorporeal liver assist device


Molecular adsorbent recirculating system


Bioartificial Liver Support System


Fractionated plasma separation and adsorption system


TECA-Hybrid Artificial Liver Support System


Radial Flow Bioreactor


Single-pass albumin dialysis


Modular Extracorporeal Liver Support


Bioartificial Liver


Selective plasma filtration therapy


Bioartificial liver devices  are experimental extracorporeal devices that use living cell lines to provide detoxification and synthesis support to the failing liver. Bio-artificial liver (BAL) Hepatassist 2000 uses porcine hepatocytes whereas ELAD system employs hepatocytes derived from human hepatoblastoma C3A cell lines. [ 19 ] [ 20 ]  Both techniques can produce, in fulminant hepatic failure (FHF), an improvement of hepatic encephalopathy grade and biochemical parameters. Potential side effects that have been documented include immunological issues (porcine endogenous retrovirus transmission), infectious complications, and tumor transmigration.


Other biological hepatic systems are Bioartificial Liver Support (BLSS) and Radial Flow Bioreactor (RFB). Detoxification capacity of these systems is poor and therefore they must be used combined with other systems to mitigate this deficiency. Today, its use is limited to centers with high experience in their application. [ 21 ]


A  bioartificial liver device (BAL)  is an artificial  extracorporeal  liver support (ELS) system for an individual who is suffering from  acute liver failure  (ALF) or  acute-on-chronic liver failure  (ACLF). The fundamental difference between artificial and BAL systems lies in the inclusion of hepatocytes into the reactor, often operating alongside the purification circuits used in artificial ELS systems. The overall design varies between different BAL systems, but they largely follow the same basic structure, with patient blood or plasma flow through an artificial matrix housing hepatocytes. Plasma is often separated from the patient’s blood to improve efficiency of the system, and the device can be connected to artificial liver dialysis devices in order to further increase the effectiveness of the device in filtration of toxins. The inclusion of functioning hepatocytes in the reactor allows the restoration of some of the synthetic functions that the patient’s liver is lacking. [ 22 ]


The first bioartificial liver device was developed in 1993 by Dr. Achilles A. Demetriou at Cedars-Sinai Medical Center. The bioartificial liver helped an 18-year-old southern California woman survive without her own liver for 14 hours until she received a human liver using a 20-inch-long, 4-inch-wide plastic cylinder filled with cellulose fibers and pig liver cells. Blood was routed outside the patient's body and through the artificial liver before being returned to the body. [ 23 ] [ 24 ]


Dr. Kenneth Matsumara's work on the BAL led it to be named an invention of the year by  Time  magazine in 2001. [ 25 ]  Liver cells obtained from an animal were used instead of developing a piece of equipment for each function of the  liver . The structure and function of the first device also resembles that of today's BALs. Animal liver cells are suspended in a solution and a patient's blood is processed by a  semipermeable membrane  that allow toxins and blood proteins to pass but restricts an immunological response. [ 25 ]


Advancements in  bioengineering  techniques in the decade after Matsumara's work have led to improved membranes and hepatocyte attachment systems. [ 26 ]  Cell sources now include primary porcine hepatocytes, primary human hepatocytes, human hepatoblastoma (C3A),  immortalized human cell lines  and  stem cells . [ 26 ]


The purpose of BAL-type devices is not to permanently replace  liver functions , but to serve as a supportive device, [ 27 ]  either allowing the liver to regenerate properly upon  acute liver failure , or to bridge the individual's liver functions until a  transplant  is possible.


BALs are essentially  bioreactors , with embedded  hepatocytes  (liver  cells ) that perform the functions of a normal  liver . They process oxygenated  blood plasma , which is separated from the other  blood  constituents. [ 28 ]  Several types of BALs are being developed, including hollow fiber systems and flat membrane sheet systems. [ 29 ]


Various types of hepatocytes are used in these devices. Porcine hepatocytes are often used due to ease of acquisition and cost; however, they are relatively unstable and carry the risk of cross-species disease transmission. [ 30 ]  Primary human hepatocytes sourced from donor organs present several problems in their cost and difficulty to obtain, especially with the current lack in transplantable tissue. [ 30 ]  In addition, questions have been raised about tissue collected from patients transmitting malignancy or infection via the BAL device. Several lines of human hepatocytes are also used in BAL devices, including C3A and HepG2 tumour cell lines, but due to their origin from hepatomas, they possess the potential to pass on malignancy to the patient. [ 31 ]  There is ongoing research into the cultivation of new types of human hepatocytes capable of improved longevity and efficacy in a bioreactor over currently used cell types, that do not pose the risk of transfer of malignancy or infection, such as the HepZ cell line created by Werner  et al. . [ 32 ]


Similar to  kidney dialysis , hollow fiber systems employ a hollow fiber cartridge. Hepatocytes are suspended in a gel solution such as  collagen , which is injected into a series of hollow fibers. In the case of collagen, the suspension is then gelled within the fibers, usually by a temperature change. The hepatocytes then contract the gel by their attachment to the collagen matrix, reducing the volume of the suspension and creating a flow space within the fibers. Nutrient media is circulated through the fibers to sustain the cells. During use, plasma is removed from the patients blood. The patient's plasma is fed into the space surrounding the fibers. The fibers, which are composed of a semi-permeable membrane, facilitate transfer of toxins, nutrients and other chemicals between the blood and the suspended cells. The membrane also keeps immune bodies, such as  immunoglobulins , from passing to the cells to prevent an immune system rejection. [ 33 ]


Currently, hollow-fibre bioreactors are the most commonly accepted design for clinical use due to their capillary-network allowing for easy perfusion of plasma across cell populations. [ 34 ]  However, these structures have their limitations, with convectional transport issues, nutritional gradients, non-uniform seeding, inefficient immobilisation of cells, and reduced hepatocyte growth restricting their effectiveness in BAL designs. [ 35 ]  Researchers are now investigating the use of cryogels to replace hollow-fibres as the cell carrier components in BAL systems.


Cryogels  are super-macroporous three-dimensional polymers prepared at sub-zero temperatures, by the freezing of a solution of cryogel precursors and solvent. The pores develop during this freezing process – as the cryogel solution cools, the solvent begins to form crystals. This causes the concentration of the cryogel precursors in the solution to increase, initiating the cryogelation process and forming the polymer walls. As the cryogel warms, the solvent crystals thaw, leaving cavities that form the pores. [ 36 ]  Cryogel pores range in size from 10-100 μm in size, forming an interconnected network that mimics a capillary system with a very large surface area to volume ratio, supporting large numbers of immobilised cells. Convection mediated transport is also supported by cryogels, enabling even distribution of nutrients and metabolite elimination, overcoming some of the shortcomings of hollow-fibre systems. [ 35 ]  Cryogel scaffolds demonstrate good mechanical strength and biocompatibility without triggering an immune response, improving their potential for long-term inclusion in BAL devices or  in-vitro  use. [ 37 ]  Another advantage of cryogels is their flexibility for use in a variety of tasks, including separation and purification of substances, along with acting as extracellular matrix for cell growth and proliferation. Immobilisation of specific ligands onto cryogels enables adsorption of specific substances, supporting their use as treatment options for toxins, [ 38 ]  for separation of haemoglobin from blood, [ 39 ]  and as a localised and sustained method for drug delivery. [ 40 ]


Developing an effective bioartificial liver (BAL) remains a formidable challenge, as it necessitates the intricate optimization of cell colonization, biomaterial scaffold design, and BAL fluid dynamics. Expanding upon prior research indicating its potential as a blood perfusion device for detoxification, some studies have explored the application of Arg-Gly-Asp (RGD)-containingPoly(2-hydroxyethyl methacrylate) (pHEMA)-alginate cryogels as scaffolds for BAL. These cryogels, incorporating alginate to mitigate protein fouling and functionalized with an RGD-containing peptide to enhance hepatocyte adhesion, represent a promising avenue for BAL scaffold development. Methods for characterizing internal flow within the porous cryogel matrix such as Particle Image Velocimetry (PIV), enables visualization of flow dynamics. PIV analysis revealed the laminar flow characteristics within cryogel pores, prompting the design of a multi-layered bioreactor consisting of spaced cryogel discs to optimize blood/hepatocyte mass exchange. Compared to the column configuration, the stacked bioreactor demonstrated significantly elevated production of albumin and urea, alongside enhanced cell colonization and proliferation over time. [ 35 ]


Recent developments in bioartificial liver (BAL) using living liver cells have shown promising advancements in the field of liver support and regeneration. These developments focus on utilizing various cell sources, scaffold materials, and bioreactor designs to enhance the functionality and viability of BAL systems. Key advancements include:


Cell Sources: Researchers have explored different cell sources for BAL, including primary hepatocytes, stem cell-derived hepatocyte-like cells, and immortalized liver cell lines. Efforts have been made to optimize cell culture conditions to maintain cell viability and functionality within BAL systems.


Scaffold Materials: Biomaterial scaffolds play a critical role in providing structural support and facilitating cell attachment and proliferation in BAL systems. Recent studies have investigated the use of natural and synthetic materials, such as hydrogels, alginate, and decellularized liver scaffolds, to create biomimetic environments conducive to liver cell growth and function.


Bioreactor Designs: Innovative bioreactor designs have been developed to enhance the performance of BAL systems by optimizing mass transfer, fluid dynamics, and cell-matrix interactions. These designs include perfusion-based bioreactors, microfluidic devices, and three-dimensional (3D) bioprinted constructs, which aim to mimic the physiological microenvironment of the liver and promote liver cell function and survival.


Functional Assessment: Advances in bioanalytical techniques have enabled researchers to assess the functionality of liver cells within BAL systems more accurately. These techniques include measuring the secretion of liver-specific biomarkers, such as albumin, urea, and bile acids, as well as evaluating metabolic activity, drug metabolism, and detoxification capacity.


There have been numerous clinical studies involving hollow-fibre bioreactors. Overall, they show promise but do not provide statistically significant evidence supporting their effectiveness. This is generally due to inherent design limitations, causing convectional transport issues, nutritional gradients, non-uniform seeding, inefficient immobilisation of cells, and reduced hepatocyte growth. [ 35 ]  As of writing, no cryogel-based devices have entered clinical trials. However, laboratory results have been promising, [ 35 ] [ 41 ]  and hopefully trials will begin soon.


The  HepatAssist , developed at the Cedars-Sinai Medical Center, is a BAL device containing porcine hepatocytes within a hollow-fibre bioreactor. These semi-permeable fibres act as capillaries, allowing the perfusion of plasma through the device, and across the hepatocytes surrounding the fibres. The system incorporates a charcoal column to act as a filter, removing additional toxins from the plasma. [ 42 ]


Demetriou  et al. [ 42 ]  carried out a large, randomised, multicentre, controlled trial on the safety and efficacy of the HepatAssist device. 171 patients with ALF stemming from viral hepatitis, paracetamol overdose or other drug complications, primary non-function (PNF), or of indeterminate aetiology, were involved in the study and were randomly assigned to either the experimental or control groups. The study found that at the primary end-point 30-day post admission mark, there was an increased survival rate in BAL patients over control patients (71% vs 62%), but the difference was not significant. However, when patients with PNF are excluded from the results there is a 44% reduction in mortality for BAL treated patients, a statistically significant advantage. The investigators noted that exclusion of PNF patients is justifiable due to early retransplantation and lack of intercranial hypertension, so HepatAssist would give little benefit to this group. For the secondary end-point of time-to-death, in patients with ALF of known aetiology there was a significant difference between BAL and control groups, with BAL patients surviving for longer. There was no significant difference for patients of unknown aetiology, however.


The conclusions of the study suggest that such a device has potentially significant importance when used as a treatment measure. While the overall findings were not statistically significant, when the aetiology of the patients was taken into account the BAL group gained a statistically significant reduction in mortality over the control group. This suggests that while the device may not be applicable to patients as an overall treatment for liver dysfunction, it can provide an advantage when the heterogeneity of patients is considered and is used with patients of specific aetiology.


The  Extracorporeal Liver Assist Device  (ELAD) is a human-cell based treatment system. A catheter removes blood from the patient, and an ultrafiltrate generator separates the plasma from the rest of the blood. This plasma is then run through a separate circuit containing cartridges filled with C3A cells, before being returned to the main circuit and re-entering the patient. [ 43 ]


Thompson  et al. [ 43 ]  performed a large open-label trial, measuring the effectiveness of ELAD on patients with severe alcoholic hepatitis resulting in ACLF. Their study involved patients screened at 40 sites across the US, UK, and Australia, and enrolled a total of 203 patients. Patients were then randomised into either ELAD (n=96) or standard medical care (n=107) groups, with even distribution for patients in terms of sex, MELD score, and bilirubin levels. Of the 96 patients in the ELAD group, 45 completed the full 120 hours of treatment – the rest were unable to complete the full regimen due to a variety of reasons, including withdrawal of consent or severe adverse events, though 37 completed >72 hours of treatment, with results showing minimal difference in mortality between those receiving either >72 hours or the full 120 hours of treatment. The study was unable to complete its goal, finding no statistically significant improvement in mortality rates for patients that received ELAD treatment over those receiving standard care at 28 and 91 days (76.0% versus 80.4% and 59.4% versus 61.7%, respectively). Biomarker measurements showed a significantly reduced level of bilirubin and alkaline phosphatase in ELAD patients, though neither improvement translated into increased survivability rates. Outcomes for patients with MELD score <28 showed trends towards improved survival on ELAD, whereas those with MELD >28 had decreased survivability on ELAD. These patients presented with raised creatinine from kidney failure, suggesting a reason why ELAD decreased survival chance over standard care. Unlike artificial ELS devices and HepatAssist, ELAD does not incorporate any filtration devices, such as charcoal columns and exchange resins. Therefore, it cannot replace the filtration capability of the kidneys and cannot compensate for multi-organ failure from more severe presentations of ACLF, resulting in increased mortality rates.


While the results of the study cannot provide conclusive evidence to suggest that a BAL device like ELAD improves the outcome of severe ACLF, it does suggest that it can aid the survival of patients with a less severe form of the disease. In those patients with a MELD <28, beneficial effects were seen 2–3 weeks post treatment, suggesting that while C3A incorporating BAL devices are unable to provide short-term aid like artificial albumin filtration devices, they instead provide more long-term aid in recovery of the patient’s liver. [ 43 ]


A randomized, phase 3 trial of the ELAD device in patients with severe alcoholic hepatitis failed to show benefit on overall survival and development was discontinued. [ 44 ]


Artificial liver support systems are aimed to temporarily replace native liver detoxification functions and they use  albumin  as scavenger molecule to clear the toxins involved in the physiopathology of the failing liver. Most of the toxins that accumulate in the plasma of patients with liver insufficiency are protein bound, and therefore conventional  renal dialysis  techniques, such as  hemofiltration ,  hemodialysis  or  hemodiafiltration  are not able to adequately eliminate them.


Liver dialysis has shown promise for patients with  hepatorenal syndrome . It is similar to  hemodialysis  and based on the same principles, but hemodialysis does not remove toxins bound to  albumin  that accumulate in liver failure. Like a  bioartificial liver device , it is a form of artificial extracorporeal liver support. [ 45 ] [ 46 ]


A critical issue of the clinical syndrome in  liver failure  is the accumulation of toxins not cleared by the failing  liver . Based on this hypothesis, the removal of  lipophilic , albumin-bound substances such as  bilirubin ,  bile acids , metabolites of  aromatic amino acids , medium-chain  fatty acids  and  cytokines  should be beneficial to the clinical course of a patient in liver failure. This led to the development of artificial filtration and absorption devices.


Liver dialysis is performed by physicians and surgeons and specialized nurses with training in gastroenterological medicine and surgery, namely, in  hepatology , alongside their colleagues in the intensive or  critical care unit  and the transplantation department, which is responsible for procuring and implanting a new liver, or a part (lobe) of one, if and when it becomes available in time and the patient is eligible. Because of the need for these experts, as well as the relative newness of the procedure in certain areas, it is usually available only in larger hospitals, such as level I trauma center teaching hospitals connected with medical schools.


Between the different albumin dialysis modalities, single pass albumin dialysis (SPAD) has shown some positive results at a very high cost; [ 47 ]  it has been proposed that lowering the concentration of albumin in the dialysate does not seem to affect the detoxification capability of the procedure. [ 48 ]  Nevertheless, the most widely used systems today are based on hemodialysis and adsorption. These systems use conventional dialysis methods with an albumin containing dialysate that is later regenerated by means of adsorption columns, filled with  activated charcoal  and  ion exchange  resins.
At present, there are two artificial extracorporeal liver support systems: the Molecular Adsorbents Recirculating System (MARS) from  Gambro  and Fractionated Plasma Separation and Adsorption (FPSA), commercialised as Prometheus (PROM) from  Fresenius Medical Care . Of the two therapies, MARS is the most frequently studied, and clinically used system to date.


While the technique is in its infancy, the prognosis of patients with liver failure remains guarded. Liver dialysis is currently only considered to be a bridge to  transplantation  or liver regeneration (in the case of  acute liver failure ) [ 49 ] [ 50 ] [ 51 ]  and, unlike  kidney dialysis  (for  kidney failure ), cannot support a patient for an extended period of time (months to years).


Artificial detoxification devices currently under clinical evaluation include the Single Pass Albumin Dialysis (SPAD), Molecular Adsorbent Recirculating System (MARS), Prometheus system, and Dialive.


Single pass albumin dialysis (SPAD) is a simple method of  albumin  dialysis using standard renal replacement therapy machines without an additional perfusion pump system: The patient's blood flows through a circuit with a high-flux hollow fiber hemodiafilter, identical to that used in the MARS system. The other side of this membrane is cleansed with an albumin solution in counter-directional flow, which is discarded after passing the filter. Hemodialysis can be performed in the first circuit via the same high-flux hollow fibers.


The  Molecular Adsorbents Recirculation System  (MARS) is the best known extracorporal liver dialysis system. It consists of two separate dialysis circuits. The first circuit consists of  human serum albumin , is in contact with the patient's blood through a semipermeable membrane and has two filters to clean the albumin after it has absorbed toxins from the patient's blood. The second circuit consists of a hemodialysis machine and is used to clean the albumin in the first circuit, before it is recirculated to the semipermeable membrane in contact with the patient's blood.


SPAD, MARS and continuous veno-venous haemodiafiltration (CVVHDF) were compared  in vitro  with regard to detoxification capacity. [ 52 ]  SPAD and CVVHDF showed a significantly greater reduction of ammonia compared with MARS. No significant differences could be observed between SPAD, MARS and CVVHDF concerning other water-soluble substances. However, SPAD enabled a significantly greater  bilirubin  reduction than MARS. Bilirubin serves as an important marker substance for albumin-bound (non-water-soluble) substances. Concerning the reduction of  bile acids  no significant differences between SPAD and MARS were seen. It was concluded that the detoxification capacity of SPAD is similar or even higher when compared with the more sophisticated, more complex and hence more expensive MARS.


Albumin dialysis is a costly procedure: for a seven-hour treatment with MARS, approximately €300 for 600 mL  human serum albumin  solution (20%), €1740 for a MARS treatment kit, and €125 for disposables used by the dialysis machine have to be spent. The cost of this therapy adds up to approximately €2165. Performing SPAD according to the protocol by Sauer et al., however, requires 1000 mL of human albumin solution (20%) at a cost of €500. A high-flux dialyzer costing approximately €40 and the tubings (€125) must also be purchased. The overall costs of a SPAD treatment is approximately €656—30% of the costs of an equally efficient MARS therapy session. The expenditure for the MARS monitor necessary to operate the MARS disposables is not included in this calculation.


The  Prometheus  system ( Fresenius  Medical Care,  Bad Homburg , Germany) is a device based on the combination of  albumin   adsorption  with high-flux  hemodialysis  after selective filtration of the albumin fraction through a specific polysulfon filter (AlbuFlow). It has been studied [ 53 ]  in a group of eleven patients with  hepatorenal syndrome  (acute-on-chronic liver failure and accompanying kidney failure). The treatment for two consecutive days for more than four hours significantly improved serum levels of conjugated bilirubin, bile acids, ammonia, cholinesterase, creatinine, urea and blood pH. Prometheus was proven to be a safe supportive therapy for patients with liver failure.


Dialive (Yaqrit Limited, London, UK) incorporates albumin removal and replacement and, endotoxin removal. It is at " Technology readiness level " (TRL) 5, which means it is validated in the disease environment. [ 54 ] [ 55 ]


MARS was developed by a group of researchers at the  University of Rostock  (Germany), in 1993 and later commercialized for its clinical use in 1999. [ 56 ]  The system is able to replace the detoxification function of the liver while minimizing the inconvenience and drawbacks of previously used devices. [ 57 ] [ 58 ] [ 59 ]


In vivo  preliminary investigations indicated the ability of the system to effectively remove bilirubin, biliary salts, free fatty acids and tryptophan while important physiological proteins such as albumin, alpha-1-glicoproteine, alpha 1 antitrypsin, alpha-2-macroglobulin, transferrin, globulin tyrosine, and hormonal systems are unaffected. [ 60 ]  Also, MARS therapy in conjunction with CRRT/HDF can help clear cytokines acting as inflammatory and immunological mediators in hepatocellular damage, and therefore can create the right environment to favour hepatocellular regeneration and recovery of native liver function.


MARS is an extracorporeal hemodialysis system composed of three different circuits: blood,  albumin  and low-flux dialysis. The blood circuit uses a double lumen  catheter  and a conventional hemodialysis device to pump the patient's blood into the MARS FLUX, a biocompatible polysulfone high-flux dialyser. With a membrane surface area of 2.1 m 2 , 100 nm of thickness and a cut-off of 50 KDa, the MARSFLUX is essential to retaining the albumin in the  dialysate . Blood is dialysed against a  human serum albumin  (HSA) dialysate solution that allows blood detoxification of both  water-soluble  and protein-bound toxins, by means of the presence of albumin in the dialysate (albumin dialysis). The albumin dialysate is then regenerated in a close loop in the MARS circuit by passing through the fibres of the low-flux diaFLUX filter, to clear water-soluble toxins and provide electrolyte/acid-base balance, by a standard dialysis fluid. Next, the albumin dialysate passes through two different adsorption columns; protein-bound substances are removed by the diaMARS AC250, containing activated charcoal and anionic substances are removed by the diaMARS IE250, filled with cholestyramine, an anion-exchange resin. The albumin solution is then ready to initiate another detoxifying cycle of the patient's blood that can be sustained until both adsorption columns are saturated, eliminating the need to continuously infuse albumin into the system during treatment (Fig. 1).


A systematic review of the literature from 1999 to June 2011 was performed in the following databases:


Hepatic encephalopathy  (HE) represents one of the more serious extrahepatic complications associated with liver dysfunction. [ 61 ] [ 62 ]  Neuro-psychiatric manifestations of HE affect consciousness and behaviour.


Evidence suggests that HE develops as some neurotoxins and neuro active substances, produced after hepatocellular breakdown, accumulates in the brain as a consequence of a portosystemic shunt and the limited detoxification capability of the liver. Substances involved are ammonia, manganese, aromatic aminoacids, mercaptans, phenols, medium chain fatty acids, bilirubin, endogenous benzodiazepines, etc.
The relationship between ammonia neurotoxicity and HE was first described in animal studies by Pavlov et al. [ 63 ]
Subsequently, several studies in either animals or humans have confirmed that, a ratio in ammonia concentration higher than 2 mM between the brain and blood stream, causes HE, and even a comatose state when the value is greater than 5 mM. Some investigators have also reported a decrease in serum ammonia following a MARS treatment (Table 3).


Hours/patient


(μg/dL)


Manganese and copper serum levels are increased in patients with either acute or acute on chronic liver failure. Nevertheless, only in those patients with chronic hepatic dysfunction, a bilateral magnetic resonance alteration on Globos Pallidus is observed, [ 68 ]  probably because this type of patients selectively shows higher cerebral membrane permeability.
Imbalance between aromatic and branched chain aminoacids (Fischer index), traditionally involved in HE genesis, [ 69 ] [ 70 ] [ 71 ]  can be normalized following a MARS treatment. The effects are noticeable even after 3 hours of treatment and this reduction in the Fisher index is accompanied with an improvement in the HE. [ 72 ]


Novelli G  et al. [ 73 ]  published their three years experience on MARS analyzing the impact of the treatment in the cerebral level for 63 patients reporting an improvement in Glasgow Coma Score (GCS) for all observed in all patients. In the last 22 patients, cerebral perfusion pressure was monitored by Doppler (mean flow velocity in middle cerebral artery), establishing a clear relationship between a clinical improvement (especially neurological) and an improvement in arterial cerebral perfusion. This study confirms other results showing similar increments in cerebral perfusion in patients treated with MARS. [ 66 ]


More recently, several studies have shown a significant improvement of HE in patients treated with MARS. In the studies by Heemann  et al. [ 74 ]  and Sen  et al. [ 75 ]  an improvement in HE was considered when encephalopathy grade was reduced by one or more grades vs. basal values; for Hassenein et al., in their randomized controlled trial, improvement was considered when a decrease of two grades was observed. [ 76 ]  In the latter, 70 patients with acute on chronic liver failure and encephalopathy grade III and IV were included. Likewise, Kramer et al. [ 77 ]  estimated an HE improvement when an improvement in peak N70 latency in electroencephalograms was observed.
Sen  et al. 44 observed a significant reduction in Child-Pugh Score (p<0,01) at 7 days following a MARS treatment, without any significant change in the controls. Nevertheless, when they looked at the Model for End-Stage Liver Disease Score (MELD), a significant reduction in both groups, MARS and controls, was recorded (p<0,01 y p<0,05, respectively).
Likewise, in several case series, an improvement in HE grade with MARS therapy is also reported. [ 78 ] [ 79 ] [ 80 ] [ 81 ] [ 82 ] [ 83 ] [ 84 ] [ 85 ] [ 86 ]


Hemodynamic instability is often associated with acute liver insufficiency, as a consequence of endogenous accumulation of vasoactive agents in the blood. This is characterized by a systemic vasodilatation, a decrease of systemic vascular resistance, arterial hypotension, and an increase of cardiac output that gives rise to a hyperdynamic circulation.
During MARS therapy, systemic vascular resistance index and mean arterial pressure have been shown to increase and show improvement. [ 78 ] [ 80 ] [ 82 ] [ 87 ] [ 88 ]
Schmidt et al. [ 89 ]  reported the treatment of 8 patients, diagnosed with acute hepatic failure, that were treated with MARS for 6 hours, and were compared with a control group of 5 patients to whom ice pads were applied to match the heat loss produced in the treatment group during the extracorporeal therapy. They analyzed hemodynamic parameters in both groups hourly. In the MARS group, a statistically significant increase of 46% on systemic vascular resistance was observed (1215 ± 437 to 1778 ± 710 dinas x s x cm −5  x m −2 ) compared with a 6% increase in the controls. Mean arterial pressure also increased (69 ± 5 to 83 ± 11 mmHg, p< 0.0001) in the MARS group, whereas no difference was observed in the controls. Cardiac output and heart rate also decreased in the MARS group as a consequence of an improvement in the hyperdynamic circulation. Therefore, it was shown that a statistically significant improvement was obtained with MARS when compared with the SMT.


Catalina et al. [ 90 ]  have also evaluated systemic and hepatic hemodynamic changes produced by MARS therapy. In 4 patients with acute decompensation of chronic liver disease, they observed after MARS therapy, an attenuation of hyperdynamic circulation and a reduction in the portal pressure gradient was measured. Results are summarized in table 4.


There are other studies also worth mentioning with similar results: Heemann  et al . [ 74 ]  and Parés  et al . [ 91 ]  among others. Dethloff T  et al . [ 92 ]  concluded that there is a statistically significant improvement favourable to MARS in comparison with Prometheus system (Table 5).


Hepatorenal syndrome is one of the more serious complications in patients with acute decompensation of cirrhosis and increased portal hypertension. It is characterized by hemodynamic changes in splanchnic, systemic and renal circulation. Splanchnic vasodilatation triggers the production of endogenous vasoactive substances that produce renal vasoconstriction and low glomerular filtration rate, leading to oliguria with a concomitant reduction in creatinine clearance. Renal insufficiency is always progressive with an inferior prognosis, [ 93 ] [ 94 ]  with survival at 1 and 2 months of 20 and 10% respectively.


Pierre Versin [ 95 ]  is one of the pioneers in the study of hepatorenal syndrome in patients with liver impairment.
Great efforts have been made trying to improve the prognosis of this type of patient; however, few have solved the problem. Orthotopic liver transplantation is the only treatment that has shown to improve acute and chronic complications derived from severe liver insufficiency. Today it is possible to combine albumin dialysis with continuous veno-venous hemodialfiltration, which provides a greater expectation for these patients [ 96 ]  by optimization of their clinical status.


MARS treatment lowers serum urea and creatinine levels improving their clearance, [ 88 ] [ 89 ] [ 90 ] [ 92 ]  and even favors resolution of hepatorenal syndrome. [ 74 ] [ 81 ] [ 82 ] [ 87 ] [ 97 ]  Results are confirmed in a randomized controlled trial published by Mitzner  et al. . [ 93 ]  in which 13 patients diagnosed with hepatorenal syndrome type I was treated with MARS therapy. Mean survival was 25,2±34,6 days in the MARS group compared to 4,6±1,8 days observed in the controls in whom hemodiafiltration and standard care (SMT) was applied. This resulted in a statistically significance difference in survival at 7 and 30 days (p<0.05). Authors concluded that MARS therapy, applied to liver failure patients (Child-Pugh C and UNOS 2A scores) who develop hepatorenal syndrome type I, prolonged survival compared to patients treated with SMT.


Although mechanisms explaining previous findings are not yet fully understood, it has been reported that there was a decrease in plasma renin concentrations in patients diagnosed with acute on chronic liver failure with renal impairment that were treated with MARS.
Likewise, other studies have suggested some efficacy for MARS in the treatment of hepatorenal syndrome. [ 98 ] [ 99 ] [ 100 ]
However, other references have been published that do not show efficacy in the treatment of these types of patients with MARS therapy. Khuroo  et al. . [ 101 ]  published a meta-analysis based on 4 small RCT's and 2 non RCT's in patients diagnosed with ACLF, concluding that MARS therapy would not bring any significant increment in survival compared with SMT.
Another observational study in 6 patients with cirrhosis, refractory ascites and hepatorenal syndrome type I, not responding to vasoconstrictor therapy, showed no impact on hemodynamics following MARS therapy; however authors concluded that MARS therapy could effectively serve as bridge to liver transplantation. [ 83 ] [ 102 ]


Total bilirubin was the only parameter analyzed in all trials that was always reduced in the groups of patients treated with MARS; Banayosy  et al. . [ 103 ]  measured bilirubin levels 14 days after since MARS therapy was terminated and observed a consistent, significant decrease not only for bilirubin but also for creatinine and urea (Table 6).


4 sessions


Impact of MARS therapy on plasma biliary acids levels was evaluated in 3 studies. In the study from Stadbauer  et al. ., [ 105 ]  that was specifically addressing the topic, it is reported that MARS and Prometheus systems lower to the same extent biliary acids plasma concentration. Heemann  et al. . [ 74 ]  and Laleman  et al. . [ 88 ]  have also published a significant improvement for these organic ions.


Pruritus  is one of the most common clinical manifestations in cholestasis liver diseases and one of the most distressing symptoms in patients with chronic liver disease caused by  viral hepatitis C . Many hypotheses have been formulated to explain physio pathogenesis of such manifestation, including incremental plasma concentration of biliary acids, abnormalities in the  bile ducts , [ 106 ]  increased central  neurotransmitters  coupling  opioid receptors , [ 107 ] [ 108 ]  etc. Despite the number of historical drugs used, individually or combined (exchange resins, hydrophilic biliary acids, antihistamines, antibiotics, anticonvulsants, opioid antagonists), there are reported cases of intractable or refractory pruritus with a dramatic reduction in patients’ quality of life (i.e. sleep disorders, depression, suicide attempts...). [ 109 ] [ 110 ]  Intractable  pruritus  can be an indication for liver transplantation.


The MARS indication for intractable pruritus is therapeutically an option that has shown to be beneficial for patients in desperate cases, although at high cost. [ 111 ] [ 112 ] [ 113 ] [ 114 ]  In several studies, it was confirmed that after MARS treatments, patients remain free from pruritus for a period of time ranging from 6 to 9 months. [ 114 ]  Nevertheless, some authors have concluded that besides the good results found in the literature, application of MARS therapy in refractory pruritus requires larger evidence. [ 112 ]


Pharmacokinetics  and  pharmacodynamics  for a majority of drugs can be significantly be modified with liver failure, affecting the therapeutic approach and potential toxicity of the drugs. In these type of patients,  Child-Pugh score  represents a poor prognostic factor to assess the metabolic capacity of the failing liver.


In patients with hepatic failure, drugs that are only metabolized in the liver, accumulate in the plasma right after they are administered, and therefore it is needed to modify drug dosing in both, concentration and time intervals, to lower the risk of toxicity. It is also necessary to adjust the dosing for those drugs that are exclusively metabolized by the liver, and have low affinity for prioteins and high distribution volume, such as  fluoroquinolones  ( Levofloxacin  and  Ciprofloxacin ). [ 115 ] [ 116 ] [ 117 ] [ 118 ]


Extracorporeal detoxification with albumin dialysis increases the clearance of drugs that are bound to plasmatic proteins (Table 7).


In the meta-analysis published by Khuroo  et al. . [ 101 ]  which included 4 randomized trials [ 74 ] [ 89 ] [ 93 ] [ 103 ]  an improvement in survival for the patients with liver failure treated with MARS, compared with SMT, was not observed.


However, neither in the extracorporeal liver support systems review by the  Cochrane [ 119 ]  (published in 2004), nor the meta-analysis by Kjaergard  et al. . [ 120 ]  was a significance difference in survival found for patients diagnosed with ALF treated with extracorporeal liver support systems.
Nevertheless, these reviews included all kind of liver support systems and used a heterogeneous type of publication (abstracts, clinical trials, cohort, etc.).


There is literature showing favorable results in survival for patients diagnosed with ALF, and treated with MARS., In a randomized controlled trial, Salibà  et al. . [ 121 ]  studied the impact on survival of MARS therapy for patients with ALF, waiting on the liver transplant list. Forty-nine patients received SMT and 53 were treated with MARS. They observed that patients that received 3 or more MARS sessions showed a statistically significance increase in transplant-free survival compared with the others patients of the study. Notably, 75% of the patients underwent liver transplantation in the first 24 hours after inclusion in the waiting list, and besides the short exposure to MARS therapy, some patients showed a better survival trend compared to controls, when they were treated with MARS prior to the transplant.


In a case-controlled study by Montejo  et al. . [ 104 ]  it was reported that MARS treatment do not decrease mortality directly; however, the treatment contributed to significantly improve survival in patients that were transplanted. In studies by Mitzner  et al. . [ 93 ]  and Heemann  et al. . [ 74 ]  they were able to show a significance statistical difference in 30-day survival for patients in the MARS group. However, El Banayosy  et al. . [ 103 ]  and Hassanein  et al. . [ 76 ]  noticed a non significant improvement in survival, probably because of the short number of patients included in the trials. In the majority of available MARS studies published with patients diagnosed with ALF, either transplanted or not, survival was greater in the MARS group with some variations according to the type of trial, ranging from 20-30%, [ 122 ] [ 123 ]  and 60-80%. [ 83 ] [ 124 ] [ 125 ] [ 126 ]  Data is summarized in Tables 8, 9 and 10.


MARS (%)


Controls


For patients diagnosed with acute on chronic liver failure and treated with MARS therapy, clinical trial results showed a not statistically significant reduction in mortality (odds ratio [OR] =0,78; confident interval [CI] =95%: 0,58 – 1,03; p= 0,1059, Figure 3)


A non-statistically significant reduction of mortality was shown in patients with ALF treated with MARS (OR = 0,75 [CI= 95%, 0,42 – 1,35]; p= 0,3427). (Figure 4)


Combined results yielded a non-significant reduction on mortality in patients treated with MARS therapy. However, the low number of patients included in each of the studies may be responsible for not being able to achieve enough statistical power to show differences between both treatment groups. Moreover, heterogeneity for the number of MARS sessions and severity of liver disease of the patients included, make it very difficult for the evaluation of MARS impact on survival.


Recently, a meta-analysis on survival in patients treated with an extra-hepatic therapy has been published. [ 131 ]  Searching strategies yielded 74 clinical trials: 17 randomized controlled trials, 5 case control and 52 cohort studies. Eight studies were included in the meta-analysis: three addressing acute liver failure, one with MARS therapy [ 103 ]  and five addressing acute on chronic, being four MARS related. [ 74 ] [ 75 ] [ 76 ] [ 93 ]  Authors concluded that extra-hepatic detoxifying systems improve survival for acute liver insufficiency, whereas results for acute decompensation of chronic liver diseases suggested a non significant survival benefit. Also, due to an increased demand for liver transplantation together with an augmented risk of liver failure following large resections, development of detoxifying extrahepatic systems are necessary.


Safety, defined as presence of adverse events, is evaluated in few trials. Adverse events in patients receiving MARS therapy are similar to those in the controls with the exception of thrombocytopenia and hemorrhage that seems to occur more frequently with the MARS system. [ 132 ]


Heemann et al. [ 74 ]  reported two adverse events most probably MARS related: fever and sepsis, presumably originated at the catheter.


In the study by Hassanein  et al. , [ 76 ]  two patients in the MARS group abandoned the study owing to   hemodynamic instability, three patients required larger than average platelets transfusion and three more patients presented gastrointestinal bleeding.


Laleman  et al. . [ 88 ]  detected one patient with thrombocytopenia in both the MARS and Prometheus treatment groups, and an additional patient with clotting of the dialysis circuit and hypotension, only in the Prometheus group.


Kramer  et al. . (Biologic-DT) [ 77 ]  wrote about 3 cases with disseminated intravascular coagulation in the interventional group, two of them with fatal outcomes.


Mitzner  et al. . [ 93 ]  described, among patients treated with MARS, a thrombocytopenia case and a second patient with chronic hepatitis B, who underwent TIPS placement on day 44 after randomization and died on day 105 of multiorgan failure, as a consequence of complications related to the TIPS procedure.


Montejo  et al. . [ 104 ]  showed that MARS is an easy technique, without serious adverse events related to the procedure, and also easy to implement in ICU settings that are used to renal extracorporeal therapies.


The MARS International Registry, with data from more than 500 patients (although sponsored by the manufacturer), shows that the adverse effects observed are similar to the control group. However, in these severely ill patients it is difficult to distinguish between complications of the disease itself and side effects attributable to the technique.


Only three Studies addressing cost-effectivenenss of MARS therapy have been found.
Hassanein et al. [ 133 ]  analysed costs of randomized patients with ACLF receiving MARS therapy or standard medical care. They used the study published in 2001 by Kim et al. [ 134 ]  describing the impact of complications in hospitalization costs in patients diagnosed with alcoholic liver failure. Cost of 11 patients treated with standard medical care (SMT) were compared to those that received MARS, in addition to SMT (12 patients). In the MARS group, there was less in-hospital mortality and complications related to the disease, with a remarkable reduction in cost which compensated the MARS related expenditure (Table 11).


There were 5 survivors in the control group, with a cost per patient of $35.904, whereas in the MARS group, 11 patients out of 12 survived with a cost per patient of $32.036 which represents a $4000 savings per patient in favors of the MARS group.
Hessel et al. [ 135 ]  published a 3-year follow-up of a cohort of 79 patients with ACLF, of whom 33 received MARS treatments and 46 received SMT. Survival was 67% for the MARS group and 63% for the controls, that was reduced to 58 and 35% respectively at one year follow-up, and then 52 and 17% at three years.


Hospitalization costs for the MARS treated group were greater than that for the controls (€31,539 vs. €7,543) and similarly direct cost at 3-year follow-up (€8,493 vs. €5,194). Nevertheless, after adjusting mortality rate, the annual cost per patient was €12,092 for controls and €5,827 for MARS group; also in the latter, they found an incremental cost-effectiveness ratio of 31.448 € per life-year gained (LYG) and an incremental costs per QALY gained of 47171 €.


Two years later, same authors published the results of 149 patients diagnosed with ACLF. [ 136 ]  There were 67 patients (44,9%) treated with MARS and 82 patients (55,1%) were allocated to receive SMT. Mean survival time was 692 days in the MARS group (33% at 3 years) and 453 days in the controls (15% at 3 years); the results were significant (p=0,022). Differences in average cost was €19,853 (95% IC: 13.308-25.429): 35.639 € for MARS patients and 15.804 € for the control group. Incremental cost per LYG was 29.985 € (95% IC: 9.441-321.761) and €43,040 (95% IC: 13.551-461.856) per quality-adjusted life years (QALY).


Liver support systems, such as MARS, are very important to stabilize patients with acute or acute on chronic liver failure and avoid organ dysfunction, as well as a bridge-to-transplant. Although initial in-hospital costs are high, they are worth for the favorable outcome.


Etiology:


Goals of MARS Therapy


MARS Therapy Indication


Treatment Schedule:


[ 147 ] [ 148 ]


[ 97 ] [ 137 ] [ 140 ] [ 150 ]


Same contraindications as with any other extracorporeal treatment may be applied to MARS therapy.


Blood Flow


The trend is to use high flow rates, although it is determined by the technical specifications of the combined machine and catheters’ size


Intermittent treatments:


Continuous treatments:


Dyalisate Flow Rate


Replacement Flow Rate


Heparin Anticoagulation


Similarly to CVVHD, it depends on previous patient's coagulation status. In many cases it will not be needed, unless the patient presents a PTT inferior to 160 seconds. In patients with normal values, a bolus of 5000 to 10000 IU of heparin could be administered at the commencement of the treatment, followed by a continuous perfusion, to keep PTT in ratios from 1,5 to 2,5 or 160 to 180 seconds.


Monitoring


A biochemical analysis is recommended (liver and kidney profile, ionic, glucose) together with a hemogram at the end of first session and before starting the following one.


Coagulation analysis must be also performed before starting the session to adjusting heparin dose.


In case that medication susceptible to be eliminated by MARS is being administered, it is also recommended to monitor their levels in blood


End of the Session


and both catheter's lumens heparinized


Federal Drug Administration  (FDA) cleared, in a document dated on May 27, 2005, MARS therapy for the treatment of drug overdose and poisoning. The only requirement is that the drug or poison must be susceptible to be dialysed and removed by activated charcoal or anionic exchange resins.


More recently, on December 17, 2012, MARS therapy has been cleared by the FDA for the treatment of  hepatic encephalopathy  due to a decompensation of a chronic liver disease. Clinical trials conducted with MARS treatment in HE patients having a decompensation of chronic liver disease demonstrated a transient effect from MARS treatments to significantly decrease their hepatic encephalopathy scores by at least 2 grades compared to standard medical therapy (SMT).


The MARS is not indicated as a bridge to liver transplant. Safety and efficacy has not been demonstrated in controlled, randomized clinical trials.


The effectiveness of the MARS device in patients that are sedated could not be established in clinical studies and therefore cannot be predicted in sedated patients


The  LiverNet  is a database dedicated to the liver diseases treated with the support of extracorporeal therapies. To date, the most currently used system is the Molecular Adsorbent Recirculating System (MARS), which is based on the selective removal of albumin bound molecules and toxins from the blood in patients with acute and acute-on-chronic liver failure. The purpose is to register prospectively all patients treated worldwide with the MARS system in order to:


The liverNet is an eCRF database (www.livernet.net) using a SAS platform that allows major advantages for the centres including the automatic calculations of most liver rand ICU scoring systems, instant queries online, instant export of all patients included in the database of each centre to an Excel file for direct statistical analysis and finally instant online statistical analysis of selective data decided by the scientific committee. Therefore, the LiverNet is an important tool to progress in the knowledge of liver support therapies.


The  Model for End-Stage Liver Disease , or  MELD , is a scoring system for assessing the severity of  chronic liver disease . It was initially developed to predict mortality within three months of surgery in patients who had undergone a  transjugular intrahepatic portosystemic shunt  (TIPS) procedure, [ 1 ]  and was subsequently found to be useful in determining prognosis and prioritizing for receipt of a  liver transplant . [ 2 ] [ 3 ]  This score is now used by the  United Network for Organ Sharing  (UNOS) and  Eurotransplant  for prioritizing allocation of  liver transplants  instead of the older  Child-Pugh score . [ 3 ] [ 4 ]


MELD uses the patient's values for serum  bilirubin , serum  creatinine , and the  international normalized ratio for prothrombin time (INR)  to predict survival. It is calculated according to the following formula: [ 3 ]


M
 E
 L
 D

 =

 d
 e
 f

 3.78
 ×
 ln

 (

 serum bilirubin (mg/dL)

 )

 +
 11.2
 ×
 ln

 (

 INR

 )
 +
 9.57
 ×
 ln

 (

 serum creatinine (mg/dL)

 )

 +
 6.43

 {\displaystyle \mathrm {MELD} {\overset {\mathrm {def} }{=}}3.78\times \ln \left({\text{serum bilirubin (mg/dL)}}\right)+11.2\times \ln({\text{INR}})+9.57\times \ln \left({\text{serum creatinine (mg/dL)}}\right)+6.43}


MELD scores are reported as whole numbers, so the result of the equation above is rounded.


UNOS has made the following modifications to the score: [ 5 ]


The etiology of liver disease was subsequently removed from the model because it posed difficulties such as how to categorize patients with multiple causes of liver disease. Modification of the MELD score by excluding etiology of liver disease did not significantly affect the model's accuracy in predicting three-month survival.


Patients with a diagnosis of liver cancer will be assigned a MELD score based on how advanced the cancer is.  [ citation needed ]


In interpreting the MELD Score in hospitalized patients, the 3 month observed mortality (considering 3,437 adult liver transplant candidates with chronic liver disease who were added to
the OPTN waiting list at 2A or 2B status between November, 1999, and December, 2001) is: [ 6 ]


Applications of MELD score include:


MELD was originally developed at the  Mayo Clinic  by Dr. Patrick Kamath, and at that point was called the "Mayo End-stage Liver Disease" score. It was derived in a series of patients undergoing TIPS procedures. The original version also included a variable based on the underlying etiology (cause) of the liver disease. [ 1 ]  The score turned out to be predictive of prognosis in chronic liver disease in general, and—with some modifications—came to be applied as an objective tool in assigning need for a liver transplant. The etiology turned out to be relatively unimportant, and was also regarded as relatively subjective; it was therefore removed from the score. [ 3 ]


The successor of MELD, an advanced scoring system, made by collaboration between  Massachusetts General Hospital  and  IBM , called  MELD-Plus  was introduced in 2017. [ 7 ]


The  United Network for Organ Sharing  proposed that MELD-Na score (an extension of MELD) may better rank candidates based on their risk of pre-transplant mortality and is projected to save 50-60 lives total per year. [ 8 ]  Furthermore, a study published in the  New England Journal of Medicine  in 2008, estimated that using MELD-Na instead of MELD would save 90 lives for the period from 2005 to 2006. [ 9 ]  In his viewpoint published in June 2018, co-creator of  MELD-Plus , Uri Kartoun, suggested that "...MELD-Plus, if incorporated into hospital systems, could save hundreds of patients every year in the United States alone." [ 10 ]


Paracentesis  (from  Greek  κεντάω, "to pierce") is a form of  body fluid sampling  procedure, generally referring to  peritoneocentesis  (also called  laparocentesis  or  abdominal paracentesis ) in which the  peritoneal cavity  is punctured by a needle to sample  peritoneal fluid . [ 1 ] [ 2 ]


The procedure is used to remove fluid from the peritoneal cavity, particularly if this cannot be achieved with medication. The most common indication is  ascites  that has developed in people with  cirrhosis .


It is used for a number of reasons: [ 3 ]


The procedure is often performed in a doctor's office or an outpatient clinic. In an expert's hands, it is usually very safe, [ 4 ]  although there is a small risk of infection, excessive bleeding or perforating a loop of bowel. These last two risks can be minimized greatly with the use of ultrasound guidance. [ 4 ] [ 5 ]


The use of  ultrasound  has become the standard of care when preparing a patient for paracentesis. Confirmation of an ascitic effusion reduces the risks associated with a dry or blind tap of the abdomen. Anatomic landmarks, such as the midline  linea alba  approach, were traditionally used as reference points for needle insertion. Phased array or curvilinear ultrasound transducers are typically used in the hospital and outpatient setting to identify ascites in the abdominal cavity. Fluid within the abdominal cavity appears hypoechoic or anechoic (black) on ultrasound.  Morison's pouch  (hepatorenal recess) is a common starting location in concordance with ultrasound FAST ( focused assessment with sonography for trauma ) exam. Fluid collection can occur in a number of different locations and may be difficult to find, especially if the patient only exhibits a small volume of ascites. Measurement of the amount of fluid within the abdominal cavity is not necessary or very successful. Identification of sufficient fluid within the abdominal cavity for fluid analysis or to achieve a therapeutic benefit is all that is required to proceed to paracentesis. Ultrasound guidance of the paracentesis can also be used as an additional safety measure to ensure the needle stays within the ascitic fluid and avoidance of important vessels within the abdominal cavity. [ 5 ]


The patient is requested to urinate before the procedure; alternately, a  Foley catheter  is used to empty the bladder. The patient is positioned in the bed with the head elevated at 45–60 degrees to allow fluid to accumulate in lower abdomen. After cleaning the side of the abdomen with an antiseptic solution, the physician numbs a small area of skin and inserts a large-bore needle with a plastic sheath 2 to 5 cm (1 to 2 in) in length to reach the peritoneal (ascitic) fluid. The needle is removed, leaving the plastic sheath to allow drainage of the fluid. The fluid is drained by gravity, a syringe, or by connection to a vacuum bottle. Several litres of fluid may be drained during the procedure; however, if more than two litres are to be drained, it will usually be done over the course of several treatments. [ 6 ]  After the desired level of drainage is complete, the plastic sheath is removed and the puncture site bandaged. [ 6 ]  The plastic sheath can be left in place with a flow control valve and protective dressing if further treatments are expected to be necessary. [ 6 ]