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Is there a role for octreotide, a somatostatin analog, in the treatment of functional GI disorders?
350
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 127, No. 1
to prevent 1 case of post-ERCP pancreatitis. Three patients in the somatostatin group and 9 patients in the placebo group had moderate pancreatitis; others (3 in the somatostatin group and 9 in the placebo group) had mild pancreatitis. The median duration of post-ERCP hospital stay in the somatostatin group and placebo group was 2 (1–3) and 3 (1– 4) days, respectively (P ⫽ 0.04), and the total extra hospital stay because of post-ERCP pancreatitis in the somatostatin and placebo groups was 48 and 94 days, respectively. Use of somatostatin resulted in a reduction of 0.34 days of hospitalization per patient treated. There were no deaths related to ERCP and there were no adverse effects attributable to somatostatin. Although these results are impressive, in the US, the sale (of somatostatin) is not on! Hence, for now, the only option left for the US endoscopists is to place a pancreatic stent, which has been shown to be very effective in the prevention of post-ERCP pancreatitis (Gastrointest Endosc 1993;39: 652– 657, Gastroenterology 1998;115:1518 –1524, Endoscopy 2002; 34:280 –285, Gastrointest Endosc 2003;57:291–294). Failure to place a pancreatic stent is associated with a very high risk of postERCP pancreatitis (Gastrointest Endosc 2004;59:8 –14). Which is a better option? A pancreatic stent or pharmacotherapy (somatostatin)? The search should continue. . .
Whenever you are asked if you can do a job, tell ’em, “Certainly, I can!” Then get busy and find out how to do it. —Theodore Roosevelt GOTTUMUKKALA S. RAJU, M.D.
Reply. Prevention of post-ERCP pancreatitis has been a topic of great interest in recent years because the incidence of post-ERCP pancreatitis remains high (5%–15%) despite technical improvements (N Engl J Med 1996;335:909 –918). A recent meta-analysis concluded that somatostatin and gabexate were effective in the prevention of post-ERCP pancreatitis (Gastrointest Endosc 2000;51:1–7). However, the routine use of such agents is not cost-effective because a substantial number of patients need to be treated for 1 patient to benefit from the treatment. The risk factors for post-ERCP pancreatitis are now quite well established. The use of pharmacological agents in selected high-risk cases is an appealing approach, especially if a drug given “on demand” during or after the procedure proves to be effective because a number of conditions associated with post-ERCP pancreatitis are not predictable before the procedure (J Pancreas 2003;4:22–32, 2003;4:33– 40). This study by our group showed that somatostatin was effective in preventing pancreatitis when given as a bolus dose after diagnostic ERCP in patients predicted to be at high risk because of the need of therapeutic procedures. Although it is still controversial which type of therapeutic procedures is associated with a high risk, the 13.3% incidence of pancreatitis in the control group did indicate that the study patient population was a high-risk group. During the study period, the incidence of post-ERCP pancreatitis in patients undergoing purely diagnostic ERCP in our unit was 5%. All of the procedures were performed by 6 endoscopists, each with a personal experience of at least 500 ERCP procedures and a yearly case volume of about 80 procedures per endoscopist. The study was performed in a surgical endoscopy unit that deals with mainly choledocholithiasis and malignant biliary obstruction, and hence no patients with sphincter of Oddi dysfunction were enrolled. Pancreatic stenting is an alternative method that has been shown to be effective in preventing post-ERCP pancreatitis in high-risk patients. However, this approach has its own deficiencies. Stent placement following biliary interventions can be difficult. In prospective
studies, failure rates ranged from 5% to 10% (JOP 2003;4:58 – 67). Failure of stenting was associated with a high incidence of pancreatitis (up to 66%), and the resulting pancreatitis could be severe with pancreatic necrosis (Gastrointest Endosc 2004;59:8 –14). Furthermore, there is a low but definite risk of complications such as guidewire perforation during pancreatic stenting (Gastroenterology 1998;115:1518 –1524). Stents without proximal flaps are associated with the risk of early stent migration, whereas stents with flaps require endoscopic removal at a later date. The need of another endoscopic procedure makes it less attractive in terms of cost-effectiveness. Together with the cost of the stent itself and the extra time involved in pancreatic stenting, it is likely that the use of a single dose of somatostatin “on demand” in high-risk patients may be a more cost-effective approach, although this needs to be testified with a comparative study. Nonetheless, for pharmacological prevention of post-ERCP pancreatitis to “sell” better, further studies are needed to search for a cheaper or more effective agent, and such agent should be studied selectively in high-risk patients with an “on demand” approach similar to the design in our study. RONNIE T. POON, M.S., F.R.C.S. (EDIN), F.A.C.S.
IS THERE A ROLE FOR OCTREOTIDE, A SOMATOSTATIN ANALOG, IN THE TREATMENT OF FUNCTIONAL GI DISORDERS? Foxx-Orenstein A, Camilleri M, Stephens D, Burton D (Clinical Neuroscience Translational and Epidemiological Research Program, Mayo Clinic, Rochester, Minnesota). Effect of somatostatin analogue on gastric motor and sensory functions in healthy humans. Gut 2003;52:1555–1561. The current understanding of the pathogenesis of functional gastrointestinal (GI) disorders (FGID) suggest a contributing role for both altered gastrointestinal motility and heightened visceral sensitivity (N Engl J Med 2003;349:2136 –2146). However, although there is evidence for the contribution of each of these factors, their interrelationship and relative contribution to the patients’ symptoms is still not well understood. Furthermore, the specific effects of currently used treatments for FGID on the motor and sensory function of the GI tract is not well characterized. Several studies have examined the effects of somatostatin and its analog, octreotide, on gastrointestinal motor function. These studies demonstrated primarily an inhibitory effect on gastric and small bowel motor functions as well as on the secretion of several intestinal neuropeptides (hormones) that are involved in the gut’s physiological response to food (Gut 1995:36:743–748). Few recent reports have suggested that octreotide may also have an effect on the intestinal sensory mechanisms. For example, octreotide has been shown to reduce colonic sensation in healthy controls (Gastroenterology 1993; 104:1390 –1397) and in patients with irritable bowel syndrome (Aliment Pharmacol Ther 2004;19:123–131). Foxx-Orenstein et al. (Gut 2003;52:1555–1561) conducted a randomized, double blinded, placebo-controlled study to investigate the effects of 2 doses of octreotide on gastric motor and sensory functions compared with placebo. Thirty-nine
July 2004
healthy volunteers were randomized to receive 30 g octreotide, 100 g octreotide, or placebo in a parallel design study (13 participants in each treatment group). Gastric motor function was assessed by: (1) gastric emptying test using a 4-hour standard scintigraphic 99mTc labeled egg meal; (2) gastric volumes at fasting and after 300-mL Ensure meal using a 3-dimensional single photon emission computed tomography (SPECT) imaging; and (3) gastric emptying of nutrient liquids using a 3-hour 111In-DTPA radiolabeled nutrient drink. Gastric sensory function was assessed in conjunction with the gastric liquid emptying. Subjects ingested a nutrient drink (Ensure 1 kcal/mL) at a controlled rate of 30 mL per minute until a maximum tolerated volume was reached. Participants scored their sensation of fullness at 5-minute intervals using a 6-grade scale, and their symptoms of bloating, fullness, nausea, and pain at 30-minute intervals using a 100-mm visual analog scale. Octreotide delayed gastric emptying T1/2 (P ⬍ 0.001) and lag time (P ⫽ 0.016), which was significant for both doses of octreotide tested compared with placebo. The effect of octreotide on liquid emptying T1/2 was not significant. Both doses of octreotide (30 and 100 g) also significantly increased fasting gastric volumes relative to placebo (P ⬍ 0.05). In contrast, postprandial gastric volumes were greater with placebo (817 mL) than with 30 g (693 mL) or 100 g (695 mL) octreotide treatment, and the change in gastric volumes after a meal (relative to fasting) was significantly lower with octreotide (both doses) relative to placebo (P ⬍ 0.05). The maximum ingested volume at the point of maximum sensation did not differ significantly between placebo (1331 mL), octreotide 30 g (1335 mL), and octreotide 100 g (1384 mL). In addition, there were no differences in the aggregated postprandial symptom scores (for bloating, fullness, nausea, and pain) at 30 minutes after maximum sensation between the 3 groups. This study confirms the inhibitory effects of octreotide on gastric emptying and demonstrates its pharmacologic effect on gastric volumes in fasting and postprandial states. In addition, it provides an interesting observation that octreotide treatment is associated with reduced fullness sensation. The findings of similar maximum tolerated volumes and aggregate symptom scores, despite significant delay in gastric emptying and reduced gastric volumes, suggest an effect on sensory mechanisms. The authors concluded that octreotide has important effects on stomach emptying, volumes, and sensations in healthy individuals and that further studies are required in disease states. Comment. The clinical use of the long-acting somatostatin analog, octreotide, in gastrointestinal disorders has been primarily related to its inhibitory effects on intestinal neuropeptides associated with gut motor and secretory functions. Some examples for these clinical applications include: symptomatic control in patients with advanced endocrine-producing tumors, dumping syndrome, short bowel syndrome, chronic diarrhea (associated with diabetes mellitus, human immunodeficiency virus [HIV], or scleroderma), and others.
SELECTED SUMMARIES
351
However, several reported human studies suggest that octreotide might also have an effect on intestinal sensory function. The recently reported observations by Foxx-Orenstein et al. (Gut 2003;52:1555– 1561) regarding a decrease in gastric sensation with octreotide treatment is in agreement with 2 previously reported studies on the gastric effect of octreotide. However, unlike the previous studies by Mertz at al. (Neurogastroenterol Motil 1995;7:175–185) and Mearadji et al. (Aliment Pharmacol Ther 1998;12:1163–1169), in which gastric motor and sensory functions were evaluated by intragastric balloon distention, Foxx-Orenstein et al. have used a noninvasive, SPECT imaging technique to investigate the stomach volume change in response to a more physiologic stimulation by meal loading. Similar to Mertz et al. and Mearadji et al., who reported reduced sensation of fullness to phasic balloon distention with octreotide treatment, the current study supports a sensory modulating effect of octreotide. The results show similar maximum ingested volumes and aggregated symptom scores despite a smaller change in postprandial gastric volumes, thus suggesting an octreotide-induced decrease in gastric sensation. The sensory modulating effect of octreotide in humans has also been documented in other segments of the gastrointestinal tract. Hasler et al. (Gastroenterology 1993;104:1390 –1397) reported that octreotide reduces sensation to rectal distention in healthy volunteers. Interestingly, this effect was not associated with reduced perception of cutaneous thermal or electrical stimulation, suggesting a selective visceral afferent effect. Johnston et al. (Am J Gastroenterol 1999;94: 65–70) reported octreotide induced increase in esophageal sensation thresholds for balloon distention in healthy volunteers. The potential of a drug with a combined effect on gut motor, secretory, and sensory functions draw obvious interest to its possible effect in functional GI disorders where alterations in these functions are well documented. Several groups of investigators have looked at the effects of octreotide in irritable bowel syndrome (IBS). These studies focused mainly on diarrhea-predominant IBS (D-IBS) due to the drug known inhibitory effects on intestinal motor and secretory functions. Hasler et al. (J Pharmacol Exp Ther. 1994;264:1206 – 1211) reported reduced perception of rectal distention with octreotide (100 micrograms subcutaneously) treatment in a small placebo-controlled study in patients with D-IBS, and similar findings were reported by Bardette et al. (Dig Dis Sci 1994;39:1171–1178). However, while the former investigators related their finding to octreotide effect on reducing patients’ elevated rectal pressures, the latter group found no modifying effect of the drug on rectal muscle tone. Thus, although agreeing on the overall effect of reducing rectosigmoid sensation, the findings and the interpretation of the results with regard to the possible site and mechanism of the effect were conflicting or inconsistent. Two recent studies addressed the questions regarding the site and mechanism by which octreotide attenuate sensation of balloon distention. Using an animal model of visceral nociception, Su et al. (Gut 2001;48:676 – 682) examined the effect of octreotide on visceromotor (measured by abdominal muscles electromyography) and pressor (measured by mean arterial blood pressure) responses to noxious colorectal distention. They found that when given intravenously, octreotide was ineffective in reducing either visceromotor or pressor response to colorectal distention. However, when administered into the intrathecal space, it had a dose-dependant attenuation effect. In addition, a wide range of octreotide treatment (0.5 to 2.4 mg/kg) did not alter activity recordings from pelvic nerve afferent fibers, supporting a central, probably spinal, site of action of octreotide in this model of visceral nociception.
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SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 127, No. 1
In a more recent human study, Schwetz at al. (Aliment Pharmacol Ther 2004;19:123–131) examined the effect of octreotide on perceptual responses to rectosigmoid distention in patients with IBS and healthy controls. The investigators reported that octreotide effectively decreased distention-induced discomfort sensation. However, this effect was noticeable only in the IBS group. In addition, octreotide prevented the induction of rectal hypersensitivity by repetitive sigmoid stimulation (also called sigmoid conditioning-induced sensitization). These findings lead the investigators to propose that octreotide effect on visceral sensation is mainly anti-hyperalgesic rather than analgesic. Furthermore, the ability of octreotide to eliminate the sensitization effect induced by repetitive sigmoid stimulation indicates a central (spinal or supraspinal) site of action. In addition, rectal compliance was not affected by octreotide administration in either group, suggesting that the effect is not mediated through changes in the mechanoelastic properties of the rectosigmoid and supporting a central rather than peripheral effect. Therefore, does the emerging data suggesting potential beneficial effects of octreotide in IBS justify its clinical use, in certain clinical scenarios, in IBS? The answer is probably no, for several reasons: (1) the data is still very limited; (2) the site and mechanism of the effect are not yet understood; (3) there are safety issues because of the drug’s known possible systemic and gastrointestinal adverse effects; (4) the inconvenience of the administration (subcutaneous or intravenous); and (5) the costs. Nevertheless, it seems that the effects and potential use of octreotide in functional GI disorders deserve further research, which might lead to better understanding of the mechanisms and possible mediators that are associated with the beneficial effects observed with octreotide. Finally, in view of the lack of effective treatment for IBS, particularly in severe cases, the reported effects of octreotide are encouraging, at least with regard to the potential of future use of GI hormones in the treatment of functional GI disorders. As more specific longacting agents with selective effects are developed, it is anticipated that the use of GI hormone/neuropeptides receptor-acting agents may provide novel therapies for functional GI disorders. YEHUDA RINGEL, M.D.
SBP AND THE PATHOGENESIS OF RENAL FAILURE–THE HIDDEN TRIANGLE Ruiz-del-Arbol L, Urman J, Gonzalez M, Navasa M, Monescillo A, Albillos A, Jimenez W, Arroyo V (Liver Hemodynamic Unit, Department of Gastroenterology, Hospital Ramon y Cajal, University of Alcala de Henares, Madrid, and Liver Unit, Institut de Malalties Digestives, Hospital Clinic, Institut de Investigacions Biomediques August Pi I Sunyer, University of Barcelona, Spain). Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003;38:1210 –1218. The main cause of death in patients with spontaneous bacterial peritonitis (SBP) is renal failure. The investigators performed standard and specific biochemistry and measured systemic and hepatic hemodynamics in 23 patients treated for SBP, both at diagnosis and at resolution of infection. Eight patients developed renal failure. At diagnosis, these 8 patients showed significantly higher values for tumor necrosis factor
(TNF)-␣, blood urea nitrogen (BUN), plasma renin activity (PRA), serum norepinephrine levels (NE), peripheral vascular resistance (PVR), and hepatic venous pressure gradient (HPVG), but lower cardiac output (CO) than patients not developing renal failure. In contrast to the rest of the patients with SBP, during therapy in the renal failure patients, CO and mean arterial pressure (MAP) fell, while PRA, NE, HVPG, and Child–Pugh score increased. The only deaths occurred in 6 of the 8 patients with renal failure, despite rapid resolution of the infection. Comment. SBP is defined by an increase in the polymorphonuclear neutrophil count to ⬎250 per milliliter of ascitic fluid, with or without positive ascitic or blood cultures, which may be negative in up to 60% of cases (Gastroenterology 1988;95:1351–1355, J Hepatol 2000;32:142–153). The condition is common in cirrhotic patients with ascites, occurring in 10%–30% of such patients hospitalized for treatment of ascites (Clin Infect Dis 1998;26:1066 –1070), and in 3.5% of cirrhotic outpatients with ascites being treated by repeated paracentesis (Hepatology 2003;37:897–901). SBP is also common in ascitic patients suffering from acute upper gastrointestinal bleeding (Br J Surg 1986;73:724 –726). Patients with SBP may present with symptoms and signs of peritonitis, septicemia or with encephalopathy (PSE), or renal failure of no obvious cause. However, a significant percentage of patients with SBP may be asymptomatic, and therefore all patients admitted to hospital with ascites should undergo routine diagnostic paracentesis. In general, the pathogenesis of SBP is thought to be caused by either translocation of bacteria across the small intestine, in association with small intestinal bacterial overgrowth, via intestinal lymphatics, such as the mesenteric lymph glands resulting in seeding of bacteria into the peritoneal cavity (J Hepatol 2001;34:32–37), or via the systemic circulation (J Hepatol 2001;34:150 –155, Hepatology 2002;36:135–141). The proliferation of ascitic bacteria is then enhanced by abnormalities of ascitic immune defense mechanisms, and deficiencies in antimicrobial activity (Eur J Gastroenterol Hepatol 2002;14:351–354). Until recently, the diagnosis of SBP depended on a laboratory white cell count, performed on a sample of ascitic fluid. The use of reagent strips recently has been introduced, providing a rapid bedside diagnosis of SBP with a sensitivity of 89%, specificity of 99%, and a positive predictive value of 98% compared with the “gold standard” white cell count (Hepatology 2003;37:893– 896). Once the diagnosis has been made, optimal treatment with antibiotics such as oral cephalosporins, e.g. cefotaxime, are effective in approximately 90% of patients (Hepatology 1993;17:251–257, J Hepatol 2000;32:142-153). Combinations of amoxicillin and clavulanic acid (J Hepatol 2000;32:596 – 602), or oral ciprofloxacillin (Hepatogastroenterology 2003;50:1426 –1430), may be more cost effective. Once a cirrhotic patient has been treated successfully for SBP, there is good evidence that they will suffer a recurrence in ⬎80% of cases (Hepatology 1988;8:27–31). Randomized controlled trials have clearly shown that after the first attack, long-term prophylaxis with oral antibiotics, such as norfloxacin, will significantly prevent recurrent SBP and are cost-effective (Hepatology 1990;12:716 –724, J Hepatol 1997;27:295–298, Gastroenterology 1997;113:1289 –1294), just as prophylactic antibiotics will prevent SBP in cirrhotic patients with ascites and gastrointestinal bleeding (Hepatology 1999;29:1655–1661). One of the major causes of death in patients with SBP is hepatorenal syndrome (HRS). HRS has been divided into 2 types by the International Ascites Club (Hepatology 1996;23:164 –171). Type 1 is defined as rapid onset, precipitated by upper gastrointestinal bleed-
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 127, No. 1
to prevent 1 case of post-ERCP pancreatitis. Three patients in the somatostatin group and 9 patients in the placebo group had moderate pancreatitis; others (3 in the somatostatin group and 9 in the placebo group) had mild pancreatitis. The median duration of post-ERCP hospital stay in the somatostatin group and placebo group was 2 (1–3) and 3 (1– 4) days, respectively (P ⫽ 0.04), and the total extra hospital stay because of post-ERCP pancreatitis in the somatostatin and placebo groups was 48 and 94 days, respectively. Use of somatostatin resulted in a reduction of 0.34 days of hospitalization per patient treated. There were no deaths related to ERCP and there were no adverse effects attributable to somatostatin. Although these results are impressive, in the US, the sale (of somatostatin) is not on! Hence, for now, the only option left for the US endoscopists is to place a pancreatic stent, which has been shown to be very effective in the prevention of post-ERCP pancreatitis (Gastrointest Endosc 1993;39: 652– 657, Gastroenterology 1998;115:1518 –1524, Endoscopy 2002; 34:280 –285, Gastrointest Endosc 2003;57:291–294). Failure to place a pancreatic stent is associated with a very high risk of postERCP pancreatitis (Gastrointest Endosc 2004;59:8 –14). Which is a better option? A pancreatic stent or pharmacotherapy (somatostatin)? The search should continue. . .
Whenever you are asked if you can do a job, tell ’em, “Certainly, I can!” Then get busy and find out how to do it. —Theodore Roosevelt GOTTUMUKKALA S. RAJU, M.D.
Reply. Prevention of post-ERCP pancreatitis has been a topic of great interest in recent years because the incidence of post-ERCP pancreatitis remains high (5%–15%) despite technical improvements (N Engl J Med 1996;335:909 –918). A recent meta-analysis concluded that somatostatin and gabexate were effective in the prevention of post-ERCP pancreatitis (Gastrointest Endosc 2000;51:1–7). However, the routine use of such agents is not cost-effective because a substantial number of patients need to be treated for 1 patient to benefit from the treatment. The risk factors for post-ERCP pancreatitis are now quite well established. The use of pharmacological agents in selected high-risk cases is an appealing approach, especially if a drug given “on demand” during or after the procedure proves to be effective because a number of conditions associated with post-ERCP pancreatitis are not predictable before the procedure (J Pancreas 2003;4:22–32, 2003;4:33– 40). This study by our group showed that somatostatin was effective in preventing pancreatitis when given as a bolus dose after diagnostic ERCP in patients predicted to be at high risk because of the need of therapeutic procedures. Although it is still controversial which type of therapeutic procedures is associated with a high risk, the 13.3% incidence of pancreatitis in the control group did indicate that the study patient population was a high-risk group. During the study period, the incidence of post-ERCP pancreatitis in patients undergoing purely diagnostic ERCP in our unit was 5%. All of the procedures were performed by 6 endoscopists, each with a personal experience of at least 500 ERCP procedures and a yearly case volume of about 80 procedures per endoscopist. The study was performed in a surgical endoscopy unit that deals with mainly choledocholithiasis and malignant biliary obstruction, and hence no patients with sphincter of Oddi dysfunction were enrolled. Pancreatic stenting is an alternative method that has been shown to be effective in preventing post-ERCP pancreatitis in high-risk patients. However, this approach has its own deficiencies. Stent placement following biliary interventions can be difficult. In prospective
studies, failure rates ranged from 5% to 10% (JOP 2003;4:58 – 67). Failure of stenting was associated with a high incidence of pancreatitis (up to 66%), and the resulting pancreatitis could be severe with pancreatic necrosis (Gastrointest Endosc 2004;59:8 –14). Furthermore, there is a low but definite risk of complications such as guidewire perforation during pancreatic stenting (Gastroenterology 1998;115:1518 –1524). Stents without proximal flaps are associated with the risk of early stent migration, whereas stents with flaps require endoscopic removal at a later date. The need of another endoscopic procedure makes it less attractive in terms of cost-effectiveness. Together with the cost of the stent itself and the extra time involved in pancreatic stenting, it is likely that the use of a single dose of somatostatin “on demand” in high-risk patients may be a more cost-effective approach, although this needs to be testified with a comparative study. Nonetheless, for pharmacological prevention of post-ERCP pancreatitis to “sell” better, further studies are needed to search for a cheaper or more effective agent, and such agent should be studied selectively in high-risk patients with an “on demand” approach similar to the design in our study. RONNIE T. POON, M.S., F.R.C.S. (EDIN), F.A.C.S.
IS THERE A ROLE FOR OCTREOTIDE, A SOMATOSTATIN ANALOG, IN THE TREATMENT OF FUNCTIONAL GI DISORDERS? Foxx-Orenstein A, Camilleri M, Stephens D, Burton D (Clinical Neuroscience Translational and Epidemiological Research Program, Mayo Clinic, Rochester, Minnesota). Effect of somatostatin analogue on gastric motor and sensory functions in healthy humans. Gut 2003;52:1555–1561. The current understanding of the pathogenesis of functional gastrointestinal (GI) disorders (FGID) suggest a contributing role for both altered gastrointestinal motility and heightened visceral sensitivity (N Engl J Med 2003;349:2136 –2146). However, although there is evidence for the contribution of each of these factors, their interrelationship and relative contribution to the patients’ symptoms is still not well understood. Furthermore, the specific effects of currently used treatments for FGID on the motor and sensory function of the GI tract is not well characterized. Several studies have examined the effects of somatostatin and its analog, octreotide, on gastrointestinal motor function. These studies demonstrated primarily an inhibitory effect on gastric and small bowel motor functions as well as on the secretion of several intestinal neuropeptides (hormones) that are involved in the gut’s physiological response to food (Gut 1995:36:743–748). Few recent reports have suggested that octreotide may also have an effect on the intestinal sensory mechanisms. For example, octreotide has been shown to reduce colonic sensation in healthy controls (Gastroenterology 1993; 104:1390 –1397) and in patients with irritable bowel syndrome (Aliment Pharmacol Ther 2004;19:123–131). Foxx-Orenstein et al. (Gut 2003;52:1555–1561) conducted a randomized, double blinded, placebo-controlled study to investigate the effects of 2 doses of octreotide on gastric motor and sensory functions compared with placebo. Thirty-nine
July 2004
healthy volunteers were randomized to receive 30 g octreotide, 100 g octreotide, or placebo in a parallel design study (13 participants in each treatment group). Gastric motor function was assessed by: (1) gastric emptying test using a 4-hour standard scintigraphic 99mTc labeled egg meal; (2) gastric volumes at fasting and after 300-mL Ensure meal using a 3-dimensional single photon emission computed tomography (SPECT) imaging; and (3) gastric emptying of nutrient liquids using a 3-hour 111In-DTPA radiolabeled nutrient drink. Gastric sensory function was assessed in conjunction with the gastric liquid emptying. Subjects ingested a nutrient drink (Ensure 1 kcal/mL) at a controlled rate of 30 mL per minute until a maximum tolerated volume was reached. Participants scored their sensation of fullness at 5-minute intervals using a 6-grade scale, and their symptoms of bloating, fullness, nausea, and pain at 30-minute intervals using a 100-mm visual analog scale. Octreotide delayed gastric emptying T1/2 (P ⬍ 0.001) and lag time (P ⫽ 0.016), which was significant for both doses of octreotide tested compared with placebo. The effect of octreotide on liquid emptying T1/2 was not significant. Both doses of octreotide (30 and 100 g) also significantly increased fasting gastric volumes relative to placebo (P ⬍ 0.05). In contrast, postprandial gastric volumes were greater with placebo (817 mL) than with 30 g (693 mL) or 100 g (695 mL) octreotide treatment, and the change in gastric volumes after a meal (relative to fasting) was significantly lower with octreotide (both doses) relative to placebo (P ⬍ 0.05). The maximum ingested volume at the point of maximum sensation did not differ significantly between placebo (1331 mL), octreotide 30 g (1335 mL), and octreotide 100 g (1384 mL). In addition, there were no differences in the aggregated postprandial symptom scores (for bloating, fullness, nausea, and pain) at 30 minutes after maximum sensation between the 3 groups. This study confirms the inhibitory effects of octreotide on gastric emptying and demonstrates its pharmacologic effect on gastric volumes in fasting and postprandial states. In addition, it provides an interesting observation that octreotide treatment is associated with reduced fullness sensation. The findings of similar maximum tolerated volumes and aggregate symptom scores, despite significant delay in gastric emptying and reduced gastric volumes, suggest an effect on sensory mechanisms. The authors concluded that octreotide has important effects on stomach emptying, volumes, and sensations in healthy individuals and that further studies are required in disease states. Comment. The clinical use of the long-acting somatostatin analog, octreotide, in gastrointestinal disorders has been primarily related to its inhibitory effects on intestinal neuropeptides associated with gut motor and secretory functions. Some examples for these clinical applications include: symptomatic control in patients with advanced endocrine-producing tumors, dumping syndrome, short bowel syndrome, chronic diarrhea (associated with diabetes mellitus, human immunodeficiency virus [HIV], or scleroderma), and others.
SELECTED SUMMARIES
351
However, several reported human studies suggest that octreotide might also have an effect on intestinal sensory function. The recently reported observations by Foxx-Orenstein et al. (Gut 2003;52:1555– 1561) regarding a decrease in gastric sensation with octreotide treatment is in agreement with 2 previously reported studies on the gastric effect of octreotide. However, unlike the previous studies by Mertz at al. (Neurogastroenterol Motil 1995;7:175–185) and Mearadji et al. (Aliment Pharmacol Ther 1998;12:1163–1169), in which gastric motor and sensory functions were evaluated by intragastric balloon distention, Foxx-Orenstein et al. have used a noninvasive, SPECT imaging technique to investigate the stomach volume change in response to a more physiologic stimulation by meal loading. Similar to Mertz et al. and Mearadji et al., who reported reduced sensation of fullness to phasic balloon distention with octreotide treatment, the current study supports a sensory modulating effect of octreotide. The results show similar maximum ingested volumes and aggregated symptom scores despite a smaller change in postprandial gastric volumes, thus suggesting an octreotide-induced decrease in gastric sensation. The sensory modulating effect of octreotide in humans has also been documented in other segments of the gastrointestinal tract. Hasler et al. (Gastroenterology 1993;104:1390 –1397) reported that octreotide reduces sensation to rectal distention in healthy volunteers. Interestingly, this effect was not associated with reduced perception of cutaneous thermal or electrical stimulation, suggesting a selective visceral afferent effect. Johnston et al. (Am J Gastroenterol 1999;94: 65–70) reported octreotide induced increase in esophageal sensation thresholds for balloon distention in healthy volunteers. The potential of a drug with a combined effect on gut motor, secretory, and sensory functions draw obvious interest to its possible effect in functional GI disorders where alterations in these functions are well documented. Several groups of investigators have looked at the effects of octreotide in irritable bowel syndrome (IBS). These studies focused mainly on diarrhea-predominant IBS (D-IBS) due to the drug known inhibitory effects on intestinal motor and secretory functions. Hasler et al. (J Pharmacol Exp Ther. 1994;264:1206 – 1211) reported reduced perception of rectal distention with octreotide (100 micrograms subcutaneously) treatment in a small placebo-controlled study in patients with D-IBS, and similar findings were reported by Bardette et al. (Dig Dis Sci 1994;39:1171–1178). However, while the former investigators related their finding to octreotide effect on reducing patients’ elevated rectal pressures, the latter group found no modifying effect of the drug on rectal muscle tone. Thus, although agreeing on the overall effect of reducing rectosigmoid sensation, the findings and the interpretation of the results with regard to the possible site and mechanism of the effect were conflicting or inconsistent. Two recent studies addressed the questions regarding the site and mechanism by which octreotide attenuate sensation of balloon distention. Using an animal model of visceral nociception, Su et al. (Gut 2001;48:676 – 682) examined the effect of octreotide on visceromotor (measured by abdominal muscles electromyography) and pressor (measured by mean arterial blood pressure) responses to noxious colorectal distention. They found that when given intravenously, octreotide was ineffective in reducing either visceromotor or pressor response to colorectal distention. However, when administered into the intrathecal space, it had a dose-dependant attenuation effect. In addition, a wide range of octreotide treatment (0.5 to 2.4 mg/kg) did not alter activity recordings from pelvic nerve afferent fibers, supporting a central, probably spinal, site of action of octreotide in this model of visceral nociception.
352
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 127, No. 1
In a more recent human study, Schwetz at al. (Aliment Pharmacol Ther 2004;19:123–131) examined the effect of octreotide on perceptual responses to rectosigmoid distention in patients with IBS and healthy controls. The investigators reported that octreotide effectively decreased distention-induced discomfort sensation. However, this effect was noticeable only in the IBS group. In addition, octreotide prevented the induction of rectal hypersensitivity by repetitive sigmoid stimulation (also called sigmoid conditioning-induced sensitization). These findings lead the investigators to propose that octreotide effect on visceral sensation is mainly anti-hyperalgesic rather than analgesic. Furthermore, the ability of octreotide to eliminate the sensitization effect induced by repetitive sigmoid stimulation indicates a central (spinal or supraspinal) site of action. In addition, rectal compliance was not affected by octreotide administration in either group, suggesting that the effect is not mediated through changes in the mechanoelastic properties of the rectosigmoid and supporting a central rather than peripheral effect. Therefore, does the emerging data suggesting potential beneficial effects of octreotide in IBS justify its clinical use, in certain clinical scenarios, in IBS? The answer is probably no, for several reasons: (1) the data is still very limited; (2) the site and mechanism of the effect are not yet understood; (3) there are safety issues because of the drug’s known possible systemic and gastrointestinal adverse effects; (4) the inconvenience of the administration (subcutaneous or intravenous); and (5) the costs. Nevertheless, it seems that the effects and potential use of octreotide in functional GI disorders deserve further research, which might lead to better understanding of the mechanisms and possible mediators that are associated with the beneficial effects observed with octreotide. Finally, in view of the lack of effective treatment for IBS, particularly in severe cases, the reported effects of octreotide are encouraging, at least with regard to the potential of future use of GI hormones in the treatment of functional GI disorders. As more specific longacting agents with selective effects are developed, it is anticipated that the use of GI hormone/neuropeptides receptor-acting agents may provide novel therapies for functional GI disorders. YEHUDA RINGEL, M.D.
SBP AND THE PATHOGENESIS OF RENAL FAILURE–THE HIDDEN TRIANGLE Ruiz-del-Arbol L, Urman J, Gonzalez M, Navasa M, Monescillo A, Albillos A, Jimenez W, Arroyo V (Liver Hemodynamic Unit, Department of Gastroenterology, Hospital Ramon y Cajal, University of Alcala de Henares, Madrid, and Liver Unit, Institut de Malalties Digestives, Hospital Clinic, Institut de Investigacions Biomediques August Pi I Sunyer, University of Barcelona, Spain). Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003;38:1210 –1218. The main cause of death in patients with spontaneous bacterial peritonitis (SBP) is renal failure. The investigators performed standard and specific biochemistry and measured systemic and hepatic hemodynamics in 23 patients treated for SBP, both at diagnosis and at resolution of infection. Eight patients developed renal failure. At diagnosis, these 8 patients showed significantly higher values for tumor necrosis factor
(TNF)-␣, blood urea nitrogen (BUN), plasma renin activity (PRA), serum norepinephrine levels (NE), peripheral vascular resistance (PVR), and hepatic venous pressure gradient (HPVG), but lower cardiac output (CO) than patients not developing renal failure. In contrast to the rest of the patients with SBP, during therapy in the renal failure patients, CO and mean arterial pressure (MAP) fell, while PRA, NE, HVPG, and Child–Pugh score increased. The only deaths occurred in 6 of the 8 patients with renal failure, despite rapid resolution of the infection. Comment. SBP is defined by an increase in the polymorphonuclear neutrophil count to ⬎250 per milliliter of ascitic fluid, with or without positive ascitic or blood cultures, which may be negative in up to 60% of cases (Gastroenterology 1988;95:1351–1355, J Hepatol 2000;32:142–153). The condition is common in cirrhotic patients with ascites, occurring in 10%–30% of such patients hospitalized for treatment of ascites (Clin Infect Dis 1998;26:1066 –1070), and in 3.5% of cirrhotic outpatients with ascites being treated by repeated paracentesis (Hepatology 2003;37:897–901). SBP is also common in ascitic patients suffering from acute upper gastrointestinal bleeding (Br J Surg 1986;73:724 –726). Patients with SBP may present with symptoms and signs of peritonitis, septicemia or with encephalopathy (PSE), or renal failure of no obvious cause. However, a significant percentage of patients with SBP may be asymptomatic, and therefore all patients admitted to hospital with ascites should undergo routine diagnostic paracentesis. In general, the pathogenesis of SBP is thought to be caused by either translocation of bacteria across the small intestine, in association with small intestinal bacterial overgrowth, via intestinal lymphatics, such as the mesenteric lymph glands resulting in seeding of bacteria into the peritoneal cavity (J Hepatol 2001;34:32–37), or via the systemic circulation (J Hepatol 2001;34:150 –155, Hepatology 2002;36:135–141). The proliferation of ascitic bacteria is then enhanced by abnormalities of ascitic immune defense mechanisms, and deficiencies in antimicrobial activity (Eur J Gastroenterol Hepatol 2002;14:351–354). Until recently, the diagnosis of SBP depended on a laboratory white cell count, performed on a sample of ascitic fluid. The use of reagent strips recently has been introduced, providing a rapid bedside diagnosis of SBP with a sensitivity of 89%, specificity of 99%, and a positive predictive value of 98% compared with the “gold standard” white cell count (Hepatology 2003;37:893– 896). Once the diagnosis has been made, optimal treatment with antibiotics such as oral cephalosporins, e.g. cefotaxime, are effective in approximately 90% of patients (Hepatology 1993;17:251–257, J Hepatol 2000;32:142-153). Combinations of amoxicillin and clavulanic acid (J Hepatol 2000;32:596 – 602), or oral ciprofloxacillin (Hepatogastroenterology 2003;50:1426 –1430), may be more cost effective. Once a cirrhotic patient has been treated successfully for SBP, there is good evidence that they will suffer a recurrence in ⬎80% of cases (Hepatology 1988;8:27–31). Randomized controlled trials have clearly shown that after the first attack, long-term prophylaxis with oral antibiotics, such as norfloxacin, will significantly prevent recurrent SBP and are cost-effective (Hepatology 1990;12:716 –724, J Hepatol 1997;27:295–298, Gastroenterology 1997;113:1289 –1294), just as prophylactic antibiotics will prevent SBP in cirrhotic patients with ascites and gastrointestinal bleeding (Hepatology 1999;29:1655–1661). One of the major causes of death in patients with SBP is hepatorenal syndrome (HRS). HRS has been divided into 2 types by the International Ascites Club (Hepatology 1996;23:164 –171). Type 1 is defined as rapid onset, precipitated by upper gastrointestinal bleed-