A controlled study of the effect of midazolam on abnormal sphincter of Oddi motility

BACKGROUND: The effect of a medication on sphincter of Oddi motility should be characterized if it is to be used during sphincter of Oddi manometry. Controversy exists as to whether midazolam influences sphincter of Oddi motility. This study assessed the effect of midazolam on the hypertensive sphincter of Oddi. METHODS: The study population consisted of 36 patients who presented with recurrent abdominal pain resulting from sphincter of Oddi dysfunction. The study was nonrandomized, prospective, and placebo controlled. Patient allocation was consecutive. Sphincter of Oddi manometry was performed in standard fashion. Manometric tracings were interpreted while the investigator was blinded to treatment allocation. Eighteen patients in the test group received 2 mg of midazolam intravenously whereas the 18 patients in the control group received saline solution intravenously. Manometric parameters were measured before and 3 minutes after the intravenous infusion. Changes in manometric findings before and after the administration of saline solution and midazolam were compared. RESULTS: Midazolam caused a significant reduction in basal sphincter of Oddi pressure (24 mm Hg) as compared with saline solution (p < 0.001). Diagnostic concordance (normal vs. abnormal) between the basal sphincter pressure before and after midazolam was seen in only 77% of patients. CONCLUSIONS: Midazolam significantly altered sphincter of Oddi motility. The decrease in sphincteric pressures would have altered diagnosis and management in 4 of 18 patients. Midazolam should not be used during sphincter of Oddi manometry.     

Endoscopic electromyography of the sphincter of Oddi.

Endoscopic electromyography of the human sphincter of ODDI has provided useful information for the patho-physiological studies on the choledocho-duodenal junction. The pattern and rhythm of the electromyogram observed on the spincter of ODDI were different from those of the duodenum recorded simultaneously in basal tracings of our initial four cases. In the half of other ten cases with consecutive tracings, the different pattern and rhythm of electromyograms between the sphincter of ODDI and the duodenum were also confirmed. It was possible, from our results, to speculate that the functional independence of the sphincter of ODDI from the duodenal wall muscles was in existence.     

Effects of morphine on the human sphincter of Oddi.

The effects of morphine on intraluminal pressures recorded from the sphincter of Oddi (SO) at endoscopic retrograde cholangiopancreatography in 19 patients who were without evidence of biliary or pancreatic disease were studied. Morphine was given in four successive doses of 2.5, 2.5, 5, and 10 micrograms/kg iv at five minute intervals. Morphine in subanalgesic doses increased the frequency of SO phasic pressure waves to a maximum of 10-12/min, caused the phasic waves to occur simultaneously along the sphincter segment, increased phasic wave amplitude from 72 (26) (SE) to 136 (31) mmHg, and increased SO basal pressure from 10 (1) to 29 (9) mmHg (p less than 0.05). The effects of morphine on the SO are mediated by more than one opioid receptor type, as naloxone competitively antagonised the increase in phasic wave frequency induced by morphine, but did not affect the increase in SO basal pressure elicited by morphine. When given after naloxone, morphine decreased phasic wave amplitude, an inhibitory effect that is normally masked by morphine's dominant naloxone sensitive excitatory effect. Mu receptors do not appear to be involved in control of spontaneous SO motor function, as naloxone alone did not affect SO motor activity. The excitatory effects of morphine on the SO are not mediated by cholinergic nerves, as they were not blocked by atropine. Cholinergic nerves, however, may have a role in regulating spontaneous SO motor function because atropine alone depressed phasic wave activity and basal pressure. Although morphine does cause 'spasm' of the human SO, its effects are more complex than is commonly believed.     

Effects of ethanol on the sphincter of Oddi: an endoscopic manometric study.

The effects of ethanol, given either intragastrically or intravenously, on the sphincter of Oddi was evaluated by endoscopic manometry. In 12 subjects intragastric ethanol (150 ml of 32%) was given over 10 minutes. In five control subjects saline solution (150 ml of 0.9%) was given intragastrically instead of ethanol. In five other subjects ethanol was infused intravenously (6 ml/kg of 10%) for 36 minutes. Ethanol given intragastrically produced a significant inhibitory effect on sphincter of Oddi pressure. Peak pressure fell from a control value of 75.7 +/- 26.35 mmHg to 39 +/- 15.39 mmHg (p less than 0.001) at 35 minutes. Basal pressure fell from a control value of 30.17 +/- 19.47 mmHg to 11.83 +/- 6.35 mmHg (p less than 0.01) at 35 minutes. Wave height fell from a control value of 41.33 +/- 15.4 mmHg to 27.16 +/- 11.25 mmHg (p less than 0.02) at 35 minutes. No effects on sphincter of Oddi wave frequency were observed. No significant modifications of sphincter motor activity were observed after intragastric saline infusion. Ethanol given intravenously also produced an appreciable inhibitory effect on sphincter of Oddi pressure, without affecting its wave frequency.     

Paradoxical response of sphincter of Oddi to intravenous injection of cholecystokinin or ceruletide. Manometric findings and results of treatment in biliary dyskinesia.

Sixty two patients with a clinical suspicion of biliary dyskinesia were investigated with endoscopic manometry of the sphincter of Oddi before and after intravenous injection of cholecystokinin or ceruletide. In 52 patients injection was followed by decreased pressure in the sphincter of Oddi; 43 of these had normal prestimulatory values (group I), while the values were raised in the other nine patients (group II). A paradoxical response to intravenous injection was observed in 10 women (group III): increased baseline sphincteric pressure occurred in eight and increase in the amplitude of phasic contractions in four patients. The prestimulatory sphincteric pressure was raised in five and normal in the remaining patients. Eight patients were treated with papillotomy (seven) or balloon dilatation of the sphincter (one). They experienced relief of pain during a follow up period of 11-16 months. Intravenous injection of cholecystokinin or ceruletide may disclose a special type of biliary dyskinesia even in patients with normal prestimulatory manometric findings. Hormone injection increases the diagnostic yield of endoscopic manometry in patients suspected of biliary dyskinesia.     

Effects of atropine and pirenzepine on sphincter of Oddi motility. A manometric study

We studied the Oddi sphincter motility by endoscopic manometry in 10 consecutive patients randomized in a double-blind fashion, after i.v. administration of two anticholinergic compounds (0.5 mg atropine sulfate and 10 mg pirenzepine). Pirenzepine significantly decreased the basal sphincteric pressure, as well as the amplitude and frequency of the phasic contractions. The only significant effect of atropine was the modification of the frequency of the phasic contractions, but only for a short period of time. Our results suggest that muscarinic innervation must be present for a normal sphincter of Oddi motility.     

Pancreatitis after sphincter of Oddi manometry.

The nature, frequency, severity, and possible causes of complications after 207 sphincter of Oddi manometry measurements were studied in 146 patients. Acute pancreatitis was diagnosed in 6% (12 of 207) of the investigations and in 8% (12 of 146) of the patients examined. The pancreatitis was mild in all patients. After cannulation of the pancreatic duct, acute pancreatitis occurred in 10 of 95 (11%) patients compared with one of 93 (1%) when the manometry catheter entered the bile duct only (p less than 0.02). Seven (58%) of the patients who developed acute pancreatitis, however, were found to be suffering from chronic pancreatitis. Some 26% of all sphincter of Oddi manometry measurements on patients with this diagnosis were complicated by an acute attack of pancreatitis compared with 3% (p less than 0.001) in patients without signs of chronic pancreatitis. In all patients the pancreatitis developed within three hours of manometry. We conclude that pancreatitis may occasionally follow sphincter of Oddi manometry measurement, even in patients without pancreaticobiliary disease, and that underlying chronic pancreatitis constitutes a definite risk. Sphincter of Oddi manometry measurement in control subjects should therefore be performed only in centres where the safety of the procedure has been established, and the presence of chronic pancreatitis should be excluded beforehand. Cannulation of the pancreatic duct should be avoided. Manometry can be safely performed, however, as an outpatient procedure.     

Topical glyceryl trinitrate relaxes the sphincter of Oddi.

BACKGROUND/AIM: Nitric oxide (NO) may be involved in non-adrenergic non-cholinergic (NANC) inhibitory innervation of the sphincter of Oddi (SO). The effects of topical application of glyceryl trinitrate (GTN), a NO donor, upon SO motility were examined. METHODS: Nineteen patients undergoing routine SO manometry for investigation of abdominal pain were studied. After routine recording of SO motility, they were randomised into three groups to receive 10 ml of normal saline, 5 mg GTN (0.5 mg/ml) or 10 mg (1 mg/ml) GTN. Drug solutions were infused topically onto papilla via the manometry catheter and recordings were continued for a further 5 minutes. RESULTS: There was no significant change in SO motor variables following application of normal saline. GTN reduced SO tonic and phasic contractions. In four patients, there was complete abolition of all phasic contraction. CONCLUSIONS: Local application of GTN inhibits SO motility. This may have application for diagnostic and therapeutic biliary endoscopy.     

Effect of nalbuphine on the motility of the sphincter of Oddi in patients with suspected sphincter of Oddi dysfunction

BACKGROUND: Nalbuphine is an ideal supplementary analgesic drug for midazolam-induced conscious sedation during operative endoscopy because it has no cardiovascular effect and only a moderate depressive effect on respiration. However, no data are available as to whether nalbuphine is suitable as an analgesic drug during endoscopic sphincter of Oddi manometry. The aim of the present study was to investigate the effect of nalbuphine on the sphincter of Oddi motility in patients with a suspected sphincter of Oddi dysfunction. METHODS: Seventeen patients who were suspected clinically to have SOD after cholecystectomy were prospectively investigated. Five mg of midazolam was administered intravenously before the procedure to induce conscious sedation. After approximately 5 minutes of stationary sphincter of Oddi manometry recording (baseline), either 10 mg of nalbuphine or saline solution (placebo) was administered intravenously in random fashion and pressure was recorded for a further 5 minutes. Maximum sphincter of Oddi basal pressure and average phasic contraction amplitude and frequency were measured before and after the infusion of the drug or saline solution. RESULTS: Nalbuphine administration effectively enhanced the sedation obtained with midazolam without any adverse effect. When the sphincter of Oddi manometric periods before and after the administration of nalbuphine versus placebo were compared, there was a significantly increased basal sphincter of Oddi pressure only in the nalbuphine group: respectively, 49 (18) and 77 (29) mm Hg (p = 0.003) versus 51 (24) and 49 (23) mm Hg (p = 0.9). The phasic contraction amplitude did not change in response to nalbuphine, but the phasic contraction frequency increased significantly, from 5 (3) to 8 (4) per minute (p = 0.04). CONCLUSIONS: Nalbuphine has a stimulatory effect on sphincter of Oddi motility in patients with a suspected sphincter of Oddi dysfunction. Nalbuphine should not be used as premedication before endoscopic ERCP if sphincter of Oddi manometry is to be performed.     

Management of patients with biliary sphincter of Oddi disorder without sphincter of Oddi manometry

Background  

The paucity of controlled data for the treatment of most biliary sphincter of Oddi disorder (SOD) types and the incomplete response to therapy seen in clinical practice and several trials has generated controversy as to the best course of management of these patients. In this observational study we aimed to assess the outcome of patients with biliary SOD managed without sphincter of Oddi manometry.     

The human sphincter of Oddi. Physiology and pathophysiology

The sphincter of Oddi (SO) is critically located at the junction of the common bile duct (CBD), main pancreatic duct, and the duodenum. It is a high-pressure zone with phasic contractions that regulate bile and pancreatic juice flow. The SO is probably regulated by several gastrointestinal hormones, and its basal pressure and phasic contractions can be elevated or decreased significantly by exogenous drugs. Its role in gallstone formation is probably negligible, but severing the SO allows one to extract CBD stones with an endoscope. Abnormal function of the SO can cause biliarylike pain. Of patients with persistent pain after cholecystectomy, 14% have abnormal SO manometric findings. Endoscopic or surgical sphincterotomy can cure these patients of their pain. The SO may play a significant role in the development of pancreatitis in certain patients, either because of the relationship of the CBD orifice to the pancreatic duct orifice created by the SO or because of the response of the SO to exogenous agents, such as alcohol.     

The sphincter of Oddi and pancreatitis

A review of three widely studied mechanisms by which pancreatitis is produced—biliary-pancreatic reflux, obstruction of the pancreatic duct and duodenopancreatic reflux—shows serious objections to each when they are considered individually. The possibility is considered that all three may contribute, each acting at different times. It is likely that the pathogenesis of pancreatitis will remain obscure until methods for studying the sphincter of Oddi are improved and biochemical changes in pancreatic disease are better understood.     

The effects of somatostatin and octreotide on the human sphincter of Oddi.

OBJECTIVE: Somatostatin acts at different sites in the human gastrointestinal tract and generally inhibits the release and effects of many gastrointestinal hormones and neuropeptides. Together with its long-acting analogue octreotide, somatostatin is widely used in the treatment of hormone-producing tumours, variceal bleeding, etc., but multi-centre trials have failed to prove a beneficial effect in the treatment of acute pancreatitis or in the prevention of post-ERCP pancreatitis (pancreatitis following endoscopic retrograde cholangiopancreatography). The aim of the present work was to study the effects of somatostatin and octreotide on the human sphincter of Oddi by means of quantitative hepatobiliary scintigraphy (QHBS). METHOD: Fifteen cholecystectomized patients were enrolled in the study, six in the somatostatin group and nine in the octreotide group. QHBS was performed initially with a standard protocol (baseline data), then repeated after 0.1 mg octreotide or a 250 microg bolus + 250 microg/h somatostatin administration. In the 60th min of QHBS, 0.5 mg glyceryl trinitrate (GTN) was administered sublingually. RESULTS: QHBS demonstrated that both somatostatin and octreotide caused a marked impairment in the bile flow: the half-time of excretion (T1/2) over the common bile duct was significantly prolonged compared with baseline data (somatostatin group: common bile duct T1/2 180 min versus 59.7+/-31 min; octreotide group: common bile duct T1/2 140.9+/-60.5 min versus 30.7+/-11.7 min). Glyceryl trinitrate administration accelerated the transpapillary bile flow, with significant decreases in the elevated T1/2 in both groups. CONCLUSION: Increased transpapillary flow induced by glyceryl trinitrate may be beneficial in the treatment of acute or post-ERCP pancreatitis.     

Choledochoduodenal flow: effect of the sphincter of Oddi in opossums and cats

The aim of this study was to test in vivo (a) whether the sphincter of Oddi acts as a resistor or also as a pump, (b) the effect of an IV infusion of cholecystokinin (CCK) on choledochoduodenal flow, and (c) the ability of the choledochoduodenal junction to prevent duodenobiliary reflux in two animal species, opossums (n = 11) and cats (n = 8). Opossums were implanted with bipolar electrodes on the sphincter of Oddi and the adjacent duodenum. Cats were not. Experiments were performed in vivo using a propulsion evaluation system to test whether the Sphincter of Oddi was able to pump fluid from the bile duct to the duodenum against pressure gradients. In 5 opossums and 4 cats, choledochoduodenal flow was evaluated during the IV infusion of CCK (20 ng.kg-1.min-1). The opossum sphincter of Oddi moved fluid against duodenal pressure gradients of 6-45 cm H2O. The spike-burst frequency (6.4 +/- 1.7 min-1) was maximal at peak bile duct pressures and decreased as bile duct pressure decreased (4.9 +/- 1.6 min-1; P less than 0.001). Pressure pulses in the bile duct were observed at a frequency that correlated with sphincter of Oddi spike-burst frequency (r = 0.84; P less than 0.001). In cats, choledochoduodenal flow occurred only along a hydrostatic gradient; the sphincter of Oddi never acted as a pump but only as a resistor. Infusion of CCk significantly increased the frequency of sphincter of Oddi contractions in opossums, but the transfer of fluid from bile duct to duodenum was significantly reduced. In cats, the rate of fluid flow from the bile duct to the duodenum during CCK infusion did not differ from control values. Reflux of duodenal fluid into the biliary tree was never observed, even at duodenal pressures as high as 100 cm H2O. In conclusion, in vivo, the sphincter of Oddi is able to pump fluid from the bile duct to the duodenum against a pressure gradient in opossums, but, in cats, choledochoduodenal flow requires a bilioduodenal pressure gradient. The increase in sphincter of Oddi contraction frequency induced by CCK in opossums resulted in a decrease in active transsphincteric flow. Duodenobiliary reflux could not be elicited in opossums and cats under the conditions of these experiments.     

Endoscopic manometry of the sphincter of Oddi

Endoscopic manometry of the sphincter of Oddi is a new and invasive test which is currently being evaluated in patients with biliary-type pain, particularly after cholecystectomy, and idiopathic recurrent pancreatitis. Technical aspects of the test appear to have been clarified, but data are incomplete on the potential effect on manometric records of variables such as patient anxiety, prolonged endoscopy and the injection of radiological contrast material prior to the procedure. Despite these considerations, abnormal manometric records are frequent in patients with post-cholecystectomy pain and idiopathic recurrent pancreatitis, and minor abnormalities have been associated with choledocholithiasis. The term structural stenosis is currently being applied to those in whom the sphincter basal pressure is high while biliary dyskinesia describes a variety of manometric changes including rapid phasic contractions, an excess of waves oriented in a retrograde direction and an abnormal response to the intravenous infusion of cholecystokinin octapeptide. Reasons for the motility disorders remain unclear but may include histopathological changes in sphincter tissue, enteric nerve dysfunction, autonomic dysfunction, hormonal/metabolic changes and psychiatric disorders. Heterogeneity within the patient population needs to be carefully addressed in any prospective study of potential benefit from drugs or other procedures such as endoscopic sphincterotomy and operative sphincteroplasty.