Gastrointestinal Stasis Research Articles

Pharmacokinetics of intravenous and intramuscular buprenorphine in the horse

The purpose of this study was to determine the pharmacokinetics of buprenorphine following intravenous (i.v.) and intramuscular (i.m.) administration in horses. Six horses received i.v. or i.m. buprenorphine (0.005 mg/kg) in a randomized, crossover design. Plasma samples were collected at predetermined times and horses were monitored for adverse reactions. Buprenorphine concentrations were measured using ultra-performance liquid chromatography with electrospray ionization mass spectrometry. Following i.v. administration, clearance was 7.97±5.16 mL/kg/min, and half-life (T(1/2)) was 3.58 h (harmonic mean). Volume of distribution was 3.01±1.69 L/kg. Following i.m. administration, maximum concentration (C(max)) was 1.74±0.09 ng/mL, which was significantly lower than the highest measured concentration (4.34±1.22 ng/mL) after i.v. administration (P<0.001). Time to C(max) was 0.9±0.69 h and T(1/2) was 4.24 h. Bioavailability was variable (51-88%). Several horses showed signs of excitement. Gut sounds were decreased 10±2.19 and 8.67±1.63 h in the i.v. and i.m. group, respectively. Buprenorphine has a moderate T(1/2) in the horse and was detected at concentrations expected to be therapeutic in other species after i.v. and i.m. administration of 0.005 mg/kg. Signs of excitement and gastrointestinal stasis may be noted.

Innovative Delivery Systems for Migraine

Migraine is a disabling, painful primary headache disorder that is associated with various combinations of neurological, gastrointestinal, autonomic and pain symptoms. Gastrointestinal disturbances associated with migraine, including nausea and vomiting, affect a majority of migraineurs and often result in a delay in taking or avoidance of pharmacological intervention. Gastric stasis and vomiting may lead to delayed or inconsistent absorption of orally administered medications. Many migraineurs awake early in the morning with their attack progressing and already associated with nausea and vomiting. As a result, there is a need for a novel, non-invasive, non-oral delivery system for fast and effective acute treatment of migraine. There are two non-oral delivery systems currently available in the US for the acute treatment of migraine: three nasal sprays and two injectable formulations. Although nasal sprays depend partially on nasal mucosal absorption, a significant amount of drug is swallowed, transits the stomach and is absorbed in the small intestine, which is not as rapid or effective a route of delivery for those migraineurs with gastric stasis. Sumatriptan is rapidly absorbed by subcutaneous injection with or without a needle, but the invasiveness and discomfort of the delivery, the high incidence of adverse events and the high recurrence rate all limit its use for many patients. Iontophoretic delivery of medication is a non-invasive transdermal approach that uses small amounts of electrical current to promote rapid movement of the ionized drug through the skin and into the systemic circulation. This delivery bypasses hepatic first-pass metabolism and also avoids gastric transit delay and slowing of small intestinal absorption associated with gastrointestinal stasis in migraineurs. Two pharmacokinetic studies have demonstrated that iontophoretic transdermal delivery of sumatriptan results in rapid and consistent achievement of therapeutic plasma concentrations. These studies also suggest that, by avoiding patient exposure to a rapid rise in and high plasma concentrations of sumatriptan as seen with injectable sumatriptan, transdermal delivery using iontophoresis may significantly reduce typical triptan-related adverse events. A large, randomized, double-blind, placebo-controlled, multicentre clinical trial showed statistically significant efficacy, good tolerability and virtually no triptan-related adverse events. Iontophoretic delivery of sumatriptan, with a novel transdermal patch device, offers patients a migraine-specific medication that is non-invasive and non-oral. Clinically, transdermal delivery provides rapid and effective relief of migraine while bypassing the gastrointestinal tract, with minimal classic triptan-related adverse effects. This unique approach facilitates the rapid absorption of this migraine-specific triptan, which should improve the chances of consistently achieving a therapeutic plasma concentration of sumatriptan, resulting in effective migraine relief.

TNF activates astrocytes and catecholaminergic neurons in the solitary nucleus: Implications for autonomic control

Tumor necrosis factor [TNF] produces a profound anorexia associated with gastrointestinal stasis. Our work suggests that the principal site of action of TNF to cause this change in gastric function is via vagal afferents within the nucleus of the solitary tract [NST]. Excitation of these afferents presumably causes gastric stasis by activating downstream NST neurons that, in turn, suppress gastric motility via action on neurons in the dorsal motor nucleus of the vagus that project to the stomach. Results from our parallel studies on gastric vago-vagal reflexes suggest that noradrenergic neurons in the NST are particularly important to the generation of reflex gastroinhibition. Convergence of these observations led us to hypothesize that TNF action in the NST may preferentially affect putative noradrenergic neurons. The current study confirms our observations of a dose-dependent TNF activation of cells [as indicated by cFOS production] in the NST. The phenotypic identity of these TNF-activated neurons in the NST was ∼ 29% tyrosine hydroxylase [TH]-positive [i.e., presumably noradrenergic neurons]. In contrast, less than 10% of the nitrergic neurons were activated after TNF exposure. Surprisingly, another 54% of the cFOS-activated cells in the NST were phenotypically identified to be astrocytes. Taken together with previous observations, the present results suggest that intense or prolonged vagal afferent activity [induced by visceral pathway activity, action of gut hormones or cytokines such as TNF] can alter local astrocyte immediate early gene expression that, in turn, can provoke long-term, perhaps permanent changes in the sensitivity of vagal-reflex circuitry.

Hyperammoniemia in rats with barbiturate coma

Sodium thiopental in the comatogenic (but not soporogenic) dose caused hyperammoniemia in rats. Blood ammonium level increased 3-fold within 3 h and 5-fold within 18 h. Blood urea level increased by one-third within 18 h against the background of unchanged creatinine level and hematocrit. Urinary excretion of ammonium did not decrease, while its release with exhaled air increased, indicating intensification of ammonium formation in the body. Barbiturate coma did not change the slope of curves of dose-dependent increase of ammonium or urea levels in the blood of rats injected with ammonium acetate, which attested to the absence of appreciable disorders in the ammonium detoxifying function of the liver. Ammonium hyperproduction could be caused by gastrointestinal stasis verified by X-ray examination and confirmed by correlation between blood urea level and stool retention in narcotized rats.

Fulminant hyperammonaemia induced by thiopental coma in rats

Fulminant hyperammonaemia as a threshold effect of coma-inducing dose of sodium thiopental has been revealed in rats. Blood ammonia content increased progressively after the introduction of 1.0 LD 50 (but not 0.8 LD 50) of sodium thiopental three times in 3 h and five times in 18 h. The urinary ammonia excretion was not impaired while the volatilization of ammoniac from the body of ST-treated rats was higher, giving evidence of the augmentation of ammonia production. Blood urea increased by one third despite of insignificant alterations of haematocrit and blood creatinine. Ammonia hyperproduction in the digestive tract could result from gastrointestinal stasis, which has been verified by roentgenography and confirmed by correlation of hyperammonaemia with the stool retardation. In thiopental coma rats the slope of a dose-dependent increase of the blood ammonia and the blood urea after the intraperitoneal injection of ammonium acetate did not exceed that in intact animals. So the ammonia hyperproduction in the digestive tract could be the main contributing cause of fulminant hyperammonaemia in rats with thiopental coma and thus be involved into pathogenesis of the coma.

TNF α -p55 receptors: medullary brainstem immunocytochemical localization in normal and vagus nerve-transected rats

Tumor necrosis factor alpha (TNF α) is a potent modulator of autonomic reflex mechanisms that control the stomach. Evidence suggests that TNF α action directly on vago-vagal reflex control circuits causes the autonomic misregulation of digestion manifested as gastrointestinal stasis, nausea, and emesis associated with illness. Neurophysiological studies indicated that TNF α may have effects on vagal afferents in the solitary nucleus, as well as neurons of the solitary nucleus (NST) and dorsal motor nucleus (DMN) of the vagus. The aim of this study was to determine the location of the TNFR1 receptor (p55) in the medulla using immunocytochemical methods. We devised a technique for localizing the p55 receptor using heat-induced antigen recovery in fixed tissue sections. This protocol allowed us to demonstrate that dense p55-immunoreactivity (p55-ir) is constitutively present on central (but not peripheral) vagal afferents in the solitary tract (ST) and nucleus; p55-ir is also present on afferents entering the spinal trigeminal nucleus. Unilateral supra-nodose vagotomy eliminated p55-ir from ipsilateral central vagal afferents. Virtually all neurons in the brainstem appeared to express p55-ir at a low level, i.e., just above background. However, vagotomy caused a dramatic up-regulation of p55-ir in vagal motor neurons. This increase in p55-ir in axotomized neurons may play a pivotal role in the connection between the occurrence of the injury and the initiation of apoptotic processes resulting in elimination of damaged neurons.

Effect of L-NAME on decreased ileal muscle contractility induced by peritonitis in rats

Background/Purpose: It is now well established that intestinal inflammation is associated with disturbed contractility. The aim of this study was to determine the effects of peritonitis on longitudinal ileum smooth muscle responses to KCl, carbachol and substance P (SP) and to examine the role of nitric oxide (NO) and Nomega-nitro-L-arginine methylester (L-NAME) on ileal contractility in this peritonitis model. Methods: Peritonitis was induced by cecal ligation and puncture (CLP) in 20 rats. While 10 of these received 1 mL distilled water as placebo, the other 10 received 5 mg/kg (subcutaneously) L-NAME before the operation. Another group of 10 rats underwent a sham operation. Twenty-four hours after the operation, the rats were killed, and their ileum was excised. Ileum segments were placed in longitudinal direction in a 10-mL organ bath; concentration-response relationship for KCl, carbachol, and SP were obtained by adding the reagent cumulatively to the bath. Results: The KCl-, carbachol-, and SP-induced contractions were decreased markedly, with no change in the pD2 values in the peritonitis group compared with controls. Peritonitis-induced changes in the contractile responses were restored significantly by in vivo L-NAME pretreatment. Conclusions: The model of CLP-induced peritonitis in rats showed that KCl-induced nonreceptor-mediated, carbachol- and SP-induced receptor-mediated contractions are significantly decreased by inflammation in the longitudinal ileum muscle. Increased synthesis of NO may be responsible for these decreases in contractile responses because they were restored significantly by in vivo L-NAME injection. Inhibition of NOS with L-NAME injection may afford a new therapeutic approach to the treatment of gastrointestinal stasis in septic patients. J Pediatr Surg 37:901-905. Copyright 2002, Elsevier Science (USA). All rights reserved.

Primary Bile Reflux Gastritis: Which Treatment is Better, Roux-en-Y or Biliary Diversion?

Primary bile reflux gastritis is an unusual and elusive problem. Postgastrectomy bile reflux has been long recognized and treated variously with Roux-en-Y gastrojejunostomy, Braun enteroenterostomy, and Henley jejunal interposition. All of these procedures have been fraught with postoperative side effects, the worst of which is stasis. A new procedure utilizing biliary diversion has been proposed to divert bile from the gastric lumen without vagotomy or gastric resection. This procedure was used for 16 patients with diagnosed bile reflux, and results were compared with those of a previous group of 21 patients who had been treated with Roux-en-Y gastrojejunostomy. The patient groups were similar in age, sex, weight, symptoms, and results of investigative studies. The earlier group all had vagotomy, antrectomy, and gastrojejunal anastomosis to a 45-cm Roux limb. The later group all had an end-to-side choledochojejunostomy to a 45-cm Roux limb, taken 45 cm from the ligament of Treitz. The patients in the bile diversion group had fewer complications and shorter hospital stays. In addition, they had few postoperative complaints, no further operations for either bile reflux or upper gastrointestinal stasis, and no long-term deaths due to gastrointestinal problems or malnutrition. Their eventual postoperative gastric emptying improved significantly when compared with the Roux-en-Y patients, suggesting that the dysmotility observed preoperatively may well have been a result of the bile injury to the stomach, rather than an underlying gastric dysmotility.

Acute severe pancreatitis and multiple organ failure: total parenteral nutrition is still required in a proportion of patients

AIMS: Enteral nutrition (EN) is increasingly advocated as the favoured means of nutritional support in patients with multiple organ failure resulting from acute severe pancreatitis. In a proportion of patients, however, EN may not be feasible either because of gastrointestinal stasis and high nasogastric aspirates or because of superseding complications of pancreatitis such as fistulation. In these cases total parenteral nutrition (TPN) is indicated. METHODS: Patients with acute severe pancreatitis admitted to the intensive care unit (ICU) were commenced on either nasogastric or, where established, jejunostomy EN. Rates of EN were controlled by protocol and volumes of nasogastric aspirate. TPN was commenced when volumes of EN were persistently inadequate or when this route was contraindicated (e.g. high-volume small bowel fistula). Physiological and outcome data were collected prospectively and included severity of illness scoring (Acute Physiology and Chronic Health Evaluation (APACHE) II), length of stay, duration of EN and TPN, and hospital outcome. RESULTS: Of 69 patients with acute severe pancreatitis, 31 were transferred from other ICUs. The median APACHE II score was 18 (range 4-40) and the overall hospital mortality rate was 39 per cent. Seventeen patients (25 per cent) were managed with EN alone, ten (14 per cent) with TPN alone and 19 (28 per cent) with a combination of both. Twenty-three (33 per cent) did not have any nutritional support during their ICU stay. The mortality rate was worse among patients who received TPN only than in those who had EN (60 versus 24 per cent). CONCLUSIONS: EN is likely to remain the route of choice for nutritional support in the ICU. However, in high-risk patients with acute severe pancreatitis EN may not be feasible and TPN is often required. This may reflect a greater severity of illness.

Effect of Cisapride, Erythromycin, and Metoclopramide on Gastrointestinal Transit Time in the Desert Tortoise, Gopherus agassizii

ABSTRACT The desert tortoise, Gopherus agassizii, is a common pet in the southwestern United States and like other tortoise and reptile species, can suffer from gastrointestinal stasis in captivity. We gavaged captive desert tortoises daily with erythromycin (2 mg/kg), metoclopramide (1 mg/kg) or cisapride (1 mg/kg) and compared gastrointestinal transit times to those of control tortoises. Gastrointestinal transit times were determined by feeding 30 plastic markers to the tortoises, and recording the time until 85% of the markers were recovered from the stool of each animal. When compared to controls, none of the motility agents significantly affected the total gastrointestinal transit time.

Roles of IL-1 and TNF in the decreased ileal muscle contractility induced by lipopolysaccharide.

Gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. Endotoxin [lipopolysaccharide (LPS)] impairs smooth muscle contraction, in part through inducible nitric oxide synthase (NOS II) and enhanced nitric oxide production. We studied the roles of tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1) in this process by using TNF binding protein (TNFbp) and IL-1 receptor antagonist (IL-1ra). Rats were treated with TNFbp and IL-1ra, or their vehicles, 1 h before receiving LPS or saline. At 5 h after LPS, contractility was measured in strips of ileal longitudinal smooth muscle, and NOS II activity was measured in full-thickness segments of ileum. LPS decreased maximum stress (mean +/- SE) from 508 +/- 55 (control) to 355 +/- 33 g/cm2 (P < 0.05). Pretreatment with TNFbp plus IL-1ra prevented the LPS-induced decrease. Separate studies of TNFbp alone or IL-1ra alone indicated that, at the doses and timing used, TNFbp was more effective. LPS also increased NOS II activity by >10-fold (P < 0.01) over control. This increase was prevented by TNFbp plus IL-1ra (P = not significant vs. control). We conclude that the LPS-induced increase in NOS II activity and the decrease in ileal muscle contractility are mediated by TNF and IL-1.

Case 12-1990

Case Records of the Massachusetts General Hospital from The New England Journal of Medicine — Case 12-1990 — A 21-Year-Old Man with Progressive Gastrointestinal Stasis, Hepatomegaly, and a Neurologic Disorder

Biliary appendico-duodenostomy: A nonrefluxing conduit for biliary reconstruction

Biliary conduits constructed during operations for choledochal cysts or biliary atresia are frequently complicated by reflux of gastrointestinal contents, stasis, and obstruction with resulting cholangitis. We have used the appendix as a biliary conduit for cases of biliary atresia and choledochal cyst, adapting the urologic technique of a tunneled, nonrefluxing anastomosis for reconstruction of the biliary tree--biliary appendico-duodenostomy (BAD). From our preliminary experience with this technique, it appears promising.

Roux-Y stasis syndrome after gastrectomy

The aim of the present study was to determine which factors lead to upper gastrointestinal stasis after Roux-Y reconstruction. Among the 214 patients with Roux-Y reconstructions performed between 1961 and 1983, follow-up data were obtained for 187 (87 percent) after a mean of 6.2 years. Patients with vomiting of food but not bile, postprandial pain, and nausea were considered to have the Roux-Y stasis syndrome. The syndrome was found in 49 patients with gastrojejunostomy (30 percent of those at risk) but in only 2 patients with esophagojejunostomy (8 percent, p less than 0.05). The condition was more common in women than men (p less than 0.05), but it was equally common in patients with and without vagotomy. The mean length of the Roux-Y limb in patients with stasis was 41 cm, which was longer than the 36 cm in patients without stasis (p less than 0.001). When multiple logistic regression was used, the length of the Roux-Y limb emerged as the major risk factor (p less than 0.01). In conclusion, construction of Roux-Y limbs greater than about 40 cm in length may increase the incidence of the Roux-Y stasis syndrome.

653 A RABBIT MODEL FOR THE PATHOPHYSIOLOGY OF TOTAL PARENTERAL NUTRITION-ASSOCIATED CHOLESTASIS

Gastrointestinal stasis, bacterial overgrowth and accumulation of toxic bile acids may be etiologically related to total parenteral nutrition (TPN)-associated cholestasis. New Zealand White rabbits were studied to investigate interrelations between these factors. TPN-infused animals received 150 kcal and 5 gm protein/kg/d. Pair-fed animals were fed rabbit chow to supply 5 gm protein/kg/d (PF). Free-fed animals ate >5 gm protein/kg/d (FF). Gastrointestinal transit time, as assessed by a solid marker technique, was <48h in 95% of fed animals and >72 h in 100% of TPN animals. Colons of TPN animals contained bilious liquid rather than semi-solid feces. There was no bacterial overgrowth in duodenal contents in any animal; gall bladder bile was sterile. Although the Mole. % total primary bile acids (BA) and total secondary BA were equivalent in gall bladder bile in the 3 groups, the Mole % glycolithocholic acid (GLCA) was significantly increased (p<.001) in TPN animals (4.28 Mol%) compared to PF (1.68 Mol%) and FF (1.35 Mol%). Serum total primary BA and gamma glutamyl transpeptidase concentrations were higher in TPN animals (p<.02). In this rabbit model TPN led to decreased gastrointestinal motility, increased relative biliary concentration of the toxic monohydroxy bils acid GLCA and increased serum markers of cholestasis. This animal model, which exhibits changes consistent with human TPN-associated cholestasis, should facilitate experimental studies of the etiology of this syndrome.

ANAESTHETIC MORBIDITY FOLLOWING CAESAREAN SECTION UNDER EPIDURAL OR GENERAL ANAESTHESIA

To find out whether morbidity in the first postoperative week is affected by type of anaesthetic technique, healthy patients who had caesarean sections under epidural anaesthesia were compared with those who were given a general anaesthetic. Epidural anaesthesia was associated with less pain (p<0·00001) and discomfort in the immediate postoperative period. By the second day fewer epidural patients had gastrointestinal stasis, pyrexia (p<0·05), and coughing (p<0·00001). Breastfeeding and mobilisation started earlier. Fewer mothers were coughing (p<0·005), had fever (p<0·01), or felt tired and depressed (p<0·005) by the sixth postoperative day after epidural caesarean section. The epidemiology of anaesthetic morbidity needs to be assessed in other surgical patients.

Evidence for cholinergic and vagal noncholinergic mechanisms modulating plasma motilin-like immunoreactivity.

Basal concentrations of plasma motilin-like immunoreactivity (MLI) and responses to insulin-induced hypoglycemia were measured in healthy subjects (n = 13) in diabetics with clinical evidence of autonomic neuropathy (AN; n = 7), in diabetics without AN (n = 9), and in five recently (6--12 months) vagotomized subjects. Mean basal MLI concentrations were similar in the healthy subjects (141 +/- 21.5 pg/ml) and diabetics without AN (124 +/- 22.4 pg/ml), but were significantly higher in diabetics with AN (349 +/- 71.5 pg/ml) and in vagotomized subjects (381 +/- 47.6 pg/ml). In both healthy subjects and diabetics without AN, the acute administration of insulin (0.1--0.2 U/kg) caused a fall in the mean MLI concentration, reaching a nadir within 20 min, returning to the basal concentration by 60 min, and rising above basal levels by 90 min. In diabetics with AN and vagotomized subjects, the fall in MLI persisted for 90 min. Intravenous atropine administered 15 min after the insulin injection in healthy subjects did not impair the return to basal. The responses were not related to the degree of hypoglycemia, the absolute or relative fall in blood glucose concentrations, or differences in blood glucose among healthy subjects, diabetics, or vagotomized subjects. It appears, therefore, that insulin lowers plasma MLI levels, which are restored to basal by a vagal noncholinergic mechanism. Furthermore, the vagus exerts a suppressive effect on basal MLI levels, and vagotomy and diabetic autovagotomy are associated with abnormal elevation of MLI levels. Since motilin is thought to be important in interdigestive intestinal motility, abnormalities in MLI secretion in diabetics with autonomic neuropathy may contribute to gastrointestinal stasis and erratic diabetic control.

Migraine and Drug Absorption

The majority of migraine attacks are associated with gastrointestinal symptoms which add considerably to the distress and inconvenience caused by the headache. When salicylate absorption from effervescent aspirin tablets was studied during migraine, the rate of absorption was found to be reduced relative to that found in non-migrainous volunteers and in the same patients when headache-free. There is evidence that this reduced rate of absorption is caused by gastrointestinal stasis and reduced rate of gastric emptying. Patients in whom aspirin absorption was delayed were more likely to take longer to respond and to require additional treatment. Metoclopramide, which increases gastric emptying rate, has been shown to improve the rate of absorption of aspirin during migraine and also increase the rate of recovery from the attack and avoid the need for additional treatment; effects which were not shown by thiethylperazine. It is likely that delayed absorption during migraine affects some drugs other than aspirin, such as ergotamine, and it is therefore recommended that the most rapidly absorbable formulation should be used. If such treatment is ineffective, metoclopramide may be a useful addition and should be tried before resorting to other routes of administration.

Radiologic and clinical signs of gastrointestinal stasis induced by bovine milk ingestion in allergic patients

Radiologic and clinical signs of gastrointestinal stasis induced by bovine milk ingestion in allergic patients

Some Observations on Vitamin C Deficiency in Acute Mental Disorder

It is well known that gross impairment of nutrition is a not infrequent finding in the newly-admitted psychotic patient. Some of these cases present a state of mental confusion which is directly attributable to a condition of semi-starvation brought about by personal neglect and refusal of food. Obvious clinical signs of malnutrition are present, such as anorexia, emaciation, coated tongue, constipation, and ketonuria. Rapid mental improvement frequently occurs as a result of a liberal diet and relief of gastro-intestinal stasis. But it is equally important to recognize the mild and less obvious forms of malnutrition.