Prevention of pneumonia in elderly stroke patients by systematic diagnosis and treatment of dysphagia: an evidence-based comprehensive analysis of the literature.

We conducted a systematic literature review and analysis of programs for evaluating swallowing in order to prevent aspiration pneumonia. This article derives from an evidence report on diagnosis and treatment of swallowing disorders (dysphagia) in acute-car stroke patients prepared by us as an Evidence-based Practice Center (EPC) under contract to the U.S. Agency for Healthcare Research and Quality (AHRQ). Available evidence on the diagnosis and treatment of dysphagia for preventing pneumonia is limited. We found reported pneumonia rates in one historical controlled study of a program using bedside exams (BSE) for acute stroke patients; one uncontrolled case series study of acute stroke patient-reporting of swallowing difficulty; one controlled case series study of videofluoroscopic study of swallowing (VFSS) for acute stroke patients; and one historical controlled study of fiberoptic endoscopic examination of swallowing (FEES) for patients referred for swallowing evaluation in rehabilitation centers. Comparing these results with historical controls indicates that implementation of dysphagia programs is accompanied by substantial reductions in pneumonia rates. While all these methods appeared effective, the small sizes of available studies did not allow determination of the relative efficacy of BSE, VFSS, or FEES.

Bariatric surgery for morbid obesity.

BACKGROUND: Bariatric surgery is a treatment for severely obese patients. We examined the efficacy of bariatric surgery, addressing three questions: 1) What is the overall weight reduction following bariatric surgery? 2) What complications are associated with bariatric surgery? 3) What impact does weight loss have on obesity-related comorbidity? METHODS: Fixed and random effects meta-analyses were used to determine the amount of weight reduction following bariatric surgery. The influence of a variety of co-variates that could affect study results was examined. Information from evidence-based sources was used to explore the impact of weight loss on comorbidities. RESULTS: Meta-analyses results were affected by loss to follow-up, and within-study heterogeneity of variance. Therefore, results were pooled from studies with complete patient follow-up. Meta-analysis of six studies reporting weight loss at 1 year and four studies with mean follow-up of 9 months to 7 years demonstrated BMI reductions of 16.4 kg/m(2) and 13.3 kg/m(2), respectively. Weight reduction following bariatric surgery may be associated with improvements in risk factors for cardiac disease including hypertension, type 2 diabetes and lipid abnormalities, and may decrease the severity of obstructive sleep apnea. CONCLUSION: Bariatric surgery is appropriate for obese patients (BMI >40 kg/m(2) or > or =35 kg/m(2) with obesity-related comorbidity) in whom non-surgical treatment options were unsuccessful. Additional research is needed to examine the long-term benefits of weight loss following bariatric surgery, particularly with respect to obesity-related comorbidities.

Bile and pancreatic juice replacement ameliorates early ligation-induced acute pancreatitis in rats.

BACKGROUND: In healthy rats, combined bile and pancreatic juice diversion from gut has a synergistic rather than additive effect on stimulation of exocrine pancreatic protein secretion. We hypothesized that exclusion of combined bile and pancreatic juice from gut exacerbates bile and pancreatic-duct ligation-induced acute pancreatitis in rats to a greater extent than exclusion of either bile or pancreatic juice alone. METHODS: Bile and pancreatic juice (obtained fresh from donor rats) were replaced, separately or together, via a duodenal fistula beginning immediately before 6 hours of duct ligation. Pancreatic morphologic changes were evaluated with an acute pancreatitis histology score and morphometric quantitation of acinar-cell necrosis. Plasma amylase and cholecystokinin concentrations and pancreatic subcellular distribution of cathepsin B activity were determined. Characteristics of bile and pancreatic juice obtained from donor rats were also studied. RESULTS: Combined bile and pancreatic juice replacement limited the increase in acute pancreatitis histology score by 77%, acinar cell necrosis by 95%, hyperamylasemia by 77%, and hypercholecystokininemia by 99%, while preventing subcellular redistribution of cathepsin B. Amelioration of pancreatic morphologic changes was significantly greater with combined bile and pancreatic juice replacement than with replacement of either bile or pancreatic juice alone. CONCLUSION: In this experimental corollary of early gallstone-induced acute pancreatitis, combined bile and pancreatic juice exclusion from gut contributes to disease pathogenesis to a greater extent than exclusion of either bile or pancreatic juice alone.

Intestinal lipid inhibits gastric emptying via CCK and a vagal capsaicin-sensitive afferent pathway in rats.

The mechanism by which lipid in the duodenum inhibits gastric emptying was investigated in awake rats fitted with chronic gastric and duodenal cannulas. Perfusion of the duodenum with lipid (Intralipid, 5 and 10%; total amount 50 and 100 mg) caused a significant inhibition (26 and 78%, respectively) of gastric emptying of a nonnutrient liquid (0.9% saline). Functional ablation of the capsaicin-sensitive vagal, but not the spinal, sensory innervation to the upper gastrointestinal tract significantly attenuated by 57% lipid-induced inhibition of gastric emptying. In intact rats, administration of a specific cholecystokinin (CCK)-A receptor antagonist, devazepide, significantly attenuated by 66% the response to lipid. Administration of devazepide in perivagal capsaicin-treated rats did not further reduce the response to lipid. These results suggest that lipid in the duodenum inhibits gastric emptying via a mechanism involving an action of CCK at type A receptors and capsaicin-sensitive vagal afferents.

Octreotide and cholecystokinin antagonist reduce edema in obstruction-induced acute pancreatitis.

Obstruction-induced acute pancreatitis in rats is associated with increased plasma cholecystokinin (CCK) levels. Duodenal replacement of bile reduces severity of pancreatitis and limits CCK increase. We investigated the role of CCK in the pathogenesis of obstruction-induced acute pancreatitis by pretreating rats with the somatostatin analog octreotide and the CCK antagonist L-364,718. Octreotide inhibits duodenal CCK release, and L-364,718 competitively blocks CCK receptors. We studied 31 rats after (1) sham operation (n = 7), (2) bile and pancreatic duct obstruction (BPDO) (n = 12), (3) BPDO plus octreotide (20 micrograms/kg IP and then 5 micrograms/kg/hr IV) (n = 6), and (4) BPDO plus L-364,718 (1 mg/kg IP and then 0.25 mg/kg/hr IV) (n = 6). Rats were killed after 18 hours. Pancreas weight, acute pancreatitis histology score, and plasma amylase and CCK levels were determined. Octreotide and L-364,718 limited the increase in pancreas weight. Octreotide also limited the rise in plasma CCK levels. These findings suggest that CCK may play a role in the pathogenesis of obstruction-induced acute pancreatitis.

Increased circulating cholecystokinin in obstruction-induced acute pancreatitis. II. Pancreatic duct obstruction with and without bile duct obstruction.

Pancreatic exocrine stimulation by cholecystokinin (CCK) has been implicated in the pathogenesis of experimental acute pancreatitis. Bile exclusion from the gut stimulates duodenal CCK release and exacerbates obstruction-induced acute pancreatitis. Pancreatic and bile duct obstruction increases circulating CCK concentration. We hypothesized that acute pancreatitis induced by pancreatic and bile duct obstruction would be ameliorated when bile was returned to the duodenum. As many small pancreatic ducts drain into the bile duct in rats, preservation of bile flow required the use of a bile shunt. We studied acute pancreatitis and the time course of circulating CCK increase in three groups of rats after: (1) sham operation (dissection, no obstruction), (2) bile and pancreatic duct obstruction, and (3) bile and pancreatic duct obstruction with bile shunt. The rats were killed at 3-, 6-, and 18-hr intervals after operation. Their blood was collected for measurement of CCK, amylase, and bilirubin concentrations. The pancreata were excised, weighed, and processed for histological examination. The shunting of bile back to the duodenum ameliorated the acute pancreatitis along with a simultaneous limitation of the rise in CCK concentration. This suggests that bile duct obstruction, another form of bile exclusion, exacerbates pancreatic duct obstruction-induced acute pancreatitis. The elevation in CCK concentration showed an early peak indicating that the potential role of CCK in the pathogenesis of obstruction-induced acute pancreatitis is predominantly in the early phase of its development.

Increased circulating cholecystokinin in obstruction-induced acute pancreatitis. I. Bile duct obstruction with and without pancreatic duct obstruction.

Bile exclusion from the gut exacerbates pancreatic duct obstruction-induced acute pancreatitis. We hypothesized that obstruction-induced acute pancreatitis involves an increase in circulating cholecystokinin (CCK), as bile and pancreatic juice exclusion from the gut stimulates duodenal CCK release. We studied 54 rats after the following operations: (1) sham operation (n = 18), (2) hepatic bile duct obstruction alone (n = 18), (3) hepatic bile duct and common bile-pancreatic duct obstruction (n = 18). Rats recovered and were killed in subgroups of six rats each at 3, 6, and 18 hr after operation; blood was collected for measurement of plasma CCK and amylase concentrations. Each pancreas was excised, weighed, and processed for histological examination; an acute pancreatitis score was determined. Combined bile and pancreatic duct obstruction induced acute pancreatitis and was associated with a marked increase of circulating CCK concentration. Bile duct obstruction alone did not induce acute pancreatitis but was associated with an increase of circulating CCK of lower magnitude. The time course of circulating CCK increase showed an early peak. These findings support our hypothesis and suggest that CCK plays a role in the pathogenesis of obstruction-induced acute pancreatitis.

Distribution of cholecystokinin forms in intestinal secretory granule subtypes.

Peptides and proteins destined to be released in response to stimuli are found in the regulated secretory pathway. Substances in this pathway are packaged into secretory granules, wherein they are often rendered osmotically inactive by complexing to an oppositely charged molecule. The complexing mechanism employed by members of the cholecystokinin (CCK) peptide family is unknown, but the heterogenous charges of CCK peptides makes it possible that different CCK peptides have different abilities to form intragranular complexes. If the number of osmotically active intragranular CCK peptides varies, corresponding variations in secretory granule density should result, and when intestinal CCK secretory granules were purified on isotonic density gradients, four granule peaks were observed. Granules containing greater proportions of short CCK forms tended to have the lowest buoyant densities, suggesting that they contain a greater number of osmotically active molecules than granules of lower density and that short or all intragranular CCK forms are osmotically active. CCK secretory granules also contained novel CCK forms; in addition to previously characterized forms, granules contained a CCK form that appears to be CCK-6 and a form that could arise from cleavage of CCK-58 at position 4, 10, or 12. Because intragranular enzymes are responsible for peptide posttranslational processing, the intragranular CCK forms observed in the present study are likely to be authentic CCK-processing products. Finally, CCK sorting in intestine apparently differs from that in a rat medullary thyroid carcinoma cell line, in which CCK-22 and CCK-33 are not found in the regulated secretory pathway.

Negative control by Sandostatin on pancreatic and duodenal growth: a possible implication of insulin-like growth factor I.

This study was undertaken to evaluate the effects of Sandostatin, a potent somatostatin analogue, on pancreatic and intestinal growth and plasma and pancreatic levels of insulin-like growth factor I, a known growth factor. Rats weighing 320-330 g, equipped with an intravenous cannula were infused with either bovine serum albumin or Sandostatin at a dose of 5 micrograms kg-1 h-1 for 7 days. Sandostatin caused significant reductions in pancreatic and intestinal weights accompanied by decreases in total DNA, RNA in both organs and total protein in the intestine while total pancreatic enzymes were increased. Plasma cholecystokinin and insulin-like growth factor I were reduced whereas total insulin-like growth factor I pancreatic content was increased. It is suggested that Sandostatin may reduce growth of these two organs by decreasing cholecystokinin and insulin-like growth factor release and their specific effects at the pancreatic and duodenal cellular level.

Low immunoreactivity of canine cholecystokinin-58.

The immunoreactivity of intact and trypsinized canine cholecystokinin-58 was examined using five C-terminally directed cholecystokinin antisera. Cholecystokinin-58 was nearly as immunoreactive as sulfated, amidated cholecystokinin-8 with one cholecystokinin-specific antiserum and an antiserum with moderate (18%) gastrin cross-reactivity, but two to four times less immunoreactive than the octapeptide with two other cholecystokinin-specific antisera and an antiserum with full cross-reactivity with cholecystokinin and gastrin. The cross-reactivity of cholecystokinin-58 with all antisera was increased by trypsinization, and the magnitude of the increase was related to the degree of trypsinization. These results suggest that it is not possible to measure absolute cholecystokinin levels in tissue and blood with antisera reported to date and that cholecystokinin-58 has a tertiary structure that influences its binding to cholecystokinin antibodies.

Molecular forms of cholecystokinin in rat intestine.

The predominant immunoreactive cholecystokinin (CCK) forms in acid extracts of rat intestine eluted from reverse-phase high-performance liquid chromatography columns in the positions of CCK-8, CCK-33/39, and CCK-58. Control experiments indicated that smaller CCK forms did not arise from artifactual degradation of large CCK forms. Less than 10% of CCK-8 added to and extracted from intestine was recovered in acid; CCK-8 could not be recovered by subsequent alkaline extraction, but subsequent urea extraction yielded approximately 25% of the added peptide. This suggests that CCK binds to proteins during acid extraction and that the preponderance of large CCK forms in acid extracts is not due to inhibition of CCK degradation but results from poor extraction of small CCK forms. No evidence for a CCK-22-like peptide was found in acid or subsequent urea extracts of rat intestine, suggesting CCK posttranslational processing in adult rats is like that in humans and dogs.

A cholecystokinin-metabolizing enzyme in rat intestine.

Acid extracts of rat intestine contain a material which metabolizes cholecystokinin-33 (CCK-33) to CCK-12. Soybean trypsin inhibitor had little effect on CCK metabolism by the intestinal material. The molecular weight of the CCK-metabolizing activity, estimated by gel filtration, was 34,000. These data suggest rat intestine contains a nontrypsin CCK-metabolizing enzyme. Results from gel filtration also suggest that large CCK forms can be artifactually degraded to smaller ones during chromatography.

Role of cholecystokinin in intestinal phase and meal-induced pancreatic secretion.

Amylase secretion and plasma cholecystokinin (CCK) were measured in dogs in the interdigestive state and after exogenous CCK-8 and CCK-39 (12.5 to 400 pmol.kg-1.h-1), intestinal sodium oleate, tryptophan plus phenylalanine, HCl (0.74, 2.2, 6.7, 20 mmol/h), and a meat meal (20 g/kg). Interdigestive plasma CCK did not vary, although amylase output showed periodic 15-fold increases. Plasma CCK increased linearly after doubling doses of CCK-8 and CCK-39; the slope of plasma CCK-39 vs. dose was 2.8 times steeper than that of CCK-8, suggesting a longer circulating half-life. At similar plasma concentrations, CCK-8 and CCK-39 were equipotent for stimulating pancreatic secretion. Sodium oleate and tryptophan plus phenylalanine significantly increased plasma CCK and amylase secretion in a load-dependent pattern and were equipotent for both effects. HCl stimulated bicarbonate secretion but not plasma CCK or amylase secretion. Food significantly increased plasma CCK and amylase secretion. Amylase responses to intestinal stimulants and food were significantly greater than to exogenous CCK at low plasma CCK levels. Maximal amylase responses to intestinal stimulants were similar to that after CCK-39 but occurred at 10-fold lower plasma CCK levels. These results indicate that CCK and other factors interact to regulate pancreatic responses to food and intestinal stimulants in dogs.

Chemical characterization of rat cholecystokinin-58.

Cholecystokinin-58 (CCK-58) was purified from rat intestines using an extraction method that yields large amounts of this peptide. Greater than 30% of total CCK immunoreactivity eluted before CCK-39 upon gel permeation chromatography (Sephadex G-50) if extracts were loaded onto Sep Pak cartridges before freezing. If the extracts were frozen and stored at -70 degrees C for six weeks, only 20% of the material eluted in this region and total immunoreactivity was reduced by 50%, suggesting that proteases were active under these storage conditions. This early eluting peak was purified by reverse phase and ion-exchange HPLC to a single absorbance peak. Microsequence analysis of this peak detected AVLRPDSEP which is the amino terminus of rat CCK-58 predicted from the rat preprocholecystokinin cDNA. Because degradation of CCK-58 occurred in these extracts, it is possible that CCK-58 is the predominant molecule form in the rat small intestine.

Effects of ATP synthesis inhibitors, temperature, 8-bromo c-AMP, and calcium omission on release of corticotropin releasing factor from superfused rat hypothalami.

The release of immunoreactive corticotropin-releasing factor (I-CRF) was studied in vitro using a hypothalamic superfusion system. Omission of calcium, or inclusion of ATP synthesis inhibitors in the medium significantly reduced the rates of basal and K+-induced I-CRF release. Reducing the incubation temperature of the hypothalami to 4 degrees C caused a reversible inhibition of basal I-CRF release. I-CRF release was stimulated in a dose-dependent fashion by 8-bromo c-AMP. Those results suggest that the in vitro release of CRF is energy-dependent and may involve a calcium and c-AMP-mediated mechanism.

Central nervous system action of corticotropin-releasing factor to inhibit gastric emptying in rats.

The present study evaluates the central nervous system action of rat corticotropin-releasing factor (CRF) on gastric emptying of a liquid meal in conscious rats using the phenol red method. Intracisternal injection of CRF (63-210 pmol) dose-dependently inhibited gastric emptying of a liquid meal by 37-80%. Peptide action was rapid in onset, long acting, and not mimicked by intracisternal injection of growth hormone-releasing factor. Intracisternal CRF-induced inhibition of gastric emptying was reversed by subdiaphragmatic vagotomy but not by naloxone pretreatment or adrenalectomy. Intravenous injection of CRF (21-630 pmol) also dose-dependently inhibited gastric emptying. CRF antiserum blocked the effect of intravenous but not of intracisternal injection of CRF (63 pmol). These results demonstrated that CRF injected in a picomole amount into the cerebrospinal fluid acts within the brain to inhibit gastric emptying of a liquid meal through vagal-dependent pathways.

Development of cholecystokinin radioimmunoassay using synthetic CCK-10 as immunogen.

Using an antiserum generated against synthetic CCK-10, we have developed a radioimmunoassay specific for the carboxyl-terminus of cholecystokinin (CCK). Three rabbits were immunized with synthetic sulfated carboxy-terminal CCK decapeptide (CCK-10) conjugated to keyhole limpet hemocyanin. Using 125I-CCK-39 prepared by the Iodogen method as a tracer, we found that all immunized rabbits produced antibodies against the conjugate. Antiserum R016 had the highest titer (1:225,000 after four immunizations) and was studied most extensively. R016 recognizes all molecular forms of CCK, including unsulfated and oxidized forms, but has negligible cross-reactivity with gastrin and other peptides. Using CCK-8 as a standard, the assay has a minimum detection limit of 0.5 pM and an ED50 of 11.5 pM. Serial dilutions of water/acid extracts of canine intestine were parallel to serial dilutions of sulfated CCK-8, CCK-33 and CCK-39. The assay was used to measure CCK concentrations in canine plasma after C18 Sep-Pak extraction; the concentration of immunoreactive CCK increased from a basal value of 7.8 +/- 1.0 to 9.5 +/- 1.2 and 11.1 +/- 1.2 pM 30 and 60 min postprandially (P less than 0.05 by paired analysis). This sensitive and uniquely specific CCK radioimmunoassay should be useful in characterizing several aspects of CCK physiology and the method for generating CCK antisera should be of value to other investigators.