Poisoning is common and carries considerable morbidity and mortality. Two to three patients are admitted to the Emergency Unit at Groote Schuur Hospital every day with drug overdose. As absorption occurs in the small intestine the rates at which ingested poisons pass into and through the small bowel are important factors in determining the amount of poison potentially available for absorption. Although the effects of pharmacological doses of many drugs on gastric emptying and motility are known, information on the effects of higher doses is limited. I investigated patients who took overdoses of certain commonly used drugs to determine their effects on gastric emptying and motility and small intestinal transit. The study was divided into two parts. One hundred and four patients were studied in Part 1. These patients took overdoses of tricyclic antidepressants (n = 31), carbamazepine (n = 15), phenytoin (n = 12), paracetamol (n = 29) and opioid-paracetamol mixtures (n = 17). They received standard hospital management of which sorbitol was not a part. Part 2 consisted of sixty-one patients who had sorbitol added to their treatment. These patients had taken overdoses of the tricyclic antidepressants (n = 15), carbamazepine (n = 7), phenytoin (n = 8), paracetamol (n = 13) and opioid-paracetamol mixtures (n = 18). The effects of sorbitol on gastric emptying and small intestinal transit were evaluated. A third study-the paracetamol control test was done on 5 healthy volunteers. Each subject was studied twice; the first time after taking 1 G of paracetamol and the second time after no drug ingestion.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21450号 / 医博第4417号 / 新制||医||1032(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 木原 正博, 教授 福原 俊一, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This research examines the hypothesis that the satiety effect of cholecystokinin octapeptide (CCK-8) is mediated by changes in gastric emptying. A method for collection of gastric emptying data, the double sampling procedure, is developed and validated for use in the rat. The double sampling technique permits repeated measurements of liquid gastric volume and thus describes the time course of emptying within a single experimental session. Further, the method allows determination of the amount of gastric secretion, volume emptied into the intestines, and amount of gastric load remaining in the stomach. Experiments are presented which: i) demonstrate the utility of the technique; ii) validate its accuracy in determining gastric volume; iii) indicate the stability of measurements obtained with this procedure; and iv) provide a procedure for quantitative evaluation of data obtained with this technique. Using the double sampling procedure, the ability of CCK-8 to delay gastric emptying and to influence feeding are then compared under similar experimental conditions. The effect of CCK-8 on gastric emptying is assessed in 6 hr deprived rats receiving 10 ml intragastric test loads of either .15M saline or 15% sucrose. Intraperitoneal (ip) injections of CCK-8 in doses of 1.4-22.4 ug/kg produce a dose-dependent retardation of gastric emptying of both saline and nutrient. Lower doses of CCK-8, 0.01 and 0.1 ug/kg, have no effect on gastric emptying. The effect of CCK-8 on feeding is assessed in rats tested under the same experimental conditions used in the gastric emptying studies. Doses of CCK-8 capable of retarding gastric emptying also suppress eating in a dose-dependent manner. These findings provide necessary correlational support for the hypothesis that satiety produced by CCK-8 is mediated by inhibition of gastric emptying. However, a further quantitative analysis of the correspondence of the gastric emptying and feeding effects of CCK-8 suggest that retardation of emptying may not account for the entire satiety effect of the peptide. The next set of studies provide direct tests of whether changes in gastric emptying mediate CCK-induced satiety. If gastric emptying plays a significant role in the satiety produced by CCK-8 then: i) the effects of CCK-8 on emptying and feeding should share similar kinetics, and ii) peptides that inhibit emptying should also inhibit feeding. I show that CCK-8 (5.6 ug/kg) injected coincident with introduction of an intragastric load or presentation of a test meal produces a rapid inhibition of both emptying and feeding. In contrast, the identical dose of CCK-8 administered 15 min before testing causes no inhibition of emptying, even though the peptide retains its ability to produce satiety. I also test the abilities of the peptides pentagastrin (100 ug/kg), bombesin (8 & 16 ug/kg) and secretin (2.86, 14.3 & 28.6 ug/kg) to reduce food intake and inhibit gastric emptying. Pentagastrin does not affect food intake or gastric emptying. Bombesin causes a small transient delay in emptying but a large and sustained suppression of eating. High dose secretin (14.3 ug/kg) causes no significant reduction of food intake, even though this dose of secretin inhibits emptying to the same degree as 1.4 ug/kg CCK-8, which does reduce intake. Thus, although CCK-8 does influence the rate of gastric emptying, the present results indicate that the inhibition of emptying by CCK is neither necessary nor sufficient to explain its satiety effect. / Thesis / Doctor of Philosophy (PhD)

The consequences of ingesting different carbohydrate solutions on fluid movement and availability have not been systematically examined. In addition, the role of carbohydrate in the post-exercise rehydration period has received little attention despite the need for substrate replenishment following exercise and the role of carbohydrates in stimulating water absorption in the intestine. The aims of this thesis were to assess fluid absorption characteristics and availability of solutions containing increasing concentrations of glucose and to evaluate their role in the restoration and maintenance of fluid balance following a period of exercise-induced dehydration. The ingestion of a single bolus of a commercially available hypertonic 18% carbohydrate solution (chapter 3) and a hypertonic 10% glucose solution (chapter 4) resulted in reductions in plasma volume that are most likely due to acute net secretion of water into the intestinal lumen. When investigating recovery of whole body hydration status after sweat loss, a hypertonic 10% glucose-electrolyte solution maintained whole body fluid balance for a longer period than a hypotonic 2% glucose-electrolyte solution and an electrolyte only solution when a fixed volume of fluid was consumed during a rehydration period of one hour following cycle exercise in the heat (chapter 5). When fluid was consumed ad libitum over a two hour period following similar cycle exercise in the heat, a hypertonic 10% glucose-electrolyte solution was as effective in restoring and maintaining fluid balance as a 2% hypotonic glucose-electrolyte solution and an electrolyte only solution (chapter 6). The reduced rate of gastric emptying that accompanies the ingestion of high carbohydrate solutions was likely to be the primary cause for the difference in urine production reported between thetrials during this study (chapter 7). In conclusion, ingestion of hypertonic carbohydrate solutions results in a reduction in extracellular fluid volume that is most likely due to secretion of water into the intestinal lumen and the carbohydrate content of an ingested solution is of importance in the post-exercise rehydration period.

No description available.

CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / A hemorragia subaracnÃidea (HSA) pode advir de diversos agravos ao sistema nervoso central. A HSA pode aumentar a pressÃo intracraniana (PIC) a patamares de grande morbidade. AlÃm de sintomas neurolÃgicos e cardiovasculares, bem descritos na literatura; sintomas gastrintestinais como nÃuseas, vÃmitos e gastrenterites sÃo comuns, mas pouco estudados. O retardo do esvaziamento gÃstrico (EG) à uma das alteraÃÃes fisiolÃgicas encontrada em pacientes com hipertensÃo intracraniana (HIC). Tal distÃrbio reduz as respostas terapÃuticas tendo em vista a reduÃÃo na absorÃÃo dos nutrientes e fÃrmacos, alÃm de levar à aspiraÃÃo pulmonar, que pode levar a Ãbito. Avaliamos o efeito da HSA sobre as alteraÃÃes da motilidade gastrintestinal (Esvaziamento GÃstrico - EG; TrÃnsito Intestinal â TI e ComplacÃncia GÃstrica â CG), dos parÃmetros hemodinÃmicos (PressÃo Arterial MÃdia â PAM, FreqÃÃncia CardÃaca - FC) e sobre a PIC. Bem como os mecanismos neuro-humorais relacionados a essas alteraÃÃes. Utilizamos ratos Wistar (300-350g, N=113), sob auspÃcios do COBEA (CEUA/UFC- Protocolo 41/13). ApÃs anestesia (Ketamina/Xilasina 20-10mg/Kg-IP), os animais foram contidos por estereotÃxico sendo injetados 0,1; 0,2 ou 0,3ml na cisterna magna (sangue autÃlogo â grupo HSA ou Liquor sÃmile â grupo Sham). No momento da induÃÃo da HSA os animais foram submetidos à canulaÃÃo dos ventrÃculos laterais para monitoraÃÃo da PIC e dos vasos femorais Direito a fim de se obter dados hemodinÃmicos. ApÃs 72h da induÃÃo, e sob jejum (24h) com soluÃÃo de reidrataÃÃo oral ad libitum, procedemos aos estudos de EG, TI e CG. Para determinaÃÃo da taxa de EG, uma refeiÃÃo teste (1ml/100g) (vermelho-fenol 0,5mg/ml em glicose-5%) foi administrada via gavagem. Jà o TI foi determinado com administraÃÃo direta da refeiÃÃo no duodeno por meio de cÃnula previamente implantada. Jà a CG foi avaliada utilizando um sistema de barostato a 4, 8 e 12 cm de pressÃo de distensÃo gÃstrica. A PA, FC e PIC foram aferidas no momento da avaliaÃÃo da motilidade gastrintestinal. Os dados, mÃdiaÂEPM, foram analisados pelo teste âtâ de Student (P<0,05). A HSA retardou o EG (38,90Â2,73 vs 47,00Â0,72%; 52,85Â5,14 vs 31,12Â2,0% ou 22,89Â4,46 vs 46,24Â3,56%) e aumentou a PIC (3,33Â0,47 vs 16,10Â0,47cmH2O; 7,68Â0,650 vs 30,86Â0,82cmH2O ou 17,50Â1,29 vs 37,90Â1,38cmH2O) nos diferentes volumes de sangue, seja 0,1; 0,2 ou 0,3ml respectivamente, quando comparados ao controle. A HSA tambÃm promoveu retarde no TI e diminuiÃÃo da CG, aumento da PA e diminuiÃÃo da FC. A vagotomia subdiafragmÃtica, a esplancnotomia e o prÃ-tratamento com guanetidina reverteram o efeito da HSA sobre as alteraÃÃes do EG. Os resultados sugerem que os agravos gastrintestinais advindos da HSA refletem um padrÃo de dismotilidade secundÃrios a HIC, mostrando uma forte correlaÃÃo com os valores de PIC / Subarachnoid hemorrhage (SAH) can arise from various types of damage to the central nervous system. The HSA can increase intracranial pressure (ICP) to levels high morbidity. In addition to neurological and cardiovascular symptoms, well described in the literature; gastrointestinal symptoms such as nausea, vomiting and gastroenteritis are common but little studied. The delay gastric emptying (GE) is one of the physiological changes found in patients with intracranial hypertension (ICH). This disorder reduces therapeutic responses with a view to reducing the absorption of nutrients and drugs, and lead to lung aspiration, which can lead to death. We evaluated the effect of HSA on gastrointestinal motility disorders (Gastric Emptying - EG; Intestinal Transit â IT or Gastric Compliance - CG), hemodynamic parameters (Mean Arterial Pressure - MAP, Heart Rate - HR) and the PIC. As well as neurohumoral mechanisms related to these changes. We used Wistar rats (300 - 350g, N=113) under the auspices COBEA (CEUA/UFC- Protocol 41/13). After anesthesia (Ketamine/Xylazine 20-10mg/Kg-IP), the animals were restrained by stereotactic aparatus being injected 0.1, 0.2 or 0.3 ml in the cisterna magna (autologous blood - HSA group or Liquor simile - Control group). At the time of induction of HSA, the animals were subjected to cannulation of the lateral ventricles for measurement of ICP and rigth femoral vessels in order to obtain the hemodynamic data. After 72h of induction, and fasted (24h) animals with oral rehydration solution ad libitum, proceeded studies EG, IT and CG. To determine the rate of GE a test meal (1ml/100g - phenol red - 0.5 mg/ml in 5 % glucose) was administered by gavage. The IT was already determined on direct administration of the meal into the duodenum through previously implanted cannula. Since the CG was evaluated using a barostat system at 4, 8 and 12 cm of gastric pressure distension. The MAP, HR and ICP were measured when assessing gastrointestinal motility. Data, mean  SEM, were analyzed by the "t" Student test (p<0.05). The HSA delayed gastric emptying (38.90  2.73 vs 47.00  0.72 %; 52.85  5.14 vs 31.12  2.0 % and 22.89  4.46 vs 46,24  3.56 % ) and increased the ICP (3.33  0.47 vs 16.10  0.47 cmH2O; 7.68  0.650 vs 30.86Â0.82 cmH2O and 17.50  1.29 vs 37.90  1.38 cmH2O ) in different volumes of blood, either 0.1, 0.2 or 0.3 ml, respectively, when compared to control. The HSA also promoted delay in IT and GC, increased BP and decreased HR. The subdiaphragmatic vagotomy, the esplancnotomia and pretreatment with guanethidine reversed the effect of HSA on changes in EG. The results suggest that the SAH arising gastrointestinal diseases reflect a pattern of secondary gut dysmotility, showing a strong correlation with the values of ICP

The number of operations for morbid obesity is rising fast. We have examined aspects of postoperative physiology and results after bariatric surgery. The pH in the proximal pouch after Roux-en-Y gastric bypass (RYGBP) was investigated with catheter-based and wire-less technique. Gastric emptying, PYY-levels in the fasting state and after a standardized meal was evaluated after biliopancreatic diversion with duodenal switch (DS). A clinical trial was undertaken, comparing DS to RYGBP in patients with BMI&gt;48. Main outcome variables were safety and long-term weight results as well as abdominal symptoms and laboratory results. Patients with stomal ulcer had significantly lower pH in their proximal gastric pouch as compared to asymptomatic control subjects. Long-time pH measurements with the wire-less BRAVO-system were feasible and demonstrated pH&lt;4 in median 10.5% of the time in asymptomatic post-RYGBP patients. After DS, the T50 of gastric emptying was 28±16 minutes. PYY-levels were higher after DS than in age-matched control subjects. BMI-reduction was greater after DS (24 BMI-units) than after RYGBP (17 BMI-units) in median 3.5 (2.0-5.3) years after surgery (p&lt;0.001). Fasting glucose and HbA1c levels were lower one and three years after DS as compared to RYGBP. On the other hand, DS-patients reported having more diarrhea and malodorous flatus. This thesis has resulted in deepened knowledge. Acid produced in the proximal pouch is an important pathogenetic factor in the development of stomal ulcer after RYGBP. However, symptom-free patients have an acidic environment in the proximal Roux-limb as well. After DS, gastric emptying is fast, but not instantaneous, and PYY-levels are high. DS results in superior weight reduction and better glucose control as compared to RYGBP in patients with BMI&gt;48. We believe that DS has a place in surgical treatment of the super-obese, even though symptoms of diarrhea and malodorous flatus are more common after DS.

Efter operation och anestesi får patienter ofta en negativ påverkan på magsäck och tarmar. Illamående och kräkningar är ett stort problem och många har svårt att komma igång med intag av föda och normal tarmfunktion då magsäcken och tarmarna ”står stilla”. Flera faktorer bidrar- bl.a. smärtan, det kirurgiska traumat och de läkemedel vi ger i samband med anestesin. Av de senare är opioider, d.v.s morfin och morfinliknande läkemedel, starkt bidragande. I detta avhandlings- arbete har opioiders effekter på magsäckens motilitet studerats. Med ett absorptionstest (paracetamolmetoden) studerades hos frivilliga hur opioiden remifentanil påverkar magsäckstömning och om kroppspositionen har betydelse för tömningshastigheten ut i tarmen. Remifentanil fördröjde magsäcks-tömningen och under pågående opioid behandling hade kroppspositionen ingen större betydelse, vilket det däremot hade under kontrollförsöken. Med samma metod jämförde vi hos patienter två anestesimetoder och studerade magsäcks-tömning direkt efter en operation. Ingen skillnad kunde påvisas mellan en opioidbaserad och en opioidfri anestesi, men inom respektive grupp var det en stor variation i magsäckstömning mellan individerna. Med en barostat studerades tonus i övre delen av magsäcken. Hos hälften av de frivilliga orsakade remifentanil en ökning av tonus och hos den andra hälften en minskning av tonus. Vidare undersöktes hos en grupp patienter opioiden fentanyls påverkan på den elektriska aktiviteten i magsäcken. Med en elekroga-strograf (EGG) registrerades de långsamma elektriska vågor som koordinerar muskelrörelserna i magsäcken. Hos hälften av de undersökta påverkades aktiviteten av fentanyl med en sänkt vågfrekvens eller upphörande av vågor, medan aktiviteten var opåverkad hos den övriga hälften. För att finna en förklaring till variationen gjordes genetiska analyser av genen för opioidreceptorn hos de undersökta i barostat och EGG studierna. Variationer i genomet, s.k. polymorfism, var inte associerad till utfallen i studierna. Studierna har visat på att opioider har en uttalad effekt på magsäckens motilitet och att den varierar kraftigt mellan individer. Polymorfism i genen för opioid- receptorn förklarade inte skillnaden mellan individer. Direkt efter operation bidrar sannolikt andra faktorer än anestesimetod till det variabla utfallet i magsäckstömning. / After anesthesia and/or surgical procedures, gastrointestinal motility is commonly impaired. The causes are multifactorial, with surgical trauma, pain and perioperative drugs playing a major role. This thesis explores opioid effects on gastric motility in healthy volunteers and patients undergoing surgery. Gastric emptying was studied by an absorption test (paracetamol method), and in healthy volunteers a remifentanil infusion delayed gastric emptying. Body position altered emptying during the control situations, but not during the remifentanil infusion. Further, two anesthetic methods were compared and no differences were found in immediate postoperative gastric emptying between a remifentanil/propofol based intravenous anesthesia and an opioid free inhalational anesthesia, although the interindividual variability was high. Proximal gastric tone was studied using a gastric barostat. An infusion of remifentanil caused two patterns of reaction regarding gastric tone, with half of the subjects increasing and half decreasing in gastric tone. Gastric myoelectrical activity was evaluated with electrogastrography (EGG), and a bolus dose of fentanyl caused a decrease in frequency of the gastric slow waves or disrupted this activity. However, the activity was unaffected in half of the investigated subjects. Analysis of polymorphisms (A118G and G691C) in the µ-opioid receptor gene was performed to find an explanation for the great interindividual variations seen in the barostat and EGG studies, but no association could be found. These studies have shown that opioids have pronounced effects on gastric motility with variable individual responses that are difficult to predict. Polymorphisms in the µ-opioid receptor gene could not explain the variations. Postoperatively, other factors might contribute more than opioids to the impairment in gastric motility. / ISSN 1652-4063

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.