Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding

Objectives To review randomised controlled trials of treatment with a proton pump inhibitor in patients with ulcer bleeding and determine the impact on mortality, rebleeding, and surgical intervention.Design Systematic review and meta-analysis.Data sources Cochrane Collaboration''s trials register, Medline, and Embase, handsearched abstracts, and pharmaceutical companies.Review methods Included randomised controlled trials compared proton pump inhibitor with placebo or H₂ receptor antagonist in endoscopically proved bleeding ulcer and reported at least one of mortality, rebleeding, or surgical intervention. Trials were graded for methodological quality. Two assessors independently reviewed each trial, and disagreements were resolved by consensus.Results We included 21 randomised controlled trials comprising 2915 patients. Proton pump inhibitor treatment had no significant effect on mortality (odds ratio 1.11, 95% confidence interval 0.79 to 1.57; number needed to treat (NNT) incalculable) but reduced rebleeding (0.46, 0.33 to 0.64; NNT 12) and surgery (0.59, 0.46 to 0.76; NNT 20). Results were similar when the meta-analysis was restricted to the 10 trials with the highest methodological quality: 0.96, 0.46 to 2.01, for mortality; 0.41, 0.25 to 0.68, NNT 10, for rebleeding; 0.62, 0.46 to 0.83, NNT 25, for surgery.Conclusions Treatment with a proton pump inhibitor reduces the risk of rebleeding and the requirement for surgery after ulcer bleeding but has no benefit on overall mortality.     

Optimizing the intragastric pH as a supportive therapy in upper GI bleeding.

Acid inhibitory therapy has long been considered of no benefit for upper GI bleeding. The reason was that achlorhydria in the stomach could not be achieved with any single or combination of acid inhibitory drugs. The introduction of proton pump inhibitors has, for the first time, allowed the physician to temporarily achieve achlorhydria by large doses of intravenously applied proton pump inhibitors. The first placebo-controlled clinical trials have shown that, indeed, an intragastric pH of near 7 can significantly improve the clinical outcome of upper GI bleeding. Pharmacokinetic studies with proton pump inhibitors have shown that a bolus of 80 mg pantoprazole or omeprazole followed by immediate continuous infusion of eight mg per hour will result in an intragastric pH of 7 within 20 minutes. This intragastric pH optimizes the different steps of hemostasis in the stomach.     

Effect of cell age and phenylhydrazine on the cation transport properties of rabbit erythrocytes

We studied the effect of cell age on the cation transport systems of rabbit erythrocytes by increasing the proportion of circulating young erythrocytes with either repeated bleeding or with phenylhydrazine (PHZ) treatment. We found that when the reticulocyte content of rabbit blood is increased by bleeding (from 1 to 40–50% of the circulating red cells), the response of the various transport pathways differs. The largest increase (fivefold) was found in the activity of K-CI contransport which peaked 3 days after the last bleeding. The Na-K pump activity peaked at a similar time, but the % increase was twofold less than the K-CI contransport. There was very small increase in the activity of the Na-Li exchange, whereas the Na-H exchange reached peak values 10 days after the last bleeding (twofold increase), when activities of K-Cl contransport and Na-K pump had returned to almost normal levels. In vivo PHZ treatment resulted in anemia and marked reticulocytosis (80–90% of circulating cells). Transport rates were markedly increased (Na-K pump 9.6-fold, Na-H exchange 6.8-fold, Na-Li exchange 2.75-fold; K-CI contransport: 10–20-fold). When blood from PHZ-treated rabbits was incubated in vitro for 24–48 hour, red cell volume and K content decreased. This process was associated with a 70% reduction in the activity of the K-CI contransport after 24 hours and a 90% reduction after 48 hours. The activity of the other systems also declined and approached baseline values after 48 hours. Loss of transport activity was not affected by 10 μM E-64, whereas 10 mM methylamine reduced the inactivation of the Na-H exchange and of the Na-Li exchange. PHZ treatment of rabbit red cells in vitro resulted in marked increase of the K-CI contransport and inhibition of Na-K pump, Na-H exchange, and Na-Li exchange. These effects were abolished by DTT, with the exception of the Na-K pump inhibition, which was DTT insensitive. Thus both cell age and oxidative damage are important determinants of cation transport in rabbit red cells. © 1993 Wiley-Liss, Inc.     

Open-Source Syringe Pump Library

This article explores a new open-source method for developing and manufacturing high-quality scientific equipment suitable for use in virtually any laboratory. A syringe pump was designed using freely available open-source computer aided design (CAD) software and manufactured using an open-source RepRap 3-D printer and readily available parts. The design, bill of materials and assembly instructions are globally available to anyone wishing to use them. Details are provided covering the use of the CAD software and the RepRap 3-D printer. The use of an open-source Rasberry Pi computer as a wireless control device is also illustrated. Performance of the syringe pump was assessed and the methods used for assessment are detailed. The cost of the entire system, including the controller and web-based control interface, is on the order of 5% or less than one would expect to pay for a commercial syringe pump having similar performance. The design should suit the needs of a given research activity requiring a syringe pump including carefully controlled dosing of reagents, pharmaceuticals, and delivery of viscous 3-D printer media among other applications.     

Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial.

OBJECTIVE--To investigate the possible therapeutic role of omeprazole, a powerful proton pump inhibitor, in unselected patients presenting with upper gastrointestinal bleeding. DESIGN--Double blind placebo controlled parallel group study. Active treatment was omeprazole 80 mg intravenously immediately, then three doses of 40 mg intravenously at eight hourly intervals, then 40 mg orally at 12 hourly intervals. Treatment was started within 12 hours of admission and given for four days or until surgery, discharge, or death. SETTING--The medical wards of University and City Hospitals, Nottingham. SUBJECTS--1147 consecutive patients aged 18 years or more admitted over 40 months with acute upper gastrointestinal bleeding. MAIN OUTCOME MEASURES--Mortality from all causes; rate of rebleeding, transfusion requirements, and operation rate; effect of treatment on endoscopic appearances at initial endoscopy. RESULTS--Of 1147 patients included in the intention to treat analysis, 569 received placebo and 578 omeprazole. No significant differences were found between the placebo and omeprazole groups for rates of transfusion (302 (53%) placebo v 298 (52%) omeprazole), rebleeding (100 (18%) v 85 (15%)), operation (63 (11%) v 62 (11%)), and death (30 (5.3%) v 40 (6.9%)). However, there was an unexpected but significant reduction in endoscopic signs of upper gastrointestinal bleeding in patients treated with omeprazole compared with those treated with placebo (236 (45%) placebo v 176 (33%) omeprazole; p less than 0.0001). CONCLUSIONS--Omeprazole failed to reduce mortality, rebleeding, or transfusion requirements, although the reduction in endoscopic signs of bleeding suggests that inhibition of acid may be capable of influencing intragastric bleeding. Our data do not justify the routine use of acid inhibiting drugs in the management of haematemesis and melaena.     

Microcomputer monitor and blood sampler for free-diving Weddell seals

The equipment used for the first sampling of arterial blood at depth on free-diving Weddell seals Leptonychotes weddelli is described. Blood was withdrawn through an aortic catheter by a submersible, peristaltic roller pump and stored in a single- or multiple-sample collection device. The multiple sampler allowed up to eight individual blood samples to be collected during a single dive. The blood pump was controlled by a dedicated microcomputer that allowed initiation of blood sampling at flexible combinations of depth and/or time during either the descending or ascending phase of the dive. The dedicated microcomputer also recorded swimming depth, velocity, heart rate, and body temperature at selectable time intervals. These data were transmitted to a laboratory computer, and blood samples were retrieved, when the seal surfaced to breathe.     

Low haemolysis pulsatile impeller pump: design concepts and experimental results

A pulsatile fully implantable impeller pump with low haemolysis has been produced by developing a pulsatile impeller for a nonpulsatile pump also developed in this laboratory. The impeller was designed according to the 3-dimensional theory of fluid dynamics. The impeller shroud retains the same parabolic form and the vane has a form compacted by a radial logarithmic spiral and an axial helical spiral so that the absolute vibration velocity of the blood in a peripheral direction is a minimum as the impellar changes its speed periodically to generate a physiological pulsatile blood flow. Thus the Reynolds shear and the Newton shear are a minimum for the required pulse pressure. The mean volume and mean pressure are controlled by adjusting the voltage. The shape of the pressure pulse is determined by a square was of vollage and the systole/diastole ratio. In order to abolish regurgitation of the pump, a 40 per cent systole period and a 5 V voltage pulse are desirable for 40 mmHg pulse pressure (80–120 mmHg mean pressure). The pulse frequency has almost no effect on pump output. The pump can delivery 4 l/min mean volume and 100 mmHg mean pressure (40 mmHg pulse pressure), and these conditions result in an index of heamolysis (IH) for porcine blood of 0.020—only slighly more than the nonpulsatile pump (0.016). When the pulsatile impeller was used under nonpulsatile conditions its IH was almost doubled, but when the nonpulsatile impeller was used under pulsatile conditions the IH reached 0.13. The power consumption is approximately equal to that for the nonpulsatile pump: 3 W for 4 l/min and 100 mmHg output. The pump weights 240 g (including 190 g for the motor) and, because a commercial motor has been used, costs only a few hundred US dollars.     

The maximal velocity and the calcium affinity of the red cell calcium pump may be regulated independently

The kinetics of active Ca2+ transport in inside-out red cell membrane vesicles and the Ca2+-ATPase activity of the purified Ca2+ pump were studied and the effects of calmodulin, acidic phospholipids, and controlled trypsinization were compared. In the presence of calmodulin the maximal rate and the apparent affinity of the pump for Ca2+ were greatly increased in both preparations. The lowest value of Km(Ca) was between 0.5 and 0.7 microM depending on the concentration of calmodulin and on the enzyme preparation. Positive cooperativity for Ca2+ activation with a Hill coefficient of 1.6-1.7 was observed in all cases. When acidic phospholipids (phosphatidylinositol 4-phosphate was routinely used) were added to the inside-out vesicles or to the purified enzyme, maximal transport rates equal to those obtained with calmodulin were measured but the Km(Ca) decreased to 0.25 microM and the positive cooperativity disappeared (the Hill coefficient approached 1). Highly active, calmodulin-independent proteolytic fragments of molecular mass of 81 and 76 kDa were produced with controlled trypsinization. When the trypsin treatment was directed to obtain primarily the 81-kDa fragment, the preparation showed characteristics similar to those of the intact Ca2+ pump in the presence of calmodulin; that is, the same Vmax was obtained, the Km(Ca2+) was 0.5-0.6 microM, and the Hill coefficient was about 1.6. Addition of phosphatidylinositol 4-phosphate or allowing further proteolysis to produce the 76-kDa fragment, shifted the Km(Ca) to 0.25 and reduced the Hill coefficient to 1, without changes in the maximal rate. Based on these results it is suggested that the maximal velocity and the Ca2+ affinity on the erythrocyte Ca2+ pump may be regulated independently and that independent polypeptide regions of the enzyme are involved in the regulations.     

Structural adaptations and mechanism of reflex bleeding in the larvae of the myrmecophilous ladybird Diomus thoracicus

Reflex bleeding is an effective defensive mechanism against predators. When attacked, some insects emit hemolymph, which coagulates, quickly entangling their aggressor. Bleeding occurs at weak intersegmental membranes or through dedicated organs, which can be associated or not with glandular cells.Here, we describe the behavior and morphological structures involved in reflex bleeding in the larvae of the ladybird, Diomus thoracicus, which are intranidal parasites of the ant Wasmannia auropunctata. The larvae are tolerated by the ants thanks to odor mimicry, but some rare aggressive ant behaviors were observed that trigger reflex bleeding both at a pair of thoracic tubercles and a pair of posterodorsal abdominal humps. No glandular structure was found in association with these emission points, which suggests that the material emitted was hemolymph only. A 3D reconstruction suggested that reflex bleeding seems to be controlled by muscles whose contraction increases the internal hydrostatic pressure and pushes the hemolymph into a funnel-like structure with an opening to the outside. In D. thoracicus, the morphological structures involved in reflex bleeding are among the most complex and prominent described to date.     

Extended somatostatin treatment of a patient with bleeding ulcer.

The results of a 67 hour cyclic somatostatin continuous infusion in a patient with a bleeding ulcer are reported. The subject was a 65 year old male with very heavy gastrointestinal bleeding on the 9th postoperative day following a high BI-resection. Endoscopy revealed the bleeding to be caused by two residual ulcers in the area of the anastomosis. Somatostatin treatment led to an immediate cessation of the bleeding after 1 hour. Gastric secretion as well as gastrin, insulin and growth hormone levels were significantly inhibited by somatostatin. Endoscopy at the end of the treatment period showed two ulcers in the process of healing. The raised blood glucose levels caused by somatostatin were easily controlled with max. 14 IU cristalline insulin daily. Except for dryness in the mouth, no adverse side effects were apparent. There was no evidence from laboratory investigations of hemostatic defects or bleeding tendency in the patient.     

Current Management Strategies in Acid-Related Disorders

Acid-related disorders include not only reflux esophagitis and peptic ulcer, but also a subset of patients with endoscopy-negative dyspepsia. The management strategy differs between these diseases and therefore a precise diagnosis is important. The unaided clinical diagnosis is of limited value in patients with pain or discomfort in the upper abdomen, and endoscopy is therefore an important and cost-effective diagnostic tool.Duodenal ulcer is caused by an interplay between gastric acid and Helicobacter pylori. The treatment is aimed at rapid symptom relief and healing and at the same time eradication of H. pylori. At present the best choice is the combination of a proton pump inhibitor and two effective antimicrobial drugs, e.g., clarithromycin and metronidazole. The proton pump inhibitor has dual effect in this combination it provides optimal symptom relief and healing, and it increases the anti-H. pylori-effect of the antimicrobial drugs. The risk of reinfection varies geographically; in Europe it is around 1 percent per year, and cure of the infection provides long-term, maybe life-long, cure of the ulcer disease. Some gastric ulcers are not H. pylori-related and the treatment strategy therefore includes a diagnostic test for this infection. If positive, treatment is similar to that in duodenal ulcer, while H. pylori-negative gastric ulcer patients are treated with antisecretory drugs alone.Reflux esophagitis correlates with the degree of acid exposure to the esophagus, and intensive acid inhibition is the most effective non-surgical therapy. In most cases the disease is chronic and needs continuous long-term therapy to prevent relapse. A staged reduction in dosage of the acid inhibitory drug may be attempted when the esophagitis is healed and the patient has become symptom free, but full dose therapy is often needed.Patients with endoscopy-negative dyspepsia are a heterogenous group and a more precise identification of the cause of the symptoms is a prerequisite for rational treatment. Empiric treatment can be tried in patients without alarm symptoms like bleeding or a palpable abdominal mass, and often an acid inhibitory drug is used. A more precise identification of those patients who have acid-related symptoms is possible using placebo controlled single-subject trials with an effective acid inhibitory drug, but in daily routine these drugs are simply given for a short period of time, and in case symptomatic relief is observed, the symptoms may be regarded as being acid-related and treated accordingly.     

How does salt retention raise blood pressure?

A critical question in hypertension research is: How is long-term blood pressure controlled? Excessive NaCl ingestion or NaCl retention by the kidneys and the consequent tendency toward plasma volume expansion lead to hypertension. Nevertheless, the precise mechanisms linking salt to high blood pressure are unresolved. The discovery of endogenous ouabain, an adrenocortical hormone, provided an important clue. Ouabain, a selective Na+ pump inhibitor, has cardiotonic and vasotonic effects. Plasma endogenous ouabain levels are significantly elevated in approximately 40% of patients with essential hypertension and in animals with several forms of salt-dependent hypertension. Also, prolonged ouabain administration induces hypertension in rodents. Mice with mutant Na+ pumps or Na/Ca exchangers (NCX) and studies with a ouabain antagonist and an NCX blocker are revealing the missing molecular mechanisms. These data demonstrate that alpha2 Na+ pumps and NCX1 participate in long-term regulation of vascular tone and blood pressure. Pharmacological agents or mutations in the alpha2 Na+ pump that interfere with the action of ouabain on the pump, and reduced NCX1 expression or agents that block NCX all impede the development of salt-dependent or ouabain-induced hypertension. Conversely, nanomolar ouabain, reduced alpha2 Na+ pump expression, and smooth muscle-specific overexpression of NCX1 all induce hypertension. Furthermore, ouabain and reduced alpha2 Na+ pump expression increase myogenic tone in isolated mesenteric small arteries in vitro, thereby tying these effects directly to the elevation of blood pressure. Thus, endogenous ouabain, and vascular alpha2 Na+ pumps and NCX1, are critical links between salt and hypertension. New pharmacological agents that act on these molecular links have potential in the clinical management of hypertension.     

Selection of operation in patients with bleeding esophageal varices.

The results of surgical treatment of bleeding esophageal varices over an 8-year period in 155 patients are reviewed. Primary treatment of bleeding was conservative, with intravenous administration of vasopressin and balloon tamponade. Emergency operations were carried out after 48 hours in persons with persistent bleeding who were surgical candidates. Operative mortality was higher in this group (40%) than in those undergoing elective or urgent operations (each 10%). Postoperative encephalopathy occurred in 35% of patients and was correlated closely to late death after establishment of a shunt. The mesocaval shunt is no better than the portacaval but appears to be a good alternative in an emergency. In a controlled trial the distal splenorenal shunt was found to be associated with a lower rate of postoperative encephalopathy than the portacaval shunt, but thus far the long-term survival rates have not differed.     

Density gradient system: II. A 50 channel programmable undulating diphragm peristaltic pump

A special peristaltic pump is described that has functioned as part of a system for density gradient formation and fractionation. Twenty-five pumping tubes are actuated on both the top and bottom of the pump. A Mylar diaphragm interposed between the rollers and the pumping tubes filters out the horizontal, stretching component of the forces imparted to the tubes. This greatly prolongs tube life, increases the allowable pressures that can be achieved with such a pump, and thus permits accurate delivery of viscous solutions.An explanation of the cause of the pulsations produced by peristaltic pumps is presented and the virtual elimination of these pulsations is demonstrated.Both velocity and direction of flow of the pump are controlled. By means of two independent bidirectional digital counters, preset volumes of fluid can be delivered and the total volume of liquid determined.Studies demonstrating the relative independence of fluid volume delivered at a preset count versus flow velocity and composition are presented.Other possibilities for use of the pump in automating density gradient analysis are discussed. Possibilities for employment of the pump for autoanalysis and in artificial organs are indicated.     

Servo respirator constructed from a positive-pressure ventilator.

We have constructed an electronically controlled respirator from three commercially available components: a positive-pressure ventilator, a recorder pen motor, and a differential amplifier. Using negative feedback derived from a tracheal pressure signal, the instrument functions as a servo respirator which provides precise control of tracheal pressure. The system's power and response characteristics are well suited for ventilation of anesthetized cats and dogs. The servo respirator can be used as an externally controlled respiratory pump which provides flexibility in selection of the parameters of the ventilatory cycle. Alternatively, it can function as a "demand" respirator which generates transthoracic pressure proportional to efferent respiratory discharge.     

New perspectives on the evolution of lung ventilation mechanisms in vertebrates

In the traditional view of vertebrate lung ventilation mechanisms, air-breathing fishes and amphibians breathe with a buccal pump, and amniotes breathe with an aspiration pump. According to this view, no extant animal exhibits a mechanism that is intermediate between buccal pumping and aspiration breathing; all lung ventilation is produced either by expansion and compression of the mouth cavity via the associated cranial and hyobranchial musculature (buccal pump), or by expansion of the thorax via axial musculature (aspiration pump). However, recent work has shown that amphibians exhibit an intermediate mechanism, in which axial muscles are used for exhalation and a buccal pump is used for inhalation. These findings indicate that aspiration breathing evolved in two steps: first, from pure buccal pumping to the use of axial musculature for exhalation and a buccal pump for inspiration; and second, to full aspiration breathing, in which axial muscles are used for both inhalation and exhalation. Furthermore, the traditional view also holds that buccal pump breathing was lost shortly after aspiration breathing evolved. This view is now being challenged by the discovery that several species of lizards use a buccal pump to augment costal aspiration during exercise. This result, combined with the observation that a behavior known as “buccal oscillation” is found in all amniotes except for mammals, suggests that a reappraisal of the role of buccal pumping in extant and extinct amniotes is in order.Electronic supplementary material Electronic supplementary material is available for this article at and accessible for authorised users.     

The Micro Drop Recorder; A High Resolution Monitor of the Bleeding Rate of Plant Root Systems

The micro drop recorder is an accurate automatic instrumentwhich can detect within seconds small changes in the bleedingrate of sap. It is based on the micro drop recording technique.The reliability of the micro drop recorder can be proved bycalibration using an accurate pump. We report transient changesin bleeding rate that may not be detected by measurement techniquescurrently in use. Key words: Micro drop recorder, bleeding rate, automatic measurement     

A respiratory pump for small animals (author's transl)]

A respiratory pump is described which is controlled by compressed air and contains no mechanical moving parts, neither a motor nor a piston. It can function on a self-adjusting rhythm or can be regulated externally (for example by the discharge of a phrenic nerve).     

Glucose-limited high cell density cultivations from small to pilot plant scale using an enzyme-controlled glucose delivery system

The enzyme controlled substrate delivery cultivation technology EnBase(?) Flo allows a fed-batch-like growth in batch cultures. It has been previously shown that this technology can be applied in small cultivation vessels such as micro- and deep well plates and also shake flasks. In these scales high cell densities and improved protein production for Escherichia coli cultures were demonstrated. This current study aims to evaluate the scalability of the controlled glucose release technique to pilot scale bioreactors. Throughout all scales, that is, deep well plates, 3 L bioreactor and 150 L bioreactor cultivations, the growth was very similar and the model protein, a recombinant alcohol dehydrogenase (ADH) was produced with a high yield in soluble form. Moreover, EnBase Flo also was successfully used as a controlled starter culture in high cell density fed-batch cultivations with external glucose feeding. Here the external feeding pump was started after overnight cultivation with EnBase Flo. Final optical densities in these cultivations reached 120 (corresponding to about 40 g L(-1) dry cell weight) and a high expression level of ADH was obtained. The EnBase cultivation technology ensures a controlled initial cultivation under fed-batch mode without the need for a feeding pump. Because of the linear cell growth under glucose limitation it provides optimal and robust starting conditions for traditional external feed-based processes.     

A direct fluorescence study of the transient steps induced by calcium binding to sarcoplasmic reticulum ATPase

The sarcoplasmic reticulum intrinsic fluorescence level was closely correlated with the ATPase functional state, from pH 5.5 to 8.5. The fluorescence signal was used in stopped flow measurements for direct study of transient pump kinetics after calcium binding or removal. The signal change time course, which depends solely on the free calcium concentration in the observation chamber, was analyzed as a single exponential. Rate constants (kobs) were relatively slow (5 to 20 s-1), indicating multistep interaction between calcium and the transport protein. At pH 7 and 20 degrees C, and in the presence of 100 mM potassium and 1 to 20 mM MgCl2, kobs first decreased, and then increased as the calcium concentration rose. Similar experiments were performed at pH 6. Data were analyzed according to a scheme in which sarcoplasmic reticulum . calcium complex formation is controlled by a slow isomerization step occurring either before or after the rapid calcium binding to the high affinity site. The results are discussed with reference to published rapid quenching experiments. Under our conditions, i.e. in the absence of a calcium gradient across the membrane, the calcium pump cycle step in which reorientation of the calcium binding sites occurs cannot be identified with the isomerization step mentioned above.