U. Staedt

Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design

This paper documents dose-dependent effects of ornithine aspartate (OA) on postprandial hyperammonemia and plasma amino acids. Ten patients with cirrhosis were randomized to undergo 1 out of 4 infusion series. Each series consisted of four 8-h infusions (09:00 h-17:00 h), with placebo (NaCl), 5 g, 20 g or 40 g of OA being administered on separate days in varying sequences. This 4-fold crossover design was double-blind. On infusion days, patients received 2 oral protein loads (0.25 g/kg at 09:00 h and 0.5 g/kg at 13:00 h). Venous blood samples were drawn every 2 h and the 24-h urine was collected. In addition to measuring plasma ammonia and amino acids, the urea production rate, serum glucose and serum insulin were analyzed. A significant postprandial rise in the ammonia concentration was noted during the infusions of placebo and 5 g of OA but did not occur with the dosages of 20 g (after the second protein load) and 40 g (after both protein loads). Furthermore, the latter dose, compared with placebo, significantly reduced plasma ammonia after the minor protein load. Urea production rate increased when 20 g or 40 g of OA was administered. Of the amino acids involved in the metabolic pathways of ornithine and/or aspartate, glutamate showed a rise in its plasma level following infusion of 40 g of OA, whereas glutamine did not. Concentrations of methionine, phenylalanine, tyrosine, threonine, serine and glycine declined progressively with increasing doses of OA (5-40 g). The highest dose of the drug caused hyperglycemia and hyperinsulinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperammonemia-induced depletion of glutamate and branched-chain amino acids in muscle and plasma

BACKGROUND/AIMS Exogenous hyperammonemia is known to decrease the plasma levels of branched-chain amino acids (BCAA). To investigate whether changes in intracellular amino acid concentrations of muscle are associated with and may, at least in part, mediate this effect, experiments were carried out on a total of 60 male Wistar rats. METHODS Five groups were formed in a randomized manner. Group A: no treatment; groups B1 and B2: 2-hour and 6-hour continuous central-venous infusions, respectively, of sodium salts; groups C1 and C2: 2-hour and 6-hour infusions of ammonium salts. We obtained venous blood samples and muscle biopsies. Plasma ammonia, whole blood glucose, serum insulin, blood pH, and amino acids in plasma as well as in the intracellular water of muscle were measured. RESULTS As compared with control group A, groups C1 and C2 displayed a 3.3- and a 4-fold increase, respectively, in the plasma ammonium concentration. Regarding insulin, the ammonium-infused rats were similar to group A but not to the sodium-infused B groups, which had significantly lower insulin concentrations. Administering ammonium brought about a decline in BCAA concentrations in plasma after 2 hours and in muscle after 6 hours. The ammonium-induced fall in intracellular BCAA values was preceded by an increase of glutamine as well as by a decrease of glutamate and alanine in both plasma and muscle. CONCLUSIONS It is pointed out that the inter-group differences in serum insulin, although possibly accounting for some of the findings, can by no means explain the entire pattern of amino acid concentrations seen after the ammonium infusions. Instead, our results agree with the hypothesis that hyperammonemia indirectly lowers the plasma levels of BCAA by stimulating glutamine synthesis, thus reducing the intracellular glutamate pool, which is likely to be restored, at least in part, by an intensified BCAA transamination. Clarification is needed as to whether carbon skeletons derived from valine and isoleucine additionally contribute to replenishing the glutamate pool.

Continuous Measurement of Hemodynamic Alterations During Pharmacologic Cardiovascular Stress Using Automated Impedance Cardiography

The contribution of computerized impedance cardiography in monitoring and differentiating cardiovascular responses to pharmacologic stress after the administration of dipyridamole (group 1, n = 24) or dobutamine (group 2, n = 26) was investigated during stress echocardiography. Heart rate, stroke volume index, cardiac index and systemic vascular resistance index were evaluated continuously with an automated, computerized, signal‐averaged impedance cardiography system. Dipyridamole had little average effect on heart rate, stroke volume index, and cardiac index. The responses were similar in patients with positive (n = 9) or negative (n = 15) stress echocardiography test results (as characterized by echocardiographic wall‐motion abnormalities). Dobutamine induced a similar mean increase in heart rate in patients with negative (n = 13) or positive (n = 13) results on stress echocardiography. The mean increase in stroke volume index induced by dobutamine was greater in patients with negative stress echocardiography test results than in patients with stress‐induced wall‐motion abnormalities. This distinction was also seen in the cardiac index; the mean change in patients with negative stress echocardiography test results was larger than in patients with positive results. It is concluded that automated computerized impedance cardiography not only allows surveying and monitoring hemodynamic changes during pharmacologic stress echocardiography but also contributes to differentiation of pathologic stress responses.

Detection of patients with restenosis after PTCA by dipyridamole-atropine-stress-echocardiography

Stress-echocardiography (SE) has been proven to be a valuable method for the diagnosis of coronary artery disease. For patients who cannot exercise, pharmacological stress-echocardiography represents an alternative method for the induction of cardiovascular stress. Few studies exist concerning the value of dipyridamole-SE for the detection of restenosis in patients after primary successful PTCA. It has been demonstrated that the addition of atropine can significantly increase the diagnostic potential of dipyridamole-SE, especially in patients with 1- or 2-vessel disease. The purpose of our study was to investigate the diagnostic value of high-dose dipyridamole-SE plus atropine (DASE) for the detection of restenosis after primary successful PTCA. We investigated 65 patients 3–6 months after PTCA before a control angiography was performed. Restenosis was defined as > 70% lumen narrowing, determined by quantitative coronary angiography. In 20/27 patients with restenosis the DASE was pathologic (sensitivity 74%), in 34/38 patients without restenosis the DASE was normal or showed no induced WMA (specificity 89%). Patients with tight restenosis (> 90%) were always correctly detected by DASE. Concerning the different vessels, restenosis of the LAD was correctly predicted by DASE in 11/12 patients, restenosis of the LCX in 6/9 patients and restenosis of the RCA in 8/11 patients. Conclusions: From our results of our study we conclude that DASE is a reliable diagnostic method for the non-invasive evaluation of patients after PTCA. DASE can identify patients with relevant restenosis after PTCA and help to select those patients who will probably benefit from further coronary interventions.

Evaluation of signal-averaged cardiokymography for the detection of ischemic left ventricular dysfunction

UNLABELLED Cardiokymography (CKG) is a non-invasive method for the detection of patients with coronary artery disease (CAD). Issues of the present study were to evaluate the feasibility, sensitivity and specificity of a recently developed signal-averaged CKG system for detecting patients with pharmacologically induced ischaemic left ventricular wall motion abnormalities (WMA) during pharmacologic stress echocardiography (SE). Precordial CKG curves were recorded in 100 consecutive patients who underwent dobutamine-SE for suspected CAD. For interpretation, CKG curves were classified into three different types, depending on the degree of systolic outward motion. CKG test results were regarded as positive (indicating myocardial ischaemia) if there was a change of the baseline CKG type at peak pharmacologic stress. The CKG test results were positive in 18 of 27 patients with a pathologic dobutamine-SE (sensitivity 67%), but did not show any change of the prior CKG type in 57 of 69 patients with a normal SE (specificity 83%). Patients with a true positive CKG test had significantly (P<0.05) more echocardiographic segments with WMA than patients with a false negative CKG test. CONCLUSIONS Signal-averaged CKG can detect patients with ischaemic ventricular dysfunction. Sensitivity of CKG in detecting patients with WMA depends on the extent of left ventricular ischaemia. Further studies are needed to define the diagnostic value of signal-averaged CKG in the non-invasive detection of patients with suspected CAD.

Protein- und Aminosäurenstoffwechsel bei Leberinsuffizienz—Infusionstherapeutische und diätetische Folgerungen

Die heutigen Tendenzen und Richtlinien bezuglich der Versorgung leberinsuffizienter Patienten mit Eiweis bzw. Aminosauren ergeben sich uberwiegend aus metabolischen Erkenntnissen und kontrollierten klinischen Studien der letzten 10 Jahre; sie kontrastieren in quantitativer und qualitativer Hinsicht mit alteren Vorstellungen. Subtile Methoden der Beschreibung des Proteinhaushalts und des Ernahrungszustands (Abschnitt 1) haben zusammen mit einer verbesserten Diagnostik fruher Phanomene der hepatischen Enzephalopathie (HE) annahernd zufriedenstellende Effektivitatskriterien nutritiver Masnahmen geliefert. Des weiteren ist die rationale Basis dieser Masnahmen durch neue Einblicke in den Aminosauren— und Ammoniakstoffwechsel (Abschnitt 2) wie auch in die Entstehungsweise der HE (Abschnitt 3) stabiler und breiter geworden. Das hepatologisch konzipierte Aminosaurengemische bei entsprechend gefahrdeten Kranken eine risikofreie und effiziente parenterale Ernahrung ermoglichen, wuste man schon zu Beginn der vergangenen Dekade. Davon zu unterscheiden ist das erst in jungster Zeit ausreichend legitimierte Bestreben, durch Anwendung solcher Aminosaurengemische prakomatose und komatose Zustande nicht nur zu vermeiden, sondern auch adjuvant zu behandeln (Abschnitt 4). Auf dem Sektor der oralen Ernahrung lief die Entwicklung ungefahr parallel, wobei allerdings das Fazit aus den bislang verfugbaren Befunden mehr die Prophylaxe der HE als deren Therapie betrifft (Abschnitt 5).

Haemodilution in acute ischaemic stroke comparison of two haemodilution regimen

In a prospective study we randomly allocated 50 patients with acute ischaemic stroke in the area of the middle cerebral artery within 12 hours after onset to two moderate hypervolemic haemodilution regimen consisting of 500 ml of 10% hydroxyethyl starch per day for 10 days. In the high haematocrit group the target haematocrit of 41-42% was achieved by 0-3 phlebotomies and additional replacement of that volume with the colloid in 3 days. In the low haematocrit group with 1-4 phlebotomies a target haematocrit of 37-38% was reached in 4 days. The groups did not differ regarding age, risk factors, haematocrit and neurological score. The improvement of the disturbed blood rheology was more pronounced in the low haematocrit group. One death occurred in each group. The neurological score showed a significantly greater increase in the low haematocrit group with +59% at day 5 and +125% at day 11; the data for the high haematocrit group were +34% and +89% respectively. We calculated a correlation (r = 0.36, p less than 0.02) between the rise in neurological score and the reduction of haematocrit. Our data suggest but not do prove that an early start on moderate hypervolemic haemodilution is beneficial in patients with acute ischaemic stroke and disturbed blood rheology.

Intra- and extracellular amino acid concentrations in portacaval-shunted rabbits. Role of hyperammonemia and effects of branched-chain amino acid-enriched parenteral nutrition.

SummaryIntra- and extracellular amino acid concentrations were measured in rabbits in order to elucidate the possible role of hyperammonemia in lowering the postabsorptive plasma levels of branched-chain amino acids (BCAA) and to assess the effects of BCAA-enriched total parenteral nutrition (TPN) on the amino acid pattern of muscle. The pathophysiological part of this paper deals with portacaval anastomosis (PCA) and is aimed at substantiating or rejecting our hypothesis that excessive ammonia — by stimulating glutamine synthesis — reduces the intracellular glutamate pool which is then restored, at least in part, by an intensified BCAA degradation. Regarding infusion therapy, we were mainly interested in whether an amino acid solution adapted to the metabolism in liver cirrhosis causes an accumulation of BCAA in muscle or modifies the intracellular content of glutamate and glutamine.Eighteen rabbits did not undergo surgery and served as controls (group A), while 30 were given a portacaval end-to-side anastomosis (group B). Two weeks after creating the PCA, venous blood samples were taken and muscle biopsies (Bergströms technique) were performed postabsorptively. An 18-h TPN was then started, the regimen administered included dextrose, fat and, in addition, either a conventional (group B1, n=15) or an adapted amino acid solution (group B2, n=15). We obtained second blood specimens and muscle biopsies at the end of the infusion period. With the control animals, the same time schedule for blood sampling and muscle biopsies was followed.Fourteen days after the operation, the PCA rabbits displayed a mean plasma ammonia level 5.1 times higher than that measured in the controls (p≤0.001). Conventional blood chemistry did not reveal any impairment of liver cell integrity or over-all hepatic function, whereas the nutritional state of the shunted animals worsened, as indicated by body weight and biochemical variables. Since in the PCA rabbits, the total amino acid pools of muscle and plasma were seen to be increased and decreased, respectively, the results concerning the individual amino acids are given in terms of both the absolute and percentage values, the latter more often revealing high levels of statistical significance. PCA induced a marked rise in the intra- and extracellular concentrations of glutamine, while the values of glutamate and alanine showed a decline in muscle and plasma. The extracellular levels of methionine, phenylalanine, and tyrosine were raised, while those of the BCAA were diminished. During TPN, the intracellular concentrations of glutamate and glutamine fell in the animal group B 1 but remained stable in group B2. Only a slight and insignificant accumulation of BCAA occurred in the latter group. Secondary findings confirmed that conventional TPN aggravates the pre-existing increase in the plasma levels of methionine and phenylalanine, and that BCAA-enriched TPN results in almost normalized values of these amino acids.In conclusion, the PCA-induced alterations in the intracellular amino acid concentrations support the above-formulated hypothesis concerning the role of hyperammonemia in lowering plasma BCAA values, the preferential maintenance of intra-, rather than extracellular BCAA levels being a well-known fact. The largely stable concentrations of BCAA in muscle during BCAA-enriched TPN may indicate in intensified utilization of these amino acids, which probably involves ammonia detoxification. The observation that this type of TPN prevented a fall in the muscular levels of glutamate and glutamine fits into this concept.ZusammenfassungIn der vorliegenden Studie an Kaninchen wurden intra- und extrazelluläre Aminosäurenkonzentrationen gemessen, um erstens zu untersuchen, ob die postabsorptive Verminderung der verzweigtkettigen Aminosäuren (VAS) im Plasma durch die Hyperammoniämie bedingt oder mitbedingt sein dürfte, und zweitens festzustellen, wie ein total parenterales Ernährungsregime mit hohem Gehalt an VAS das muskuläre Aminosäurenmuster beeinflußt. Gegenstand des pathophysiologischen Teils der Arbeit ist der Stoffwechsel nach Anlage einer portokavalen Anastomose (PKA). Hier geht es um die Stützung oder Widerlegung unserer Hypothese, daß vermehrt vorhandenes Ammoniak durch Stimulation der Glutaminbildung den intrazellulären Glutamat-Pool verkleinert, und dies mit der Konsequenz eines forcierten Abbaus der VAS zur wenigstens partiellen Erhaltung der Glutamatkonzentration. Was die Infusionstherapie betrifft, so interessierte vorrangig, ob eine den metabolischen Besonderheiten bei Leberzirrhose angepaßte Aminosäurenlösung die VAS in der Muskulatur akkumulieren läßt und ob eine solche Lösung die intrazellulären Glutamat- bzw. Glutaminspiegel modifiziert.Von insgesamt 48 Kaninchen dienten 18 nicht operierte als Kontrolltiere (Gruppe A), während 30 eine portokavale End-zu-Seit-Anastomose erhielten (Gruppe B). Zwei Wochen nach Herstellung der PKA wurden postabsorptiv venöse Blutproben entnommen und — nach der Methode von Bergström et al. - Muskelbiopsien durchgeführt. Unmittelbar danach begann eine 18stündige totale parenterale Ernährung (TPE). Wir applizierten als Hauptnährstoffe Glukose, Fett und ein Aminosäurengemisch, wobei das letztere entweder eine konventielle (Gruppe B 1, n= 5) oder eine adaptierte Zusammensetzung hatte (Gruppe B 2, n=15). Gegen Ende der Infusionsphase erfolgten zum zweitenmal Blutabnahmen und Muskelbiopsien. Die Kontrolltiere unterlagen bezüglich der Blut- und Muskelproben dem gleichen Zeitplan wie die operierten.14 Tage nach der Operation boten die Kaninchen mit PKA im Schnitt einen 5,1fach höheren Ammoniakspiegel als die Kontrolltiere (p<0,001). Die konventionellen blutchemischen Befunde ergaben keinen Hinweis auf eine Beeinträchtigung der Leberzellintegrität oder des allgemeinen Funktionsniveaus der Leber. Demgegenüber hatte sich der Ernährungszustand nach Anlage des Shunts verschlechtert (Körpergewicht, biochemische Parameter). Da bei den Tieren mit PKA die Gesamtmenge der Aminosäuren in den Muskelzellen vermindert und im Plasma vermehrt war, werden in dieser Arbeit die Spiegel der einzelnen Aminosäuren doppelt angegeben, nämlich als Absolut- und als Prozentwerte; die prozentualen Konzentrationen zeigten häufiger als die absoluten hochsignifikante Veränderungen. Die PKA verursachte eine erhebliche Zunahme der intra- und extrazellulären Glutaminspiegel, während für Glutamat und Alanin in der Muskulatur sowie im Plasma herabgesetzte Werte resultieren. Die Spiegel von Methionin, Phenylalanin und Tyrosin waren extrazellulär gesteigert, die der VAS verringert. Unter der TPE fielen intrazellulär die Konzentrationen von Glutamin und Glutamat in der Gruppe B 1 ab, blieben jedoch in der Gruppe B 2 konstant; die intrazellulären VAS akkumulierten in der letzten Gruppe nur sehr gering und ohne Signifikanz. Darüber hinaus bestätigten die Versuche, daß eine Standard-TPE bereits bestehende Konzentrationserhöhungen von Methionin und Phenylalanin im Plasma deutlich akzentuiert, während ein mit VAS angereichertes Infusionsregime die Spiegel dieser Aminosäuren annähernd in die Referenzbereiche bringt.Wir meinen, daß die durch eine PKA herbeigeführte Abweichungen des intrazellulären Aminosäurenmusters die eingangs formulierte Hypothese stützen, derzufolge die Hyperammoniämie zur Senkung der Plasmaspiegel der VAS zumindest beiträgt; dabei darf die bekannte Tendenz des Organismus, eher den intra- als den extrazellulären Pool der VAS aufrechtzuerhalten, nicht außer acht bleiben. Die bei TPE mit hohem Angebot an VAS weitgehend unbeeinflußten Konzentrationen derselben in der Muskulatur sprechen für eine intensivierte Nutzung dieser Aminosäuren, unter anderem wohl zum Zweck der Ammoniakentgiftung. Im übrigen paßt die Beobachtung, daß eine Abnahme der intrazellulären Spiegel von Glutamat und Glutamin durch die adaptierte TPE verhindert werden konnte, in das vorgetragene Konzept.

Einfluß einer Hämodilution mit 10%iger Hydroxyäthylstärkelösung (MW 200000/0,5) auf die Fließeigenschaften des Blutes, die arteriellen Blutgase und den konjunktivalen Sauerstoffpartialdruck bei Patienten mit Hirninfarkt

Bei 15 Patienten mit akutem Hirninfarkt wurden hamorheologische Parameter, arterielle Blutgase und konjunktivaler pO2 gemessen und mit den Daten eines altersgleichen Referenzkollektivs verg

Konjunktivaler Sauerstoffpartialdruck bei Hirninfarkt vor und nach Infusion von 500 ml 10% HAES 200/0,5

Tabelle 1. Daten yon 15 Patienten mit Hirninfarkt. Angegeben sind die Mittelwerte (2) und Standardabweichungen (s) des ipsilateral (i) und kontralateral (k) gemessenen konjunktivalen Sauerstoffpartialdrucks (konj pO2) in torr vor und nach Infusion von 500 ml 10% HAES 200/0,5 in 3 h. Als ipsilateral gilt die Hirnhemisph~ire mit dem Infarktherd. Die Referenzbereiche (+ I s) stammen von 40 kardiovascul~ir und pulmonal gesunden, gleichaltrigen Probanden