G. Kleinberger

SUBSTANCE P IS MARKEDLY INCREASED IN PLASMA OF PATIENTS WITH HEPATIC COMA

Substance P (determined as immunoreactive substance P [i-SP]), noradrenaline, and adrenaline were measured in plasma of 18 patients with hepatic coma (stage I-IV), 16 healthy controls, and 10 critically ill patients without evidence of hepatocellular disease. Plasma i-SP (119 +/- 13 fmol/ml) was significantly higher in patients with hepatic coma than in healthy controls (13 +/- 2 fmol/ml) or control patients (23 +/- 4 fmol/ml). Plasma i-SP rose in parallel with plasma noradrenaline and adrenaline. There was a significant direct correlation between plasma i-SP and noradrenaline. Increase in plasma i-SP and noradrenaline was associated with a decrease in systemic vascular resistance and an increase in cardiac index and was most pronounced in those patients who finally died in coma. Deterioration in the dying patients was accompanied by a further significant increase in plasma i-SP. Immunoreactivity was identified as authentic SP by high performance liquid chromatography in 3 representative patients. Accumulation of the vasodilating peptide SP in plasma of patients with hepatic coma may be important in the pathogenesis of the cardiovascular disturbances associated with this disease.

SERUM LEVELS OF GAMMA-AMINOBUTYRIC-ACID-LIKE ACTIVITY IN ACUTE AND CHRONIC HEPATOCELLULAR DISEASE

Serum levels of GABA (gamma-aminobutyric acid)-like activity were measured by a radioreceptor assay in 22 healthy subjects and 170 patients with liver diseases. Levels were within normal limits (mean +/- SEM in healthy controls 0.52 +/- 0.04 mumol/l; range 0.2-0.8 mumol/l GABA equivalents) in most patients with uncomplicated acute viral hepatitis, compensated chronic hepatitis, and primary biliary cirrhosis (PBC). In 96% of patients with compensated (non-PBC) cirrhosis levels were slightly high (1.5 +/- 0.06 mumol/l). In 4 patients with decompensated cirrhosis but without hepatic encephalopathy (range 3.0-6.4 mumol/l) and in most of 26 patients with overt hepatic encephalopathy due to acute or chronic hepatocellular failure (range 2.3-18.0 mumol/l) levels were very high. Levels did not correlate closely with the clinical stage of hepatic encephalopathy or with arterial plasma ammonia concentrations. particularly high levels were detected in patients with cirrhosis 12-16 h after gastrointestinal haemorrhages. These findings are compatible with the hypothesis that the GABA neurotransmitter system is involved in the pathogenesis of hepatic encephalopathy in man.

Bedside estimation of extravascular lung water in critically ill patients: comparison of the chest radiograph and the thermal dye technique

Extravascular lung water (EVLW) was estimated in 53 critically ill patients by the chest radiograph (CXR) and the thermal dye technique. The comparison between these two methods revealed a direct and positive correlation (r=0.83, p(0.001). However, EVLW-values obtained by the thermal dye technique showed considerable overlap between cases of radiographic low grade pulmonary edema and we were able to identify several reasons for radiographic over- or underestimation of EVLW. in these patients EVLW-measurement by the thermal dye technique provides additional information, thereby probably influencing further treatment.

Fructose-induced hyperlactemia in hyperosmolar syndromes

SummarySevere hyperlactemia of 8.7, 8.6 and 7.9 mmol/l, respectively, developed in three patients with hyperosmolar syndromes (two hypernatremic, 417 and 415 mosmol/kg H2O; one hyperglycemic 437 mosmol/kg H2O) during rehydration treatment with 5% fructose in water (fructose dosage 0.5 g/kg body wt. per hour). After resolution of the electrolyte disturbances, the infusion of fructose at the same dosage increased the plasma lactate concentration in two of the patients to 4.9 and 4.0 mmol/l, indicating near normalization of hepatic lactate utilization. Thus, in addition to peripheral insulin resistance and decreased muscular glucose utilization, the hyperosmolar state is associated with a reduced tolerance to fructose. This is most likely due to an osmolality-dependent impairment of hepatic gluconeogenesis. In rehydration therapy for hyperosmolar syndromes, fructose-containing infusion solutions should no longer be used.

Plasma catecholamines in hepatic coma and liver cirrhosis: Role of octopamine

SummaryPlasma levels of adrenaline, noradrenaline and octopamine were estimated by a radioenzymatic method in nine cirrhotic outpatients with encephalopathy and in ten patients with hepatic coma (coma grade III–IV). In the cirrhotic outpatients normal as well as elevated plasma levels of noradrenaline were found. Octopamine could not be detected in the plasma of these patients as well as of ten healthy volunteers. Elevated noradrenaline levels were present in all patients with hepatic coma. Plasma noradrenaline remained elevated or even further increased during the course of hepatic coma, whereas adrenaline was elevated less frequently. In eight of the ten patients with hepatic coma octopamine was again not detectable in plasma. Only in two patients high levels of octopamine up to 59.5 ng/ml could be found in addition to increased noradrenaline concentrations. The infusion of the branched chain amino acid L-valine had no influence on the plasma level of either noradrenaline or octopamine.The data indicate that the sympathetic nervous system is activated during the course of hepatic coma. An accumulation of octopamine is not a common finding in chronic liver disease and hepatic coma. Since in the two patients with elevated octopamine levels the rise in octopamine occured concomitantly with a rise in noradrenaline, a displacement of noradrenaline by the false neurotransmitter octopamine in the noradrenergic neuron of the peripheral sympathetic nervous system seems unlikely. The results indicate that the development of hypotension in the course of liver cirrhosis and hepatic coma cannot be related to a deficiency of noradrenaline.ZusammenfassungDie Plasmaspiegel von Adrenalin, Noradrenalin und Octopamin wurden mit Hilfe radioenzymatischer Methoden bei neun ambulanten Zirrhose-Patienten mit Enzephalopathie und bei zehn Patienten im Coma hepaticum (Comagrad III–IV) bestimmt. Bei den Zirrhose-Patienten wurden sowohl normale als auch erhöhte Plasmaspiegel von Noradrenalin gemessen. Octopamin war im Plasma dieser Patienten sowie bei zehn gesunden Kontrollpersonen nicht nachweisbar. Erhöhte Noradrenalinspiegel im Plasma waren bei allen Patienten im Coma hepaticum vorhanden. Die Noradrenalinkonzentration im Plasma blieb auch während des Comaverlaufes erhöht oder stieg weiter an. Der Adrenalinplasmaspiegel war hingegen nicht regelmäßig erhöht. In acht der zehn Patienten war Octopamin wiederum nicht nachweisbar. Nur bei zwei Coma-Patienten konnten Octopaminspiegel bis zu 59,5 ng/ml bei gleichzeitiger Erhöhung der Noradrenalinkonzentration gefunden werden. Die Infusion der verzweigtkettigen Aminosäure L-Valin beeinflußte weder den Noradrenalin- noch den Octopaminspiegel.Die Ergebnisse sprechen dafür, daß die Aktivität des sympathischen Nervensystems im Coma hepaticum erhöht ist. Eine Akkumulierung von Octopamin ist kein charakteristischer Befund bei chronischer Lebererkrankung und hepatischem Coma. Nachdem bei zwei Coma-Patienten die Akkumulierung von Octopamin bei einer gleichzeitigen Erhöhung des Noradrenalinspiegels auftrat, erscheint eine Verdrängung von Noradrenalin durch den falschen Neurotransmitter Octopamin im noradrenergen Neuron des peripheren Sympathikus unwahrscheinlich. Die Resultate sprechen dafür, daß die Entwicklung einer Hypotension im Rahmen der Leberzirrhose und des Coma hepaticum nicht auf einen Mangel an Noradrenalin zurückzuführen ist.

Fat elimination in acute renal failure

Lipid metabolism and elimination of parenterally administered fat were investigated in 15 patients with acute renal failure (ARF). The mean triglyceride level was elevated to 2.56 +/- 1.43 mmol/l and the mean cholesterol level was 3.32 +/- 0.66 mmol/l, which is slightly below the normal range. A type IV hyperlipoproteinaemia was present in 47 per cent of the patients. The triglyceride content of LDL and VLDL was elevated and the cholesterol concentration of HDL and of LDL was reduced markedly. The fractional removal rate of triglycerides (K2) evaluated by an intravenous fat tolerance test using a bolus technique was reduced to 2.44 +/- 1.56 per cent/min which is about half of normal and correspondingly the elimination half life was prolonged to 28.4 min. No correlation could be demonstrated between the impairment of fat elimination and residual renal function, basal and VLDL triglyceride concentration or HDL cholesterol content.

Influence of fluid replacement on extravascular lung water (EVLW) in patients with diabetic ketoacidosis.

Fluid replacement is a major issue in the treatment of patients with diabetic ketoacidosis. During this therapy, development of pulmonary edema has been reported and attributed to an increase in pulmonary microvascular pressure and a decrease in colloid-osmotic pressure (COP). Because clinically apparent pulmonary edema is associated with an increase in extravascular lung water (EVLW) and impairment of pulmonary gas exchange, we studied the effect of fluid replacement on EVLW, COP, pulmonary hemodynamics and gas exchange parameters in 8 patients with diabetic ketoacidosis (blood glucose>300 mg/dl, pH<7.1). EVLW was estimated by the thermal-dye technique. All variables were successively determined upon adminssion (A), after initial fluid replacement (IFR), when glucose had fallen below 180 mg/dl, after 8 h of intravenous glucose treatment (G), and after 24 h of total parenteral nutrition (TPN). Despite a total net fluid intake of 6.0±1.61, a significant decrease (p<0.001) in COP from 29.6±5.5 at A to 18.8±2.2 mmHg after TPE and a significant increase (p<0.001) in PCWP from 4±2 at A to 10±3 mmHg after TPE, EVLW remained almost unchanged. EVLW was 5.1±2.8 at A, 5.3±2.1 after IFR, 4.8±1.4 after G, and 5.3±1.7 ml/kg after TPN. However, PaO2 decreased from 137±17 at A to 87±10 mmHg after TPE (p<0.001), while Qs/Qt increased significantly (p<0.05). The alterations in gas exchange may be indicative of pulmonary dysfunction but as they were not associated with accumulation of EVLW, they may as well reflect the compensation of metabolic derangements in diabetic ketoacidosis.

Lung perforation by nasogastric feeding tubes.

Endotracheal misdirection of narrow bore nasogastric feeding tubes resulted in perforation of the lung, pneumothorax and hydrothorax in two intensive care patients. Both were intubated with cuffed endotracheal low pressure tubes, one patient was on respirator therapy with neuromuscular relaxation. Feeding tubes were inserted by experienced personnel with the assistance of a steel stylet without difficulties. Aspiration of fluid was misinterpreted as proof of correct positioning, the liquid being however pleural effusion and not gastric juice. Similarly auscultation of gurgling sounds in the upper epigastrium was not a reliable sign of intragastric position. Insertion of nasoenteric feeding tubes may be complicated by perforation of the upper gastrointestinal tract and lung in poorly responsive patients with cuffed endotracheal devices during neuromuscular blockage. In these patients a laryngoscope and forceps should be used to ensure free passage of the tube into the oesophagus. Röntgenographic confirmation of correct positioning of the tube immediately after insertion is mandatory.

Loading and Maintenance Dose for the Determination of Amino Acid Kinetics in Plasma

Intravenous bolus kinetics of amino acids and calculation of the kinetic parameters with an 1-compartment model revealed weak spots. Therefore, a new study design with a loading and maintenance dose and description of the plasma concentration time data with a 2-compartment model was created and studied in 9 healthy volunteers. After an over night fast the amino acid mixture Thomaeamin n 10% was infused with a loading dose of 20 mg AA/kg-1 X min-1 for 5 min and a maintenance dose of 5 mg AA/g-1 X min-1 for 55 min. The postinfusion period lasted 120 min. The PAA was determined with a Biotronic LC 6001 and the kinetic parameters were calculated by a Wang 2200 computer with the TOPFIT program package. The results showed mean values (means +/- SE) of the volume distribution between 4.7 +/- 0.6 till 9.4 +/- 1.8 liters, an elimination rate constant of 1.7 +/- 0.5 till 11.0 +/- 2.0 h-1, a total clearance of 186 +/- 37 till 846 +/- 66 ml X min-1 and transfer or endogenous production rate between 12 +/- 0.8 till 135 +/- 16 mumol kg-1 X h-1. The total transfer amounts to 17.6 mmol kg-1 X d-1 (= 2.2 g AA/kg-1 X d-1). It can be concluded that an optimal study design for the investigation of AA kinetics should increase the PAA levels 2-3 fold above basal during the infusion period.(ABSTRACT TRUNCATED AT 250 WORDS)