B. Günther

Low-dose bradykinin infusion reduces endogenous glucose production in surgical patients

The systemic effect of low-dose bradykinin infusion on total body glucose production and arterial substrate concentrations was examined during D5W infusion (1.0 mg/kg/min) in five normal-weight postsurgical subjects and compared to the response in four saline infused control patients, well matched for age, weight, and degree of postoperative stress. The primed-constant infusion of 6,6-d2-glucose was used to determine the rate of endogenous glucose production. After a basal period of 90 minutes, subjects in the study group were infused with bradykinin at increasing rates of 2.0 and 4.0 micrograms/kg/h, each infusion rate lasting for 90 minutes, whereas in controls corresponding amounts of saline were given. After 75 minutes of bradykinin, endogenous glucose production was significantly reduced as compared to basal values (1.63 +/- 0.21 mg/kg/min, P less than .0125 v 2.20 +/- 0.35 basal). This was accompanied by a significant reduction in arterial concentrations of glucose, lactate, pyruvate, and alanine. Corresponding concentrations of insulin, glucagon, glycerol, free fatty acids, and ketone bodies, as well as mean arterial blood pressure and heart rate was not affected by bradykinin. In the control group no significant changes in substrate and hormone concentrations, or the rate of glucose production were observed. The higher bradykinin infusion rate did not further affect substrate metabolism or systemic hemodynamics. These results demonstrate the inhibitory effect of low-dose bradykinin on glucose production in surgically stressed patients. The stimulation of hepatic prostaglandin synthesis by bradykinin may explain the results since prostaglandins are known to exert an inhibitory effect on hormone stimulated gluconeogenesis and glycogenolysis in liver tissue.

IMPROVEMENT OF GLUCOSE ASSIMILATION AND PROTEIN DEGRADATION BY BRADYKININ IN MATURITY ONSET DIABETICS AND IN SURGICAL PATIENTS

Impaired glucose assimilation and accelerated protein degradation are concomitant symptoms of insulin deficiency as in diabetes and also of reduced insulin sensitivity as during postoperative stress. Since it is known that kininogen levels are reduced in traumatic stress (1) and that kinin liberation is involved in the peripheral action of insulin (2,3), the influence of kinin infusion on carbohydrate tolerance and urinary nitrogen excretion was investigated in normal and diabetic subjects and in surgical patients.

Quality of treatment in routine care in a population sample of rectal cancer patients.

Variations in compliance with rectal cancer treatment guidelines and the effect of quality indicators on long-term outcomes were investigated with data from the Munich Cancer Registry. Patients diagnosed between 1996 and 1998 with an invasive primary rectal tumor which was resected were included in these analyses (n=884). Median follow up was 5.7 years. Relative and overall survival was examined. Adjusted survival was predicted by UICC stage, grade, age, local recurrence, and residual tumor status. UICC III patients receiving the recommended adjuvant therapy had a significant survival advantage in the multivariate model; UICC II patients did not. Even if there were no significant survival differences there were significant treatment and outcome (regarding local recurrence) variations between hospitals. The variations between hospitals refer to different quality indicators in the individual hospitals. The outcome (regarding survival) appears good in Munich and is comparable with other population studies. Fewer local recurrences, better reporting of the TME technique, greater use of combined therapy and fewer stomas, however, may improve the quality of care in Munich. Variations in care between hospitals should therefore be monitored and controlled. Detailed and frequent feedback to the clinicians is vital to improve quality of care and is possible with cancer registries.

Minor role of ketone bodies in energy metabolism by skeletal muscle tissue during the postoperative course.

To evaluate changes of peripheral ketone body (KB) metabolism after operation, muscle metabolism in postsurgical patients was studied at 3 hours (SI) and 24 hours (SII) after surgery by the forearm catheter technique. Data were compared to those of equivalent fasted controls (CI, CII). In a manner consistent with enhanced mobilization of endogenous substrate stores, arterial concentrations of free fatty acids (FFA), 3-hydroxybutyrate (3-HOB), and acetoacetate (AcAc) were markedly elevated immediately after surgery. This increase was accompanied by a rise in muscular utilization of AcAc (SI: 0.21 +/- 0.05 mumol/100 g/min; CI: 0.08 +/- 0.05, p less than 0.05) and 3-HOB (SI: 0.24 +/- 0.06 mumol/100 g/min; CI: 0.11 +/- 0.01, p less than 0.05). Surprisingly, on the first postoperative day, concentrations of AcAc and 3-HOB fell below those of fasting controls. Concomitantly, the utilization rate of AcAc by muscle (SII: 0.07 +/- 0.03 mumol/100 g/min; CII: 0.27 +/- 0.04, p less than 0.05) was significantly lower in patients than in controls. Reduction of the fractional extraction rate of AcAc (SI: 38.4 +/- 3.8%; SII: 24.0 +/- 6.1%, p less than 0.05), as well as a net production of 3-HOB by muscle (SII: -0.08 +/- 0.05 mumol/100 g/min; CII: 0.49 +/- 0.13, p less than 0.05) 24 hours after surgery indicated a reduced peripheral capacity for KB removal. Since this finding was related to a significantly higher rate of muscular glycerol production (SII: -0.13 +/- 0.03 mumol/100 g/min; CII: -0.06 +/- 0.02, p less than 0.05), one may suggest that increased intramuscular availability of FFA from triglyceride hydrolysis was responsible for the impairment of peripheral KB utilization. These results indicate that KBs contribute little to energy metabolism in skeletal muscle tissue in the late postoperative phase.

Substrate Balances Across Skeletal Muscle Tissue in Severe Sepsis

Substrate metabolism of skeletal muscle was studied by the forearm technique in eight patients with severe sepsis. The data were compared to those of 13 patients after elective surgery. In the septic group forearm blood flow was increased, but muscular utilisation of oxygen was diminished. Arterial concentrations of free fatty acids and ketone bodies were low. Thus, both only played a minor role in the supply of skeletal muscle with substrates. From the decreased production of lactate and alanine and the comparable utilisation of glucose we conclude that in the septic patients energy expenditure of skeletal muscle was mainly met by oxidation of glucose. In contrast to reduced lipolysis of adipose tissue intramuscular lipolysis may still be working since muscular production of lactate and glycerol was correlated. These findings suggest a changing pattern of arterial supply of substrates and utilisation of substrates by skeletal muscle during deterioration of clinical condition in the course of sepsis.

Untersuchungen zur postoperativen Insulinresistenz von Lipolyse und Ketogenese mit Hilfe der Glukose-Clamp-Technik

Der Einfluβ unterschiedlicher Insulindosen auf die Bereitstellung von freien Fettsauren und Ketonkorpern wurde bei sieben stoffwechselge-sunden Patienten am ersten Tag nach mittelgroβen Abdominaleingriffen mit Hilfe der Glukose-Clamp-Technik untersucht. Durch die Infusion von 0,2 bzw. 1,0 mE Insulin/kg KG und Minute uber jeweils neunzig Minuten wurde der Insulinspiegel auf den doppelten bzw. siebenfachen Ausgangswert angehoben. Bereits die minimale Insulingabe von 0,2 mE/kg KG und Minute fuhrte zu einem signifikanten Abfall der freien Fettsauren und Ketonkorper. Die Studie zeigt, daβ selbst im Postaggressionsstoffwechsel die Fettgewebslipolyse durch minimale Insulindosen reduziert werden kann.

Dose — Dependent Effects of Bradykinin Infusion in Postoperative Patients

The physiologoical role of locally liberated bradykinin from tissue kallikrein is still not known.The kallikrein-kinin system may be involved in many functions as vascular tone and blood pressure regulation,salivary secretion, resorption, diffusion and membrane permeability of elektrolytes, energy and substrate metabolism and inflammation (Fritz 1983). In former years mainly the vascular and inflammatory effects of bradykinin were studied with high BK-infusions in humans.In contrast,we observed metabolic effects already with very low BK-doses in diabetics and postoperative patients (Wicklmayr 1977,Jauch 1986),without cardiovascular side effects. Therefore we intended to study the BK-dose response relationship of different described alterations during BK-infusion in patients.

Bradykinin infusion in long term postoperative parenteral nutrition improves nitrogen balance and protein synthesis.

The kallikrein-kinin prostaglandin system has been shown to exerts several effects on human substrate metabolism.Bradykinin infusion may diminish postoperative insulin resistance of the whole body and increase muscular glucose uptake (Jauch et al 1986).Furthermore BK reduces the postoperatively increased glucose production of the liver (Jauch et al 1988). In volunteers as well as in diabetics it was shown that bradykinin acts together with insulin and has an insulin-like activity (Dietze et al 1982).

Excessive glucose administration in severe septic patients: a possible cause of fatty degeneration in skeletal muscle tissue

The ability to oxidise fatty acids was found to be impaired in severe septic patients with multiple organ failure. Thus, glucose still represents the major substrate for total parenteral nutrition in such conditions. To evaluate the effect of a high glucose load on peripheral substrate metabolism (priming dose: 10 g/5 min, constant infusion rate: 0.5g/kg·h) we studied muscle metabolism in five patients with hypodynamic septic shock (S) using the forearm technique. Data were compared to those of five patients 3 h after elective surgery (O), who were believed to show the typical metabolic pattern of a compensated stress response. Arterial and deep venous concentrations of glucose, lactate, pyruvate, acetoacetate (AcAc), β-hydroxbutyrate (β-HOB), free fatty acids (FFA), glycerol, oxygen, insulin, adrenalin and noradrenalin were determined in the basal period and during glucose infusion. Consistent with an impaired mobilisation of endogenous substrate stores basal arterial concentrations of FFA, β-HOB and AcAc were markedly lower in severe sepsis. In O glucose infusion resulted in a continuous increase of forearm glucose uptake, compensating falling rates of FFA and ketone body uptake due to decreased arterial supply. On the contrary, in S arterial supply of FFA, AcAc and β-HOB almost remained unchanged during glucose infusion. Nevertheless, muscular balances of FFA were affected significantly, changing from a basal release into uptake during glucose infusion (basal: −0.23 ± 0.17 μmol/100 g min; 10 min of glucose infusion: 0.30 ± 0.31; 20 min: 0.95 + 0.92∗; 40 min: 0.32 ± 0.26∗; ∗: p<0.05). This was related to a marked increase in muscular glucose uptake exceeding that of O significantly. Concomitant rates of muscular glycerol release stayed low indicating reduced hydrolytic rate of muscle triglycerides. Thus peripheral lipogenesis might arise from excessive glucose administration in such conditions due to an increased rate of muscular re-esterification of FFA. To avoid this adverse side effect administration of glucose calories should be limited to basal energy requirements.

353. Der Muskelstoffwechsel unter dem Einfluß von Fettinfusionen

SummaryIn 12 volunteers and in 15 patients recovering from abdominal surgery, we investigated the effect of a fat infusion containing middle-chain triglyceride (MCT) or long-chain triglycerides (LCT) on skeletal muscle metabolism by the forearm-catheter technique. Both infusions led to an increase in serum triglycerides, free fatty acids (FFA), and glycerol. MCT showed a more pronounced increase in FFA. Postoperatively both emulsions were cleaved more slowly. Marked alterations in lipoprotein levels were noted with MCT. MCT was preferentially taken up by forearm tissue. Glucose and ketone body extraction was diminished by both infusions, as was amino acid release. Lipid infusions seem to be a rational therapeutical approach.ZusammenfassungBei 12 gesunden Probanden und 15 operierten Patienten untersuchten wir mit der Vorderarmtechnik den Einfluß von mittel- und langkettigen Triglyceriden auf den Muskelstoffwechsel. Die Bereitstellung von Fettsäuren führte jeweils zu einer musculären Fettaufnahme und verminderten Glucose- und Ketonkörperextraktion als auch zu einer verminderten Aminosäurenabgabe. Postoperativ war dabei die Glyceridelimination vermindert. MKT führt im Vergleich zu LKT zu stärkeren Veränderungen der Lipoproteine, zu vermehrter Freisetzung von freien Fettsäuren und Glycerol und wird bevorzugt musculär aufgenommen. Beide Fettemulsionen erscheinen effektive Energiesubstrate in der postoperativen Ernährung darzustellen.