J.H. Henriksen

Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty‐three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n = 11) or a placebo (P group, n = 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance (CNa), lithium clearance (CLi), osmolal clearance (COsm), and urine sodium concentration (UNa) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 ± 19 versus 92 ± 25 mL/min, P < 0.005) and in the R group (31 ± 19 versus 41 ± 31 mL/min, P < 0.05) after terlipressin. In the N group, terlipressin induced an increase in CNa (0.89 ± 0.21 versus 1.52 ± 1.45 mL/min, P < 0.05), CLi (17.3 ± 8.9 versus 21.5 ± 11.6 mL/min, P < 0.05), and COsm (2.10 ± 0.81 versus 3.06 ± 2.0 mL/min, P < 0.05). In the R group, terlipressin induced an increase in CNa (0.11 ± 0.18 versus 0.35 ± 0.40 mL/min, P < 0.05) and CLi (5.5 ± 4.2 versus 9.5 ± 8.55 mL/min, P < 0.05). UNa increased in both groups after terlipressin (P < 0.005). Plasma norepinephrine (P < 0.05) and renin (P < 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. Conclusion: The vasopressin 1 receptor agonist terlipressin improves renal function and induces natriuresis in patients with cirrhosis and ascites without HRS. Vasoconstrictors may represent a novel future treatment modality for these patients. (HEPATOLOGY 2007.)

Elevated circulating plasma endothelin-1 concentrations in cirrhosis

As endothelin-1 (ET-1), a potent vasoconstricting peptide, may play a role in the circulatory derangement and renal impairment in cirrhosis, the aim of the present study was to investigate plasma concentrations of ET-1 in different vascular beds in relation to clinical and biochemical parameters of liver function. Median brachial venous ET-1 concentrations were substantially higher in patients with cirrhosis (3.40 pg/ml, range: 1.25-7.84, n = 24) than in controls (1.53 pg/ml, range: 0.78-2.12, n = 11) (P < 0.00005). In patients with cirrhosis ET-1 was directly correlated to serum creatinine (r = 0.70, P < 0.0001) and aspartate aminotransferase (r = 0.44, P < 0.03) and negatively correlated to serum sodium (r = -0.58, P < 0.003). In patients who underwent liver vein catheterization (n = 8), no significant differences were found in ET-1 plasma concentration between the liver, renal, or femoral veins on the one hand and the femoral artery on the other (P > 0.1), indicating no major net elimination or release in the liver, kidney or lower limb. A significant negative correlation was found between systolic and diastolic blood pressures on the one hand and circulating ET-1 on the other (r = -0.71, P < 0.05). In conclusion, circulating ET-1 is elevated in cirrhosis and related to markers of systemic circulation and renal function, thus suggesting a role for ET-1 in the circulatory derangement and nephropathy in cirrhosis. Locations of major net elimination or release of ET-1 were not identified.

Circulating noradrenaline and central haemodynamics in patients with cirrhosis.

Cardiovascular haemodynamics and circulating catecholamines were studied in 22 patients with cirrhosis. Arterial plasma noradrenaline (NA) was significantly increased (median, 0.48 ng/ml, versus controls, 0.24 ng/ml; n = 17; P less than 0.001), indicating enhanced sympathetic nervous activity. Heart rate was also increased (88 min-1 versus controls, 68 min-1; P less than 0.001), and mean arterial blood pressure was significantly decreased (81 mm Hg, versus controls, 88 mm Hg; P less than 0.002). Cardiac output was above the upper reference limit in eight patients and below the lower limit in two patients. Arterial NA was inversely correlated to stroke volume (r = -0.55; P less than 0.01) and to cardiac output (r = -0.53; P less than 0.02). Statistically significant relationships could not be demonstrated between NA and heart rate, arterial blood pressure, or right atrial pressure, but NA was slightly positively correlated to systemic vascular resistance (r = 0.51; P less than 0.02). The results may suggest that a relatively insufficient cardiac performance in the hyperkinetic circulatory state in cirrhosis may elicit an enhanced sympathetic nervous activity, which may contribute to maintenance of cardiovascular homeostasis.

Increased arterial compliance in decompensated cirrhosis

BACKGROUND/AIMSnIn patients with cirrhosis, the systemic circulation is hyperdynamic with low arterial blood pressure and reduced systemic vascular resistance. The present study was undertaken to estimate the compliance of the arterial tree in relation to severity of cirrhosis, circulating level of the vasodilator, calcitonin gene-related peptide (CGRP) and mean arterial blood pressure (MAP).nnnMETHODSnArterial compliance (COMPart=deltaV/deltaP) was determined as the stroke volume relative to pulse pressure (i.e. systolic minus diastolic blood pressure) during a haemodynamic evaluation of portal hypertension in patients with biopsy-verified cirrhosis (Child-Turcotte classes A/B/C=10/15/6).nnnRESULTSnCOMPart was significantly higher in cirrhotic patients (n=31) than in controls (n=10) (1.44 vs 1.00 x 10(-3) l/mmHg, p<0.01). It increased significantly through the Child-Turcotte classes A, B, and C (1.02, 1.47, and 2.1 x 10(-3) l/mmHg, respectively, p=0.03). The stroke volume did not change significantly with the severity of the disease, but pulse pressure decreased through class A, B, and C (79, 65, and 50 mmHg, respectively, p<0.01). COMPart was slightly, but significantly correlated to the circulating level of CGRP (r=0.34, p<0.05), and a substantial but inverse correlation was present to MAP (r= -0.63, p<0.002).nnnCONCLUSIONSnElevated arterial compliance in cirrhosis is directly related to the severity of the disease and to the elevated level of circulating vasodilator peptide CGRP, and inversely related to the level of arterial blood pressure. The altered static and dynamic functions of the arterial wall in cirrhosis may have implications for the circulatory and homoeostatic derangement, and potentially for therapy with vasoactive drugs.

Vasoactive substances in the circulatory dysfunction of cirrhosis

Patients with cirrhosis and portal hypertension exhibit characteristic haemodynamic changes with a hyperkinetic systemic circulation, abnormal distribution of the blood volume, and neurohumoral dysregulation. Moreover, the circulating levels of several vasoactive substances may be elevated. Splanchnic vasodilatation is of pathogenic significance for the low systemic vascular resistance and abnormal volume distribution, which are important elements in the development of the concomitant cardiac dysfunction, recently termed cirrhotic cardiomyopathy. The systolic and diastolic functions are impaired with direct relation to the degree of liver dysfunction. Significant pathophysiological mechanisms seem to include a reduced beta-adrenergic receptor signal transduction, defective cardiac excitationcontraction coupling, and conductance abnormalities. Various vasodilators, such as nitric oxide and calcitonin gene-related peptide, are among candidates in the vasodilatation and the increased arterial compliance recently described in advanced cirrhosis. Reflex-induced enhanced sympatho-adrenal activity, activation of the renin-angiotensin-aldosterone system, and elevated circulating vasopressin and endothelin-1 are implicated in the haemodynamic counter-regulation in cirrhosis. Recent research has focused on the assertion that the haemodynamic and neurohumoral abnormalities in cirrhosis are part of a general cardiovascular dysfunction influencing the course of the disease, with reduction of organ function and sodium-water retention as the outcome. These aspects are relevant to therapy.

Relation of Calcitonin Gene-Related Peptide to Systemic Vasodilatation and Central Hypovolaemia in Cirrhosis

BACKGROUNDnThe aetiology of the reduced systemic vascular resistance and abnormal filling of the vascular bed in cirrhosis is still obscure. As increased concentrations of the potent vasodilator calcitonin gene-related peptide (CGRP) have recently been reported in cirrhosis, we related CGRP to central and peripheral haemodynamics in patients with cirrhosis.nnnMETHODSnThirty-one cirrhotic patients and six control subjects underwent an investigation with determination of systemic haemodynamics and circulating CGRP.nnnRESULTSnCirculating CGRP was significantly increased in patients with cirrhosis (P < 0.02) and covaried directly with the severity of cirrhosis (P < 0.02). The increased CGRP covaried negatively with the reduced systemic vascular resistance (P < 0.02), the reduced central blood volume (P < 0.01), and reduced central circulation time (P < 0.002) and positively with the non-central blood volume (P < 0.05).nnnCONCLUSIONSnThese results suggest that increased CGRP may play a role in the systemic vasodilatation in cirrhosis and may contribute to the abnormal distribution of the blood volume, which may lead to abnormal sodium and water handling.

Tachyphylaxis associated with repeated epidural injections of lidocaine is not related to changes in distribution or the rate of elimination from the epidural space.

The relationship between tachyphylaxis (measured as a decrease in the rate of regression of sensory levels of analgesia) during repeated epidural injections of lidocaine and both the distribution of lidocaine within the epidural space (as measured by spread of simultaneous injection of the tracer technetium-99m diethylenetriaminepentaacetate [99mTc-DTPA]) and elimination of lidocaine from the epidural space (as measured by serum concentrations of lidocaine) was investigated in 18 patients undergoing minor surgery during lumbar epidural analgesia. Twelve patients received four injections of 20 mL of 2% lidocaine at 2-hr intervals. Epidural distribution was assessed by injection of 99mTc-DTPA diluted in saline on the preoperative day and diluted in an equal volume of 2% lidocaine on the morning before surgery and again after the fourth injection of lidocaine 6 hr later. The distribution of 99mTc-DTPA in the epidural space was unchanged during the three measurements despite significant tachyphylaxis in both sensory analgesia and motor blockade (11 of 12 patients had sensory analgesia 2 hr after the first injection in contrast to only 3 of 12 patients during the third injection). In another six patients 20 mL of 2% lidocaine were injected three times at 2-hr intervals before surgery, with measurements of serum concentrations of lidocaine after the first and last injections. Despite tachyphylaxis (no patient had sensory analgesia 2 hr after the third injection), there was no difference in the rate of disappearance of lidocaine from the epidural space as assessed by plasma lidocaine concentration curves during the first and third injection (0.5 ± 0.1 and 0.3 ± 0.04 μg·mL−1·min−1, respectively). The results confirm the development of tachyphylaxis during repeated epidural injections of lidocaine and suggest that tachyphylaxis is caused by factors other than increased elimination from the epidural space or altered distribution of lidocaine within the epidural space.

Endoscopic Doppler Ultrasound for Measurement of Azygos Blood Flow: Validation against Thermodilution and Assessment of Pharmacological Effects of Terlipressin in Portal Hypertension

Background: Endoscopic ultrasound (EUS) is a new modality allowing real-time flow measurements by means of the Doppler technique. The aim of the study was to evaluate azygos blood flow measurements by endoscopic ultrasound. Methods: Measurements of azygos blood flow by EUS and by the thermodilution technique were compared in 20 patients with portal hypertension. The ability of EUS flowmetry to detect changes in the azygos and portal venous flow after an intravenous dose of 2 mg of terlipressin was evaluated in 13 of the patients in a double-blind, randomized, placebo-controlled, cross-over design. Results: The EUS Doppler and thermodilution measurements correlated significantly (R = 0.81, P < 0.001). The azygos blood flow was found to be 14% higher by the EUS method than by thermodilution. The coefficient of variation of the EUS Doppler measurements of the azygos blood flow was 14.8%. After administration of terlipressin, the azygos blood flow, as measured by EUS Doppler, decreased significantly by 23% from 915 to 704 ml/min (P = 0.014) and the portal venous flow decreased by 28% from 1170 to 789 ml/min (P = 0.03). No effects of placebo were detected. Conclusions: These results show that EUS measurement of the azygos blood flow correlate strongly to the measurements by the thermodilution technique, and EUS is moreover well tolerated by the patients. The method is applicable for monitoring pharmacological effects on the superior porto-systemic collateral circulation and portal venous flow in patients with portal hypertension.BACKGROUNDnEndoscopic ultrasound (EUS) is a new modality allowing real-time flow measurements by means of the Doppler technique. The aim of the study was to evaluate azygos blood flow measurements by endoscopic ultrasound.nnnMETHODSnMeasurements of azygos blood flow by EUS and by the thermodilution technique were compared in 20 patients with portal hypertension. The ability of EUS flowmetry to detect changes in the azygos and portal venous flow after an intravenous dose of 2 mg of terlipressin was evaluated in 13 of the patients in a double-blind, randomized, placebo-controlled, cross-over design.nnnRESULTSnThe EUS Doppler and thermodilution measurements correlated significantly (R=0.81, P < 0.001). The azygos blood flow was found to be 14% higher by the EUS method than by thermodilution. The coefficient of variation of the EUS Doppler measurements of the azygos blood flow was 14.8%. After administration of terlipressin, the azygos blood flow, as measured by EUS Doppler, decreased significantly by 23% from 915 to 704 ml/min (P = 0.014) and the portal venous flow decreased by 28% from 1170 to 789 ml/min (P = 0.03). No effects of placebo were detected.nnnCONCLUSIONSnThese results show that EUS measurement of the azygos blood flow correlate strongly to the measurements by the thermodilution technique, and EUS is moreover well tolerated by the patients. The method is applicable for monitoring pharmacological effects on the superior porto-systemic collateral circulation and portal venous flow in patients with portal hypertension.

Pulmonary extraction of circulating noradrenaline in man

Abstract Pulmonary plasma kinetics of endogenous noradrenaline (NA) and tritium labelled L‐noradrenaline (3H‐NA) was studied in fifteen subjects during pulmonary arterial catheterization. Plasma NA concentration in femoral artery ranged from 0·5 to 8·2 nmol l−1, mean 2·3 nmol l−1, which was not significantly different from that of age‐matched control subjects. The lungs extracted both endogenous NA and 3H‐NA significantly, but no significant pulmonary extraction of endogenous adrenaline was found. The pulmonary arterial‐systemic arterial extraction ratio of NA was mean 0·08 (n= 9) as compared to that of 3H‐NA: mean 0·07 (n= 8, NS). Likewise mean pulmonary clearances of NA and 3H‐NA were not significantly different (97 ml min−1x M−2v. 124 ml min−1x M−2, NS). Estimated whole‐body clearance of noradrenaline was mean 0·80 1 min−1x M−2(n= 6) while the pulmonary clearance amounted to 19% of this value. The small, but significant, pulmonary extraction of circulating noradrenaline implies that whole‐body clearance, as estimated from infusion rate and systemic arterial sampling, will be overestimated by approximately 7%. As pulmonary extraction of NA and 3H‐NA was almost identical, the results indicate no significant pulmonary contribution to circulating noradrenaline.

Continuous infusion of tracer norepinephrine may miscalculate unidirectional nerve uptake of norepinephrine in humans

In order to evaluate uptake kinetics of norepinephrine (NE) in different tissues, a catheterization study was performed in control subjects (n = 6) and patients with enhanced sympathetic nervous activity (cirrhosis, n = 12) during constant intravenous infusion of L[3H]norepinephrine ([3H]NE) for 75 minutes. In spite of a higher NE spillover from kidneys in patients compared with controls (82 vs. 49 ng/min, p less than 0.01), renal extraction ratios of [3H]NE were similar in the two groups (0.33 vs. 0.32, NS), and no significant change was observed during the time of infusion. In contrast, liver-intestine extraction ratios of [3H]NE decreased significantly and equally with infusion time in patients (from 0.57 to 0.44, p less than 0.01) and controls (from 0.59 to 0.46, p less than 0.01). This was observed despite the fact that spillover of NE from this vascular bed was observed only in patients with cirrhosis and not in controls (41 vs. -5 ng/min, p less than 0.02). In the lower limb, net release of NE was similar in patients and controls, and extraction ratios of [3H]NE decreased almost equally with infusion time (from 0.35 to 0.30, p less than 0.01 and from 0.40 to 0.24, p less than 0.1, respectively). Whole-body clearance of [3H]NE decreased over time in patients (-6%, p less than 0.01) and controls (-20%, p less than 0.01), but significant difference was not observed between the groups. We conclude that failure to attain a steady state with respect to [3H]NE removal was demonstrated in areas of large tissue volume relative to blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)