Hemodynamic effects of hypothyroidism induced by methimazole in normal and portal hypertensive rats

Portal hypertension is accompanied by a hyperdynamic circulatory state that shares some similarities with thyrotoxicosis. This study was conducted in order to investigate the hemodynamic effects of hypothyroidism in a rat model with portal hypertension induced by partial portal vein ligation (PVL). Four groups of 10 rats each were studied: normal control and hypothyroid rats, and PVL control and hypothyroid rats. Hypothyroidism was induced by methimazole 0.04% in drinking water. Hemodynamic measurements were performed using the radioactive microsphere technique. Induction of hypothyroidism was confirmed by elevated TSH levels. In the PVL groups, hypothyroidism ameliorated the hyperdynamic circulation. Portal venous inflow and portal pressure dropped significantly: 7.1±0.2 vs 4.8±0.3 ml/min/100 g body wt (P<0.01) and 13.4±0.9 vs 10.9±0.8 mm Hg; (P<0.01), respectively. In normal rats, hypothyroidism was manifested by a hypodynamic circulatory state. These results demonstrate that hypothyroidism induced by methimazole is followed by amelioration of the hyperdynamic circulation, normalization of portal venous inflow, and reduction of portal pressure.     

Clinical events after transjugular intrahepatic portosystemic shunt: Correlation with hemodynamic findings

Background & Aims: Transjugular intrahepatic portosystemic shunt (TIPS) procedures are increasingly being used, but the relationship between the hemodynamic effects of TIPS and the clinical events on follow-up remains undefined. Hence, we have investigated the hemodynamic correlations of portal hypertension–related events after a TIPS procedure. Methods: Prospective follow-up of 122 cirrhotic patients who had a TIPS procedure performed because of variceal hemorrhage was conducted. Results: The portacaval pressure gradient (PPG) significantly decreased after the TIPS procedure (from 19.7 ± 4.6 to 8.6 ± 2.7 mm Hg; P > 0.001), but increased thereafter and at rebleeding (n = 25) was >12 mm Hg in all patients (18.4 ± 4.6 mm Hg). Twenty-six patients developed ascites; the PPG (measured in 19) was always >12 mm Hg. Increasing the PPG to >12 mm Hg occurred very frequently (83% at 1 year). Within 1 year, 77% of patients underwent balloon angioplasty or restenting. However, 80% had again a PPG of >12 mm Hg 1 year after reintervention. Hepatic encephalopathy developed in 31% of patients at 1 year; 21 of 23 patients had a PPG of <12 mm Hg. Conclusions: Total protection from the risk of recurrent complications of portal hypertension after a TIPS procedure requires that the PPG be decreased and maintained <12 mm Hg. However, reintervention will be required in most patients within 1 year and again the second year. On the other hand, such portal decompression is associated with an increased risk of hepatic encephalopathy.GASTROENTEROLOGY 1998;114:1296-1303     

Short- and long-term hemodynamic response to octreotide in portal hypertensive patients: a double-blind,controlled study

Abstract: This randomized, double-blind, placebo-controlled study on the hemodynamic effect of two different doses of octreotide administered subcutaneously was conducted among 20 cirrhotic portal hypertensive patients. The wedged hepatic venous pressure, the hepatic venous pressure gradient, the mean portal venous flow velocity, the resistive index of the superior mesenteric artery, the heart rate and the mean arterial pressure were simultaneously evaluated by hepatic vein catheterization and Doppler flowmetry at baseline, 30 and 45 min after a subcutaneous injection of octreotide [0.10 mg (7 patients), 0.05 mg (7 patients)] and of a placebo (6 patients). The portal blood flow velocity, the resistive index of the superior mesenteric artery, the heart rate and the mean arterial pressure were also measured 2, 4, 6 and 8 h after the injection. The hemodynamic changes observed 30 min after the injection did not differ from those at 45 min and the changes at 2, 4, and 6 h were similar to those at 8 h. A statistically significant decrease, in comparison to the placebo group, was observed 45 min after the injection of the two doses of octreotide in the wedged hepatic venous pressure (cumulative median decrease: —10%, p<0.005), in the hepatic venous pressure gradient (cumulative median decrease: —10%, p<0.005) and in the mean portal flow velocity (cumulative median decrease: —11%, p<0.005). A significant increase in the resistive index of the superior mesenteric artery was observed 45 min after the injection of the two doses of octreotide (cumulative median increase: + 10%, p<0.005). Lower, but significant changes in the mean portal flow velocity and in the resistive index of the superior mesenteric artery persisted until 8 h after the injection of the two doses of octreotide (cumulative median decrease of mean portal flow velocity: —7%, p<0.005 and cumulative median increase of resistive index of the superior mesenteric artery: +4%, p<0.005). Changes in the wedged hepatic venous pressure, the hepatic venous pressure gradient, the mean portal flow velocity and the resistive index of the superior mesenteric artery showed a great variability among patients. These changes were more pronounced in patients injected with the lower dose with no relationship with the plasma drug concentrations. Responder patients showed a significant higher baseline mean portal flow velocity in comparison with nonresponders (15.2±1.7 cm/s vs 11.3 ±1.3 cm/s; p<0.005).     

Hemodynamic effects of acute and chronic administration of vapreotide in rats with cirrhosis

The aim of this study was to assess the hemodynamic effects of acute and chronic administration of vapreotide, a somatostatin analog, in rats with intrahepatic portal hypertension induced by dimethylnitrosamine (DMNA) administration. Acute effects were evaluated at baseline and 30 min after placebo (N = 13) or vapreotide (8 g/kg/hr, N = 13) infusions in DMNA rats. Chronic hemodynamic effects were evaluated using subcutaneous implants for five weeks in anesthetized DMNA rats (placebo: N = 13, vapreotide: N = 13) and in sham rats (placebo: N = 10, vapreotide: N = 10). Hemodynamic measurements included splenorenal shunt blood flow (SRS BF) by the transit time ultrasound (TTU) method and cardiac output by the combined dilution–TTU method. Acute administration of vapreotide significantly decreased SRS BF (–17.3 ± 19 vs –1.1 ± 14%, P < 0.05) and portal pressure (–8 ± 9 vs 0 ± 8%, p < 0.05) compared to placebo without systemic effects. Chronic administration of vapreotide significantly reduced the increase in SRS BF (2.4 ± 1.5 vs 1.2 ± 1.0 ml/min, P < 0.05) and cardiac index (50 ± 15 vs 33 ± 10 ml/min/100 g, P < 0.0001) while portal pressure and blood flow, and mean arterial pressure were not significantly changed compared to placebo. In conclusion, the acute administration of vapreotide decreased collateral circulation blood flow while chronic administration attenuated its development. Vapreotide seems to have a vasoconstrictive effect on collateral circulation.     

Efficacy of Irbesartan, a Receptor Selective Antagonist of Angiotensin II, in Reducing Portal Hypertension

The use of angiotensin II antagonists in the treatment of portal hypertension remains controversial. Our aims were to assess the effect of Irbesartan on portal pressure and to evaluate its safety in cirrhotic patients with portal hypertension. Twenty-five cirrhotic patients were treated in a pilot study with Irbesartan 300 mg orally once daily for 60 days. Hemodynamic evaluations and biochemical tests were performed before therapy and after two months of treatment. Three patients (12%) discontinued treatment for symptomatic arterial hypotension (mean arterial pressure –26.% ± 3.1 versus basal). In the 18 responders, the hepatic venous pressure gradient diminished by a mean of 18.1% ± 10.5 from baseline (p = 0.02); the gradient decreased by 20% or more in only 5 patients (23%). The mean arterial pressure decreased significantly during therapy (92 ± 7 vs 109 ± 25 mm Hg, P < 0.001). In conclusions, Irbesartan induced a marginal reduction in portal pressure and its safety was limited by the pronounced effects on arterial pressure.     

Comparison of vasopressin and triglycyl-lysine vasopressin on splanchnic and systemic hemodynamics in dogs

Triglycyl-lysine vasopressin (tGLVP) is activated in the circulation when theN-triglycyl residue of the molecule is cleaved by endothelial peptidases, releasing lysine vasopressin. We compared the effect of an intravenous bolus dose of tGLVP (20 g/kg) with a constant infusion (2.75 mU/kg/min) of arginine and lysine vasopressin (Pitressin^R) in normal mongrel dogs. Portal pressure was artifactually increased by a constricting flow probe. Baseline values were similar in both groups; at the time of near-maximal reduction in portal pressure, both drugs equally reduced portal venous pressure (38±4 vs 39±4%), superior mesenteric arterial blood flow (40±8 vs 39±9%), portal venous flow (35±4 vs 40±5%), and heart rate (9±2 vs 11±7%. Cardiac output obtained 10–30 min after tGLVP administration was similar to that of VP, and each drug reduced cardiac output significantly when compared with its own baseline (18±4 vs 21±7%). Mean arterial pressure increased similarly with both drugs (11±3 vs 11±3%). The only difference observed was the hepatic arterial flow response. While tGLVP increased HAF 34±11%, the physiologic autoregulatory response to a decrease in portal venous flow and pressure; vasopressin was associated with no such compensatory response (1±6%). Whether this advantage of tGLVP and its more prolonged reduction of portal venous pressure (mean 103 min) are beneficial in the clinical setting requires additional studies.Dr. Groszmann is a recipient of a National Institutes Research Career Development Award AM00670-01. This work was supported by the Medical Research Service of the Veterans Administration.     

Hemodynamic characterization in experimental liver cirrhosis induced by thioacetamide administration

Systemic and splanchnic hemodynamics in experimental liver cirrhosis in rats induced by thioacetamide were evaluated by the radioactive microsphere method. Cardiac output and regional blood flow were measured in conscious and anesthetized control and cirrhotic rats. The conscious thioacetamide-treatment rats had hyperdynamic circulation with an increased cardiac index (300±10 vs 258±3 ml/min/kg body weight,P<0.001) and increased portal venous inflow compared with the controls (64.60±2.4 vs 48.39±0.88 ml/min/kg body weight,P<0.001). Under pentobarbital anesthesia, the hyperdynamic circulation of the cirrhotic rats was maintained, with an increased cardiac index (276±7 vs 229±5 ml/min/kg body weight,P<0.001) and increased portal venous inflow compared with the controls (72.47±3.0 vs 54.08±1.2 ml/min/kg body weight,P<0.001). Portal pressure, portal venous resistance, and portal systemic shunting increased significantly while splanchnic arterial resistance decreased significantly in cirrhotic rats. Thioacetamide-induced cirrhosis is a useful model for the hemodynamic study of portal hypertension and remains useful in hemodynamic studies in the basal state under pentobarbital anesthesia.     

Altered hepatic hemodynamics and improved liver function following intrahepatic vascular infusion of prostaglandin E1

Prostaglandin E1 (PGE1) has cytoprotective effects in the liver. To find how PGE1 influenced hepatic hemodynamics, oxygen metabolism, and hepatic function, we carried out an experimental and a clinical study. PGE1 was continuously administered into the hepatic artery (n = 5) or portal vein (n = 5) at a rate of 0.01 μg/kg per min in healthy mongrel dogs. In the clinical study, in eight patients PGE1 was administered through the hepatic artery at a rate of 0.01 μg/kg per min after hepatic lobectomy. In the experimental study, hepatic hemodynamics and oxygen metabolism did not change during the administration of PGE1 into the portal vein. During administration of PGE1 into the hepatic artery, hepatic arterial flow increased 1.5-fold after administration compared to the rate before administration (P < 0.01). Hepatic arterial pressure, hepatic arterial resistance, and post-sinusoidal resistance significantly decreased after administration (P < 0.01, P < 0.01, and P < 0.05, respectively). Hepatic oxygen supply increased significantly (P < 0.01). In the patients, serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels remained low after surgery, and the recovery of protein synthesis was improved compared with that in eight hepatectomized patients without PGE1 administration (controls). The intrahepatic arterial infusion of PGE1 was considered useful for the recovery of liver function. (Received Apr. 21, 1997; accepted Sept. 26, 1997)     

Anemia Worsens Hyperdynamic Circulation of Patients with Cirrhosis and Portal Hypertension

This retrospective cohort study was aimed atinvestigating the effects of anemia on the hemodynamicdisturbances associated with portal hypertension. Inall, 202 consecutive nontreated portal-hypertensive patients referred for evaluation to our HepaticHemodynamic Laboratory were included. Compared to thenonanemic patients, anemic cirrhotic patients had anincreased cardiac output (7.9 ± 1.9 vs 7.1± 2 liters/min, P < 0.01), and a decreased mean arterialblood pressure (82 ± 11 vs 94 ± 13 mm Hg,P < 0.0001) and systemic vascular resistance (838± 235 vs 1102 ± 356dyn/sec/cm⁵, P < 0.0001). Similar resultswere obtained when Child A or Child B-C patients were analyzedseparately. Multivariate logistic regression disclosedthat hemoglobin concentration, in addition to age, sexazygos blood flow, and albumin concentration, was anindependent factor influencing the degree of systemicvasodilation in cirrhotic portal-hypertensive patients.This study discloses that anemia worsens thehyperdynamic circulation associated with portalhypertension. Since hemoglobin concentration may change withtime, this parameter should be taken into account whenevaluating hemodynamics in portal-hypertensivepatients.     

Short-term effects of transjugular intrahepatic portosystemic shunt (TIPS) on functional liver plasma flow in patients with advanced cirrhosis

ABSTRACT— Aims/Background: TIPS, an effective procedure applied for the treatment of complications of portal hypertension, is potentially followed by worsening of the hyperdynamic circulation of cirrhosis and the impairment of liver function. The aim of the present study was to evaluate short-term changes of functional liver plasma flow after application of TIPS, using the hepatic (extrarenal) clearance of D-sorbitol (S-HCl). Methods: Twenty-five cirrhotic patients submitted to TIPS for prevention of variceal rebleeding entered the study. At steady-state, during constant infusion of a solution of D-sorbitol (25 mg/min), appropriate blood and urine samples were collected in order to calculate S-HCl before and 120 min after TIPS opening. In addition, the hepatic extraction ratio of D-sorbitol was directly measured at the level of the right (E_r), where TIPS was applied, and of the left (E_l) hepatic veins; meanwhile the portocaval gradient (PCG) was registered, before and after stent dilation. A comparison of values obtained before and after TIPS application was performed by Student's t-test for paired data. Results: After application of TIPS, a substantial reduction was observed in PCG (12.1 ± 4.2 vs 24.8 ± 4.3 mmHg; p<0.001) and E_r values (20.6 ± 14.8 vs 57.5 ± 22.3%; p<0.001) but not E_l values (47.4 ± 22.0 vs 53.4 ± 21.4%; p=0.178). S-HCl measured 120 min after TIPS opening was not statistically different from pre-TIPS values (389.2 ± 212.1 vs 394.6 ± 152.7 ml/min; p=0.892), although S-HCl variations in Child-Pugh class B patients were positively correlated with portal pressure variations (r=0.63, p=0.016). Conclusion: Our results demonstrate that in patients with advanced cirrhosis, TIPS procedure, while effective in reducing portal hypertension, does not lead to alterations in the functional liver plasma flow within the first 2 h.     

Effect of atrial flutter on exercise tolerance in patients with grown-up congenital heart (GUCH)

Objectives To assess the effect of atrial flutter (AFL) on exercise tolerance in patients with grown-up congenital heart (GUCH), exercise tests with modified Bruce protocol were performed in 20 patients aged 21 to 62 years with GUCH (11 females, 9 males) during symptomatic AFL and again 24 to 48 hours after DC conversion to sinus rhythm (SR). At the same time, cardiac function was assessed by means of transthoracic Doppler echocardiography. Results Mean exercise duration was significantly less during AFL (6.4 ± 4.1 min) versus SR (10.9 ± 3.7 min) (P < .001). Heart rate was faster at rest and peak exercise while in AFL (106 ± 21 beats/min vs 77 ± 14 beats/min, P < .001, and 157 ± 31 beats/min vs 129 ± 24 beats/min, P < .01, respectively). Systolic blood pressure was lower at peak exercise with AFL (112 ± 25 mm Hg vs 137 ± 24 mm Hg, P < .001), as was mean blood pressure increase (5.3 ± 24.3 mm Hg vs 22.6 ± 15.8 mm Hg) compared with SR (P < .01). Four of the 6 patients after Fontan surgery had a decrease of 16 mm Hg in systolic blood pressure at peak exercise when in AFL. The reasons for exercise termination during AFL were mainly breathlessness, chest pain, or presyncope, whereas in SR it was caused by fatigue. Echocardiography during AFL showed shorter isovolumic relaxation time (40 ± 20 ms) compared with SR (50 ± 20 ms) (P < .05). Ventricular long-axis excursion was reduced (left 1.0 ± 0.3 cm vs 1.2 ± 0.4 cm, septal 0.5 ± 0.2 cm vs 0.7 ± 0.3 cm, and right 0.7 ± 0.2 cm vs 0.9 ± 0.4 cm respectively, P < .001 for all), as were peak pulmonary and aortic flow velocities (85 ± 30 cm/s vs 105 ± 50 cm/s, P < .001, and 137 ± 118 cm/s vs 143 ± 114 cm/s, P < .02) compared with sinus rhythm. There was a close correlation between exercise duration and blood pressure increase (r = 0.6), left-sided long-axis excursion and blood pressure increase (r = 0.57), and between aortic flow velocity and right-sided long-axis excursion (r = 0.71). Conclusions Atrial flutter causes dramatic reduction in exercise tolerance in patients with GUCH, and the combination of fast heart rate and hypotension may contribute to the development of presyncope, particularly in those with Fontan surgery. Marked improvement in effort tolerance and cardiac dynamics occurs after regaining SR. Thus, improving the quality of life in patients with GUCH requires maintaining SR. (Am Heart J 2002;144:173-9.)     

Hemodynamic effects of disopyramide at rest and during exercise in normal subjects

The hemodynamlc effects of disopyramide phosphate, 2.0 mg/kg body weight, given intravenously over a period of five minutes were studied at rest and during exercise in ten patients without clinical or anglographlc evidence of heart disease. Following disopyramide, the resting cardiac index was lower (4.0 ± 0.6 vs 4.3 ± 0.6 iners/min/m², mean ± 1 SO, P <0.05), while left ventricular end-dlastollc pressure (16 ± 4 vs 11 ± 4 mm Hg, P <0.001), pulmonary arterial (PA) mean pressure (20 ± 5 vs 17 ± 5 mm Hg, P <0.05), and brachlal arterial (BA) mean pressure (105 ± 8 vs 96 ± 7 mm Hg, P <0.05) were higher than the pre-infuslon resting values. During exercise, there was no change in left ventricular end-diastollc pressure while cardiac index rose from 4.0 ± 0.6 to 6.5 ± 0.6 itters/mln/m² (P <0.001) and left ventricular stroke work index increased from 62 ± 19 to 84 ± 22 gm/beat/m² (P <0.001). The normal hemodynamlc response during exercise after disopyramide despite the apparent depression of left ventricular function at rest probably reflects the positive inotroplc effect of enhanced sympathoad-renergic activity.     

Alterations in Aortic Wave Reflection With Vasodilation and Vasoconstriction in Anaesthetized Dogs

Background

Using the reservoir-wave approach, we studied wave propagation, reflection, and re-reflection in the canine aorta with administrations of sodium nitroprusside (NP) and methoxamine (Mtx).

Methods

In 8 anaesthetized dogs, excess pressures were calculated from pressure and flow measurements at 4 locations along the aorta; wave intensity analysis was employed to identify wavefronts and the type of waves.

Results

NP (intravenous; 14 μg/min) decreased mean aortic pressure from 80 ± 3 mm Hg to 48 ± 1 mm Hg; Mtx (intravenous; 10 μg/min) increased mean pressure from 80 ± 3 mm Hg to 104 ± 4 mm Hg. NP increased negative reflection near the kidneys (reflection coefficient: −0.33 vs −0.18; P < 0.01) and produced new negatively reflecting sites just beyond the arch and in the proximal femoral arteries, consistent with a vasodilating effects of nitrates on conducting arteries. Mtx negated negative reflection from near the kidneys (−0.02 vs −0.17; P < 0.01) and increased positive femoral reflection (0.38 vs 0.26; P < 0.01). The large reflected compression wave was re-reflected from the closed aortic valve to produce a prominent increase in middiastolic pressure in the distal aorta.

Conclusions

The reservoir-wave approach explains decreasing diastolic pressure without positing waves that travel at near-infinite velocities and reveals the pressure changes that are uniquely due to wave motion.     

Intestinal blood flow in murine colitis induced with dextran sulfate sodium

The aim of this study was to assess whether colitis induced by dextran sulfate sodium (DSS; 10% in tap water for 7 days) in BALB/c mice is associated with changes in intestinal blood flow. After anaesthesia, systemic hemodynamic variable and regional blood flows and resistances in various organs were measured in both control and DSS-treated mice. Mean arterial blood pressure was significantly lower in DSS-treated mice than in controls (56 ± 4 vs 66 ± 3 mm Hg; P < 0.05), but no differences were found in regional blood flows to or vascular resistances in the lungs, liver, stomach, small intestine (upper, middle, and lower part), cecum, mesentery + pancreas, spleen, kidneys, brain, and skin. However, compared to the control mice, blood flows in the middle (0.88 ± 0.13 vs 0.55 ± 0.09 ml/min/g; P < 0.05) and distal (0.69 ± 0.11 vs 0.29 ± 0.05 ml/min/g; P < 0.05) colon were significantly higher, and vascular resistances in the proximal (0.87 ± 0.21 vs 1.36 ± 0.21 mm Hg min/ml/100 g; P < 0.05), middle (0.60 ± 0.10 vs 1.46 ± 0.35 mm Hg min/ml 100 g; P < 0.05) as well as distal (0.90 ± 0.25 vs 2.67 ± 0.49 mm Hg min/ml/100 g; P < 0.05) colon were significantly lower in mice with experimental colitis. Interestingly, there was a gradient in the intestinal blood flow in control mice from the upper small intestine (2.79 ± 0.72 ml/min/g) down to the distal colon (0.29 ± 0.05 ml/min/g); such a gradient was also present in the colitis mice. It is concluded that DSS-induced colitis in mice is associated with microcirculatory disturbances in the colon, mainly in its middle and distal parts.     

Cardiovascular effects of octreotide in patients with hepatic cirrhosis

Octreotide is thought to reduce splanchnic and variceal blood flow with minimal effects on the systemic circulation in cirrhotic patients with portal hypertension. However, we noticed significant bradycardia in some patients immediately after administration of bolus doses of octreotide. Therefore, we investigated the effect of intravenous octreotide on systemic hemodynamics in 59 patients with cirrhosis. In two double-blind, placebo-controlled protocols, 32 patients received a 25-μg bolus and 20 patients received an infusion of 50-μg/hr of octreotide/placebo. Immediately after the bolus dose of octreotide was administered, there were significant reductions in pulse rate (77 ± 3 vs. 65 ± 3 beats per minute, P < .01) and cardiac output (9.2 ± 0.8 vs. 7.9 ± 0.8 L/min; P < .01) and significant increases in mean arterial pressure (81 ± 3 vs. 87 ± 3 mm Hg; P < .05), mean pulmonary artery pressure (9.1 ± 1.0 vs. 16.6 ± 1.5 mm Hg; P < .01), right atrial pressure (3.8 ± 0.8 vs. 6.6 ± 1.0 mm Hg; P < .01), right ventricular pressure (7.1 ± 0.6 vs. 12.5 ± 1.3 mm Hg; P < .01), pulmonary capillary wedge pressure (4.8 ± 0.8 vs. 11.2 ± 1.4 mm Hg; P < .01), systemic vascular resistance, and pulmonary vascular resistance. Thirty minutes after the start of the infusion, there were significant increases in mean right atrial pressure, right ventricular pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure. This study suggests that intravenous octreotide has significant effects on the systemic circulation in patients with cirrhosis and that these effects appear to be more marked after administration of bolus doses.     

Hemodynamic effects of oral ephedrine given alone or combined with nitroprusside infusion in patients with severe left ventricular failure

Potent vasodilator or inotropic agents alone may be of limited value in some patients with severe congestive heart failure because of their exaggerated peripheral vascular effects. Nitroprusside and potent inotropic agents in combination are hemodynamically more effective than either alone. Although oral vasodilators can mimic nitroprusside, there is a need for potent oral inotropic agents. Ephedrine is an oral sympathomimetic inotropic drug. The hemodynamic effects of ephedrine alone (50 mg orally), nitroprusside alone and the two agents combined were studied in 11 patients with severe congestive heart failure. Heart rate increased from 89.9 ± 5.2 (standard error of the mean) to 98.2 ± 5.0 beats/min after ephedrine (P < 0.001) and to 96.4 ± 4.7 beats/min with ephedrine plus nitroprusside (P < 0.02); it was unchanged with nitroprusside alone. Mean systemic arterial pressure increased from 83.7 ± 2.1 to 89.2 ± 2.7 mm Hg after ephedrine (P < 0.02) and decreased to 73.4 ± 2.4 mm Hg with nitroprusside added (P < 0.01). Left ventricular filling pressure was unchanged after ephedrine but decreased from 30.9 ± 2.3 to 20.6 ± 2.1 mm Hg during nitroprusside infusion (P < 0.01). Control cardiac output averaged 3.94 ± 0.30 liters/min and increased by 1.25 ± 0.31 liters/min with nitroprusside, by 1.09 ± 0.30 liters/min after ephedrine and by 2.20 ± 0.34 liters/min with the two combined. Although the increases in cardiac output with each agent alone were significant and similar, the increase with the two combined was significantly greater than with either alone. The data suggest that ephedrine is an orally effective inotropic agent especially when combined with a vasodilator. Further evaluation of ephedrine in congestive heart failure is warranted.     

Hemodynamic effect of dobutamine in patients with severe heart failure

Dobutamine, a derivative of dopamine, was infused at a rate of 10 μg/kg per min in 15 patients with severe congestive heart failure. Cardiac output increased from an average of 3.1 to 5.6 liters/min (P < 0.001) with no change in mean arterial pressure (93.3 to 98.2 mm Hg) and only a slight increase in heart rate (98.5 to 105.2 beats/min) (P < 0.02). Pulmonary wedge pressure was decreased from an average of 27.4 to 21.1 mm Hg (P < 0.001). In seven patients a dose of 5 μg/kg per min also produced a significant increase in cardiac output but the effect was less than with the 10 μg/kg per min dose. No side effects were observed during the infusion. Dobutamine therefore is a potent inotropic drug with limited chronotropic and peripheral vascular effects and deserves therapeutic trial in the short-term management of low output heart failure.     

48-Hour Hemodynamic Effects of Octreotide on Postprandial Splanchnic Hyperemia in Patients with Liver Cirrhosis and Portal Hypertension

Octreotide is effective during 48 h in the treatment of acute variceal bleeding, probably by reducing variceal blood flow and pressure. Its basal and postprandial effects on splanchnic and systemic hemodynamics, and hormonal changes over this time interval have not yet been studied. Twenty-four patients with cirrhosis and portal hypertension were randomized to receive a liquid meal and either octreotide (Oct, 100 g bolus intravenous, followed after 2 h by a continuous infusion of 25 g/hr for 20 hr) or placebo (Plac) given at three consecutive days. Splanchnic (Doppler ultrasound) and systemic hemodynamics (noninvasive cardiac monitoring) were assessed on four consecutive days (one control day and three treatment days) during 2 hr. The postprandial increase in mean blood velocity of the superior mesenteric artery (SMA-V _mean, +44%), portal blood velocity (PV-V _mean, +44%) and total hepatic blood flow (HBF, +40%) observed in the placebo group during the control day was abolished during the first day of treatment (SMA-V_mean, +3%, P < 0.01; PV-V_mean, +6%, P < 0.05; HBF, –25%, P < 0.01) and still reduced after 48 hr in the octreotide group (SMA-V_mean, +28%, P < 0.05; PV-V_mean, +22%, P > 0.05; HBF, –8%, P < 0.05). The postprandial increase in cardiac index (CI, +10%) and decrease in systemic vascular resistance index (SVRI, –6%) were blunted after the initial injection of octreotide only (CI, –8%, P < 0.05; SVRI, +18%, P < 0.01). Endothelin-1-levels, which were increased at baseline (Plac 25 ± 17, Oct 16 ± 13 ng/liter, P > 0.05) decreased significantly after 48 hr of treatment with octreotide (Plac 27 ± 20, Oct 8 ± 4 ng/liter, P < 0.05). Octreotide is effective during 48 hr in the prevention of postprandial hyperemia in cirrhotics, even if its efficacy is decreasing over time. Moreover it may have positive effects on systemic vasodilation in cirrhotics. These findings suggest a potential role of this drug in the chronic treatment of portal hypertension.     

Effect of oral propranolol on splanchnic oxygen uptake and haemodynamics in patients with cirrhosis

In order to elucidate the effect of beta-adrenergic blockade on liver metabolism and haemodynamics, splanchnic oxygen uptake, hepatic removal of indocyanine green (ICG) and splanchnic and systemic haemodynamics were studied in 13 patients with cirrhosis before and 1.5-2 h after an oral dose of 80 mg propranolol. All patients underwent hepatic vein catheterization and had a primed continuous intravenous infusion of ICG. Azygos vein catheterization was performed in six patients. Splanchnic (hepatic-intestinal) oxygen uptake (median control 68 ml/min vs. beta-blockade 56 ml/min, P less than 0.01), azygos venous oxygen saturation (76 vs. 67%, P less than 0.05), ICG clearance (263 vs. 226 ml/min, P less than 0.01), wedged-to-free hepatic vein pressure (16 vs. 13.5 mm Hg, P less than 0.01), hepatic blood flow (1.18 vs. 0.78 l/min, P less than 0.01), cardiac index (3.42 vs. 2.53 l/min . min 2, P less than 0.01), and heart rate (72 vs. 56 beats per min, P less than 0.01) decreased significantly after oral beta-blockade. The hepatic extraction ratio of ICG increased significantly (0.32 vs. 0.45, P less than 0.01), whereas estimated 'intrinsic' ICG clearance (289 vs. 300 ml/min, n.s.), arterial blood pressure, stroke volume, and systemic vascular resistance remained essentially unchanged. The results indicate that besides the well-known cardiovascular effects of propranolol, beta-adrenergic blockade may also reduce hepatic metabolic functions as evidenced by the significantly decreased splanchnic oxygen uptake. The raised hepatic extraction ratio of ICG may be caused by reduction in hepatic blood flow as well as in intrahepatic shunting.     

The effect of augmenting portal venous inflow on intrahepatic pressure and resistance in the isolated perfused porcine liver

BACKGROUND/AIMS: The literature regarding the relationship between portal venous flow and pressure is controversial. The aim of this study was to examine the effects of doubling portal venous inflow on hepatic hemodynamics. METHODOLOGY: Portal venous pressure, intrahepatic portal venous resistance, hepatic arterial pressure and intrahepatic arterial resistance were assessed during basal portal venous inflow (756 +/- 142 mL/min; mean +/- SD) and enhanced portal venous inflow (1512 +/- 284 mL/min) in an isolated perfused normal porcine liver model (n = 6). Hepatic arterial flow was maintained constant throughout the experiments. RESULTS: During the period of enhanced portal venous flow there was an increase in: portal venous pressure (from 9 +/- 2 to 22 +/- 7 mm Hg, P = 0.0076); the difference between portal venous and hepatic venous pressures (from 2 +/- 2 to 10 +/- 5 mm Hg; P = 0.0289); hepatic arterial pressure (from 84 +/- 9 to 151 +/- 33 mm Hg, P = 0.0019); and intrahepatic arterial resistance (from 0.3488 +/- 0.0637 to 0.6387 +/- 0.2020, P = 0.0046). CONCLUSIONS: The increases in hepatic artery pressure and intrahepatic arterial resistance are a result of the hepatic arterial 'buffer response', a phenomenon not previously demonstrated in vitro. The magnitude of the observed changes in portal venous and hepatic venous pressure leads to the conclusion that, in the porcine liver, the intrahepatic venous resistance sites react by constricting to increases in portal venous inflow.