Roger Hallemans

Treatment of portal hypertension with isosorbide dinitrate alone and in combination with vasopressin

Experimental animal studies have suggested that certain vasodilators could minimize the adverse cardiovascular effects of vasopressin. We investigated the hemo-dynamic effects of isosorbide dinitrate, alone and in combination with vasopressin, in patients with liver cirrhosis. In 10 patients, isosorbide dinitrate, 5 mg sublingually, reduced portal pressure by 21% as assessed by the gradient between wedged and free hepatic venous pressure, but also decreased mean arterial pressure (MAP) by 20%, pulmonary artery wedge pressure (WP) by 50%, and oxygen delivery (&U1E0A;O2) by 13%. In 6 other patients, isosorbide dinitrate, 5 mg sublingually, combined with vasopressin, 0.4 U/min iv, reduced portal pressure by 37%, increased MAP by 13%, and mean pulmonary artery pressure (MPAP) by 70%, and decreased &U1E0A;O2 by 32%. Thus, isosorbide dinitrate reduces effectively portal hypertension in patients with liver cirrhosis, but also decreases &U1E0A;O2 to the tissues as a consequence of a fall in cardiac output due to decreased preload. At the dosage used in this study, isosorbide dinitrate does not prevent the adverse hemodynamic effects of vasopressin.

Effect of vasopressin and somatostatin on hemodynamics and blood gases in patients with liver cirrhosis.

The effects of somatostatin and vasopressin on blood gases, pulmonary and systemic hemodynamics, and portal pressure assessed by the gradient between occluded and free hepatic vein pressures, were investigated in 18 patients with liver cirrhosis. In the first 10 patients, an iv bolus of 250 microgram somatostatin, followed by an infusion of 125 microgram somatostatin over 30 min, caused a sudden rise in pulmonary and systemic vascular pressures lasting 2 to 5 min and accompanied by bradycardia. There was a slight and transient increase in venous admixture (Qsp/Qt) and alveolar-arterial oxygen tension gradients (P(A-a)O2), and a transient reduction in O2 delivery (O2 del) (-11% of the baseline values) and portal pressures (-14%). In the next 8 patients, vasopressin, 0.4 U/min infused over 30 min, caused a more persistent pulmonary and systemic hypertension and bradycardia, a slight increase in P(A.a)O2 and Qsp/Qt, a reduction in O2 del (-27%) and a decrease in portal pressures (-32%). These effects were marked during the entire vasopressin infusion period. Both somatostatin and vasopressin had vasoconstrictive properties and exerted negative effects on hemodynamics and blood gases. Vasopressin appeared to be a more potent drug than somatostatin.

Enhancement of Hypoxic Pulmonary Vasoconstriction by Metabolic Acidosis in Dogs

The effects of HCl infusion on multipoint mean pulmonary arterial pressure (PAP)/cardiac index (CI) plots in pentobarbital-anesthetized dogs whose lungs were ventilated alternately in hyperoxia (fraction of inspired O2 [FIO2], 0.4) and hypoxia (FIO2, 0.1) were investigated. Over the range of CI studied (1 to 5 l.min-1.m-2), hypoxia increased PAP in 22 dogs (responders) and did not affect PAP in 16 other dogs (nonresponders). In eight nonresponders, two repetitions of alternated 0.4 and 0.1 FIO2 exposures did not restore hypoxic pulmonary vasoconstriction (HPV), defined as a hypoxia-induced increase in PAP at a given flow. Intravenous infusion of 2 M HCl (2 mmol.kg-1.h-1) decreased arterial pH from normal to around 7.20 in eight responders and eight nonresponders. This metabolic acidosis increased PAP at all levels of CI in hyperoxia and in hypoxia in all the dogs, enhanced HPV in the responders, and restored HPV in the nonresponders. In eight responders, 2 M HCl infusion (2 mmol.kg-1.h-1) together with a 7% sodium bicarbonate infusion (adjusted to maintain arterial pH unchanged) did not affect hyperoxic or hypoxic PAP/CI plots. Pretreatment with 1 g acetylsalicylic acid iv (6 dogs) did not affect the pulmonary vasoreactivity to HCl-induced (2 M HCl, 2 mmol.kg-1.h-1) metabolic acidosis. It was concluded that in intact dogs: 1) metabolic acidosis enhances HPV; 2) at the given dose, HCl does not produce pulmonary vascular effects unrelated to the circulating blood pH; and 3) it is unlikely that the pulmonary vasoreactivity to metabolic acidosis is mediated by products of the cyclooxygenase pathway.

Hemodynamic effects of vasopressin, alone and in combination with nitroprusside, in patients with liver cirrhosis and portal hypertension.

We have investigated the effects on systemic, pulmonary, hepatic, and renal hemodynamics, and on blood gases of vasopressin, 0.4 U/min I.V. first alone, then in combination with nitroprusside 1–5 μg/kg/min I.V., in 12 patients with liver cirrhosis and portal hypertension. Portal pressures were estimated by the gradient between occluded and free hepatic vein pressures, hepatic blood flow was measured by indocyanine green infusion, renal blood flow by an isotopic method, and cardiac output by thermodilution. Vasopressin alone reduced cardiac ouput (-23%) and O2 delivery to the tissues (-25%), increased mean arterial pressure (+20%) and filling pressures of the heart (+136%), reduced portal pressures (-36%) (from 19±ltol2±l mmHg, mean ± SEM), hepatic blood flow (-35%) (1.33 ± 0.2 to 0.87 ± 0.1 1/min), and renal blood flow (-16%) (0.77 ± 0.07 to 0.65 ± 0.05 1/ min). Adding nitroprusside restored cardiac output, preload and afterload, and renal blood flow to pretreatment values. Oxygen delivery remained depressed (-12%) because of a negative effect on pulmonary gas exchange (physiologic shunt increased from 16 ± 2 to 28 ± 4%). Portal pressures remained reduced by 31% and hepatic blood flow by 25%. These results suggest that small doses of I.V. nitroprusside minimize the deleterious hemodynamic effects of vasopressin while maintaining the therapeutic benefit of portal pressure reduction in cirrhotic patients.

Systemic and regional hemodynamic effects of isosorbide dinitrate in patients with liver cirrhosis and portal hypertension

In a group of 17 cirrhotic patients with portal hypertension, we have investigated the effects of 5 mg sublingual administration of isosorbide dinitrate (IDN) on central hemodynamics, on regional (hepatic and renal) hemodynamics and on blood gases. Fifteen min after drug administration, we observed a decrease in the right atrial mean pressure from 4 +/- 1 to 3 +/- 1 mmHg (mean +/- S.E.M., P less than 0.02) and of pulmonary arterial wedge pressure from 7 +/- 1 to 4 +/- 1 mmHg (P less than 0.001) with decreases of the cardiac index from 4.2 +/- 0.2 to 3.7 +/- 0.2 l/min/m2 (P less than 0.001) and the mean arterial pressure from 89 +/- 4 to 72 +/- 3 mmHg (P less than 0.001) and an increase in heart rate from 86 +/- 4 to 94 +/- 5 beats/min (P less than 0.001). Arterial PO2 decreased from 73 +/- 2 to 66 +/- 2 mmHg (P less than 0.001). As a consequence of both cardiac index and arterial PO2 reductions, O2 transport to the tissues was reduced from 602 +/- 32 to 518 +/- 26 ml/min.m2 (P less than 0.001). The hepatic venous pressure gradient decreased from 17 +/- 1 to 14 +/- 1 mmHg (P less than 0.001) and hepatic vein PO2 did not change. The hepatic blood flow (HBF) determined in 7 patients remained unchanged. Renal blood flow (RBF) determined in 5 patients decreased from 0.76 +/- 0.11 to 0.68 +/- 0.11 l/min (P less than 0.001). In conclusion, isosorbide dinitrate reduces portal hypertension in patients with liver cirrhosis without compromising hepatic perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute hemodynamic effects of controlled oxygen therapy in decompensated chronic obstructive pulmonary disease.

The acute effects of controlled O2 therapy on hemodynamics and blood gases were investigated in 22 patients with decompensated chronic obstructive pulmonary disease (COPD). An inspired O2 fraction (FIO2) of 0.24 and 0.28 given to the first 12 patients markedly improved arterial and mixed-venous blood oxygenation with no (FIO2 0.24) or slight (FIO2 0.28) aggravation of hypercapnia, but did not change O2 delivery to the tissues. Higher FIO2 values of 0.35 and 0.40 in the next ten patients improved blood oxygenation even more, together with an increase in O2 delivery to the tissues and a significant aggravation of hypercapnia. All four FIO2 values reduced cardiac output without changing pulmonary vascular resistance. These results suggest that in patients with decompensated COPD, low-flow O2 improves oxygenation by diffusion rather than convection. On the other hand, controlled O2 therapy does not appear to be an immediately effective pulmonary vasodilating treatment in these patients.

Absence of parasympathetic control of pulmonary vascular pressure-flow plots in hyperoxic and hypoxic dogs

Hypoxic stimulation of the peripheral chemoreceptors has been reported to inhibit hypoxic pulmonary vasoconstriction (HPV). This has been explained by a reflex vagal (Chapleau et al., 1988) or sympathetic (Naeije et al., 1989) pulmonary vasodilation. We therefore investigated the effects of bilateral cervical vagotomy and of muscarinic block (atropine sulfate 0.1 mg.kg-1 i.v.) on multipoint pulmonary arterial pressure (Ppa)-cardiac index (Q) plots in 16 sodium pentobarbital-anesthetized dogs ventilated alternately in hyperoxia (fraction of inspired O2, FIO2, 0.4) and in hypoxia (FIO2 0.1). Over the range of Q studied, 2 to 5 L.min-1.m-2, hypoxia increased Ppa and did not change pulmonary capillary wedge pressure (Ppw). After bilateral cervical vagotomy or after atropine, Ppa and Ppw at all levels of Q were not modified either during hyperoxia or during hypoxia. These results show that the parasympathetic system does not affect the global hypoxia-induced pulmonary vasopressor response and thus suggest that the depressor effect of chemoreceptor stimulation on HPV is not vagally mediated.

Central and regional hemodynamic effects of nitrendipine in normotensive patients with chronic obstructive lung disease.

Summary: Central and regional hemodynamic studies were performed before and after administration of nitrendipine, a recently introduced calcium-channel blocker, in 10 normotensive patients with chronic obstructive pulmonary disease. None of them had a mean pulmonary artery pressure higher than 20 mm Hg. Ninety minutes after oral intake of 20 mg nitrendipine, cardiac output increased by 22%, heart rate increased by 12%, mean arterial pressure decreased by 7%, and pulmonary artery pressures as well as filling pressures of the heart did not change. Venous admixture and alveolar to arterial PO2 gradients increased by 54% and 22%, respectively. Hepatic blood flow increased by 33%. Renal blood flow remained unchanged and glomerular filtration rate decreased by 11%. Thus, in normotensive patients, nitrendipine administration induces systemic vasodilatation with an apparently reflex increase in cardiac output. These effects are accompanied by a deterioration in pulmonary gas exchange, increase in hepatic perfusion, no change in renal perfusion, and possibly a slight deterioration in renal function.

Chronic Alcoholism: a Predisposing Factor for Hypocalcemia in Acute Pancreatitis

The serum levels of calcium, corrected for serum albumin, were investigated in 65 consecutive patients with acute pancreatitis. Hypocalcemia was present in 55% of 38 patients in whom chronic alcoholism was the associated etiology, and in 26% of 27 other patients (p less than 0.02). In the alcoholic patients, the mean duration of hypocalcemia was significantly longer than in the non-alcoholic patients (5 vs. 1--2 days; p less than 0.001). The severity of pancreatitis seemed to be comparable in both groups of patients. This suggests that chronic alcoholism may be a predisposing factor for hypocalcemia in acute pancreatitis.

Effects of increased pulmonary vascular tone on gas exchange in canine oleic acid pulmonary edema

Pulmonary gas exchange was investigated before and after an increase in pulmonary vascular tone induced by administration of acetylsalicylic acid (ASA), indomethacin, or almitrine in 32 pentobarbital-anesthetized and ventilated (fraction of inspired O2 0.4) dogs with oleic acid lung injury. Pulmonary vascular tone was evaluated by five-point pulmonary arterial pressure (PAP)/cardiac index (Q) plots and intrapulmonary shunt was measured using a SF6 infusion. PAP/Q plots were rectilinear in all experimental conditions. In control dogs (n = 8), oleic acid (0.09 ml/kg iv) increased PAP over the range of Q studied (1-5 l.min-1.m-2). At the same Q, arterial PO2 fell from 186 +/- 11 to 65 +/- 8 (SE) Torr and intrapulmonary shunt rose from 5 +/- 1 to 50 +/- 6% 90 min after oleic acid injection. These changes remained stable during the generation of two consecutive PAP/Q plots. ASA (1 g iv, n = 8), indomethacin (2 mg/kg iv, n = 8), and almitrine (8 micrograms.kg-1.min-1 iv, n = 8) produced a further increase in PAP at each level of Q. ASA and indomethacin, respectively, increased arterial PO2 from 61 +/- 4 to 70 +/- 3 Torr (P less than 0.05) and from 70 +/- 6 to 86 +/- 6 Torr (P less than 0.05) and decreased intrapulmonary shunt from 61 +/- 5 to 44 +/- 4% (P less than 0.05) and from 44 +/- 5 to 29 +/- 4% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)