Myocardial efficiency during levosimendan infusion in congestive heart failure.

AIMS: Levosimendan, a novel calcium-dependent calcium sensitizer of the myocardial contractile proteins, also enhances diastolic relaxation and induces peripheral vasodilation by opening potassium channels. To assess the combined energetical effects of levosimendan infusion in vivo, we performed positron emission tomography in patients with decompensated chronic heart failure. METHODS AND RESULTS: Eight hospitalized patients with New York Heart Association functional class III or IV heart failure received levosimendan or placebo intravenously in a randomized double-blind cross-over study. During steady-state, dynamic positron emission tomography with [11C]acetate was used to assess myocardial oxygen consumption and [15O]H2O to measure myocardial blood flow. Cardiac performance and dimensions were assessed by pulmonary artery catheterization and echocardiography. Compared with healthy volunteers, myocardial oxygen consumption during placebo was elevated in the right ventricle but comparable in the left ventricle. During administration of levosimendan, cardiac output increased by 32% (P = .002) mainly because of higher stroke volume. Coronary, pulmonary, and systemic vascular resistance values were significantly reduced. Mean myocardial blood flow increased from 0.76 to 1.02 mL/min/g (P = .033). Levosimendan was neutral on myocardial oxygen consumption and left ventricular efficiency, but it improved right ventricular mechanical efficiency by 24% (P = .012). CONCLUSIONS: Levosimendan has an energetically favorable short-term profile in the treatment of congestive heart failure. It enhances cardiac output without oxygen wasting, particularly by improving efficiency in the right ventricle.

Central hemodynamics during reamed intramedullary nailing of unilateral tibial fractures.

BACKGROUND: Intramedullary nailing of a long-bone fracture results in intravasation of bone marrow contents into the right atrium and pulmonary vascular bed and, therefore, may alter cardiac and pulmonary hemodynamics. METHODS: Central hemodynamic changes were recorded in 12 healthy adults with a unilateral simple tibial fracture undergoing intramedullary nailing. The patients were cannulated with a pulmonary artery catheter. Reamed intramedullary nailing was performed during general anesthesia. Preoperative and immediate postoperative hemodynamic variables were compared and intraoperative changes studied. RESULTS: During the operation, the right ventricular preload as represented by central venous pressure and the right ventricular afterload as presented by mean pulmonary arterial pressure increased significantly. Preoperative and postoperative arterial oxygen tension values demonstrated hypoxia. Abnormal pulmonary shunting and increased oxygen consumption were observed as well. CONCLUSION: Changes in cardiac and pulmonary hemodynamics are already present after the trauma and before the reamed intramedullary nailing procedure.

Enalaprilat decreases plasma endothelin and atrial natriuretic peptide levels and preload in patients with left ventricular dysfunction after cardiac surgery.

OBJECTIVE: To study the acute effects of angiotensin-converting enzyme inhibition by intravenous enalaprilat infusion in patients with left ventricular dysfunction after cardiac surgery. DESIGN: Prospective, consecutive sample, before-after trial. SETTING: Surgical intensive care unit in a tertiary care university hospital. PARTICIPANTS: Eight patients with left ventricular dysfunction after cardiac surgery. Patients were defined as having left ventricular dysfunction if the pulmonary capillary wedge pressure persisted above 18 mmHg in spite of conventional vasoactive medication (inotropic or vasodilating and diuretic drugs) and intermittent mandatory ventilation during the first postoperative week. INTERVENTIONS: Enalaprilat was infused initially at 1 mg/ hour. The rate was doubled every 30 minutes until pulmonary capillary wedge pressure decreased at least 20% or until a maximum total dose of 10 mg was achieved. MEASUREMENTS AND RESULTS: Central hemodynamics, systemic oxygenation, and hormonal regulation of circulation (plasma renin activity, plasma endothelin, atrial natriuretic peptide, norepinephrine, epinephrine, and vasopressin concentrations, serum angiotensin-converting enzyme activity, and serum levels of aldosterone) were assessed at baseline before enalaprilat infusion, and repeatedly over 2 hours after the infusion. Enalaprilat infusion (median dose, 2.0 mg; infusion time, 48 minutes) caused a significant decrease in pulmonary capillary wedge pressure (p = 0.004), lasting until the end of the 2 hours' follow-up. This coincided with inhibition of serum angiotensin-converting enzyme activity (p < 0.001), an increase in plasma renin activity (p = 0.022), and decreases in plasma endothelin (p = 0.035), atrial natriuretic peptide (p = 0.005), and serum aldosterone (p = 0.001) concentrations. Cardiac output, venous admixture, and oxygen delivery and consumption remained unchanged. CONCLUSIONS: Adding enalaprilat to conventional therapy makes it possible to unload the left ventricle and to relieve overt neurohormonal activation temporarily while maintaining cardiac function and systemic oxygenation.

Enalaprilat controls postoperative hypertension while maintaining cardiac function and systemic oxygenation after neurosurgery.

OBJECTIVE: The efficacy of intravenous enalaprilat in lowering postoperative hypertension. DESIGN: Prospective, randomized, controlled, single blind trial. SETTING: Surgical ICT in a university hospital (tertiary care center). PATIENTS: 18 neurosurgical patients subjected to the extirpation of a supratentorial intracerebral tumour were studied after detection of postoperative hypertension. This was defined as a constant elevation of systolic arterial pressure over 160 mmHg or diastolic arterial pressure over 95 mmHg. INTERVENTIONS: Enalaprilat 0.015 mg kg-1 was injected within 5 min to 9 patients. MEASUREMENTS AND RESULTS: Central haemodynamics and systemic oxygenation were assessed at baseline before enalaprilat injection, and repeatedly during four hours after the injection. The statistical analysis was performed with analysis of variance for repeated measurements. As compared to control patients, the blood pressure lowering effect of enalaprilat became evident within 15 min and lasted for over four hours (p = 0.008). It was mainly due to the reduced systemic vascular resistance. Enalaprilat also induced a small decline in myocardial perfusion pressure. Cardiac performance, preload, heart rate and systemic oxygenation were not affected by enalaprilat. CONCLUSIONS: We found intravenous enalaprilat effective and safe in lowering postoperative hypertension following neurosurgery as assessed by it's effects on central haemodynamics and systemic oxygenation.

Enalaprilat in acute intractable heart failure after myocardial infarction: a prospective, consecutive sample, before-after trial.

OBJECTIVE: To evaluate the acute effects of intravenous enalaprilat infusion in critically ill patients with intractable heart failure after acute myocardial infarction. DESIGN: Prospective, consecutive sample, before-after trial. SETTING: Medical intensive care unit in a university hospital. PATIENTS: Eight consecutive patients with intractable acute heart failure after acute myocardial infarction. All study patients continued receiving inotropic, vasodilating, and diuretic medication at a constant rate. Six patients received steady intermittent mandatory ventilation and two patients were on a continuous positive airway pressure mask during the investigation, all with constant positive end-expiratory pressure. Heart failure was defined as intractable if the pulmonary artery occlusion pressure remained > 20 mm Hg despite this conventional therapy. INTERVENTIONS: Enalaprilat was infused at a rate of 1 mg/hr until the pulmonary artery occlusion pressure decreased by > or = 20%. MEASUREMENTS AND MAIN RESULTS: Central hemodynamics, oxygenation, and hormonal regulation (plasma renin activity, plasma norepinephrine, epinephrine, endothelin, atrial natriuretic peptide, and vasopressin concentrations, serum angiotensin-converting enzyme activity, and serum concentrations of aldosterone) were assessed at baseline before enalaprilat infusion, and repeatedly during 2 hrs after the infusion. The statistical analysis was performed with analysis of variance for repeated measurements. Enalaprilat infusion (median dose 0.3 mg and infusion time 21 mins) caused significant but short-lasting decreases in pulmonary artery occlusion pressure (p = .007), mean arterial pressure (p = .003), mean pulmonary arterial pressure, and rate pressure product. These findings coincided with inhibition of serum angiotensin-converting enzyme activity, an increase in plasma renin activity, and a decrease in plasma endothelin concentrations (p = .041). Enalaprilat had no significant effects on the other hormones studied. Cardiac output and stroke volume index, venous admixture, oxygen extraction ratio, and mixed venous and arterial oxygen saturations remained unchanged. CONCLUSIONS: Adding enalaprilat to conventional therapy makes it possible to transiently relieve pulmonary congestion while maintaining cardiac function and systemic oxygenation. The decrease in plasma endothelin concentrations may have further clinical implications, because endothelin is known to have potent vasoconstricting effects on the coronary circulation and it may also contribute to the extension of myocardial infarction. Whether these observed benefits can be maintained with repeated bolus injections or with continuous infusion of enalaprilat, remains to be settled.

Haemodynamic effects of enalaprilat and preload in acute severe heart failure complicating myocardial infarction.

In this study, the acute haemodynamic effects of angiotensin converting enzyme (ACE) inhibition with intravenous enalaprilat alone or in combination with preload restoration were determined in patients with severe heart failure complicating acute myocardial infarction. Ten patients with raised pulmonary arterial wedge pressure (PAWP > or = 18 mmHg) were first studied during constant conventional vasodilation with diuretic and inotropic medication, by monitoring central haemodynamics and arterial blood gases. The same variables were measured before enalaprilat infusion, after preload reduction with enalaprilat (1 mg.h-1, rate doubled every 30 min until PAWP decreased > or = 25% or up to total cumulative dose of 10 mg) and after preload restoration with fluid loading (4% albumin given 15 ml.min-1 to restore PAWP to baseline) during continuous low dose enalaprilat infusion. Enalaprilat alone (median dose 0.9 mg) reduced significantly the PAWP (from 25 to 17 mmHg; P = 0.004), the mean arterial pressure (from 87 to 83 mmHg; P = 0.008), the mean pulmonary arterial pressure and the right atrial pressure. The cardiac index, stroke volume index and systemic vascular resistance index remained unchanged. Preload restoration during continuous enalaprilat infusion (median dose of 4% albumin 230 ml, and enalaprilat 0.2 mg) did not further enhance left ventricular function; rather, there was a nearly significant decrease in myocardial perfusion pressure. Arterial oxygenation remained unchanged throughout the study. In conclusion, adding intravenous enalaprilat to conventional therapy makes it possible to relieve pulmonary congestion while maintaining the cardiac function and arterial oxygenation. Preload restoration during continuous ACE inhibition offers no further advantages, and may have adverse effects, since the myocardial perfusion pressure may fall.

Enalapril premedication attenuates the blood pressure response to tracheal intubation and stabilizes postoperative blood pressure after controlled hypotension with sodium nitroprusside in neurovascular patients.

Oral premedication with enalapril, 0.1 mg/kg was compared with placebo in 22 patients subjected to craniotomy and ligation of an intracranial aneurysm or extirpation of an arteriovenous malformation. Balanced hypotensive anesthesia was used with sodium nitroprusside (SNP) as the main hypotensive agent. The hypertensive response to laryngoscopy and tracheal intubation was significantly attenuated by enalapril (p = 0.020). The mean blood pressure was lower and more stable in the intensive care unit after enalapril than after placebo (p = 0.044). The median SNP dose rate tended to be lower in the enalapril-pretreated patients [0.6 (range of 0-3.5) micrograms/kg/min] compared to the placebo group [1.4 (0.4-5.8) micrograms/kg/min] (p = 0.12). Concentrations of plasma catecholamines, vasopressin, and endothelin as well as serum osmolality, arterial blood gases, and plasma electrolytes and level of consciousness were repeatedly measured. Enalapril had no significant effects on these variables. Plasma renin activity was increased and serum angiotensin converting enzyme (ACE) activity was reduced in the expected manner by enalapril. We found premedication with an ACE inhibitor favorable for hypotensive anesthesia in neurovascular patients as assessed by the circulatory responses.

Extradural administration of bupivacaine: pharmacokinetics and metabolism in pregnant and non-pregnant women.

We found a similar time (about 0.4 h) to maximum serum concentration after extradural administration of bupivacaine 1.78 (SD 0.27) mg kg-1 to six pregnant patients at term, 1.58 (0.13) mg kg-1 to six women younger than 65 yr and 1.50 mg kg-1 to six women older than 65 yr. There were no significant differences in terminal half-life. No unconjugated 4'-hydroxy-bupivacaine was detected in the serum and urine of pregnant patients, in contrast with the other groups. The pregnant patients had significantly greater serum concentrations of the N-dealkylated metabolite, N-desbutyl-bupivacaine (DBB), than the non-pregnant groups. In contrast with 4'-hydroxy-bupivacaine, no conjugated forms of bupivacaine and desbutyl-bupivacaine were detected in urine. The mean total urinary excretion of bupivacaine and its metabolites and their conjugates varied between 2.46 and 3.22% of the total dose administered in the three patient groups, indicating that both 4'-hydroxylation and N-dealkylation are minor metabolic pathways in man.

Plasma volume substitution.

Blood loss up to 10-15% of the total blood volume can be substituted by mere crystalloids. A quicker and more stable volume replacement can be accomplished with colloid solutions. Combination of artificial colloids (e.g., dextran 60, dextran 70 or hydroxyethyl starches with high degree of hydroxyethylation) with crystalloids (isotonic balanced solutions) produces a long lasting volume effect. Due to dose limitation recommendations for the artificial colloids, volume substitution may be continued, at a later stage, by albumin.

Effects of three colloid solutions on plasma volume and hemodynamics after coronary bypass surgery.

The effects of 4% plasma protein solution (group P), 6% dextran-70 (group D), and 5.5% oxypolygelatin (group G) on plasma volume and hemodynamics were compared with each other and with controls (group C) who received only maintenance infusion 20 h after coronary bypass surgery. After infusing 10 ml/kg of colloid at 1 g/min, the immediate increases in plasma volume were 6.1 ml/kg in group P, 8 ml/kg in group D, and 7.9 ml/kg in group G. After one hour, the corresponding increases were 4.2 ml/kg (group P), 8.2 ml/kg (group D), and 6.2 ml/kg (group G). The increases in pulmonary capillary wedge pressure and stroke index were greatest and most persistent in group D, second largest but shortest in duration in group G, and lowest in group P. In conclusion, the volume effects of these three colloid solutions in coronary bypass patients are comparable to those obtained in other elective surgical patients.

Effects of concentrated albumin treatment after aortocoronary bypass surgery.

The effects of 20% albumin (2.5 mg/kg) on plasma volume (PV) and hemodynamics, as well as albumin pharmacokinetics, were studied in ten spontaneously breathing patients 20 h after coronary bypass surgery. The albumin was infused over 20 min, and serial changes in PV were followed for 60 min using 131I albumin dilution. Plasma albumin (P-Alb) and total protein concentrations, as well as oncotic pressure, hemodynamic, and oxygen transport variables, were followed for 90 min. Eleven patients served as controls. At baseline, 7.5% and 5.5% reductions in blood volume were found in the albumin and control groups, respectively. The maximal PV gain (4.5 ml/kg) was reached 15 min after the infusion. Coincidentally, 7.7 ml H2O was linked to 1 g of albumin retained in the circulation. The half-life of P-Alb was 16.2 h, and the distribution volume of the infused dose exceeded PV. An increased pulmonary capillary wedge pressure produced an increase in cardiac index. The right and left ventricular stroke work indices also increased. Pulmonary shunt flow, PaO2, and urinary output did not change appreciably.

Restoration of volume by crystalloid versus colloid after coronary artery bypass: hemodynamics, lung water, oxygenation, and outcome.

We compared Ringer's acetate-gluconate solution with 6% dextran-70 infused during rewarming after coronary bypass surgery. In a randomized study, 18 patients received 56 +/- 15 ml/kg of crystalloid (group 1), and 14 patients received 16 +/- 6 ml/kg of dextran (group 2). Data were taken at the following intervals: 4 to 5 h after terminating the cardiopulmonary bypass, after rewarming, the next morning on controlled ventilation and continuous positive airway pressure (CPAP) breathing, and after extubation. The patients were followed for 14 days. Prophylactic nitroglycerin infusion may have increased the need for plasma expansion. After volume loading, the stroke index increased in both groups, but the left ventricular stroke work index increased in group 2 only. After transition to the CPAP mode, hydrostatic pressures increased, more in group 2, doubling the pulmonary shunt flow. Pulmonary extravascular thermal volume did not change in either group. We conclude that hemodynamic stability occurred faster with dextran, and ventilatory weaning was somewhat easier with crystalloid.

Measurement of sequential changes in plasma volume immediately after aortocoronary bypass surgery.

This study assessed the reliability of 131I albumin-dilution for measuring induced changes in plasma volume (PV) immediately after coronary bypass surgery. After injection of the tracer, blood samples were collected from 18 control patients to obtain 131I albumin decay curves in the plasma. These curves were used to construct a mathematical model describing tracer decay. PV was then calculated in control patients, and in 51 study patients who received plasma expanders on the first postoperative morning. At 1, 15, 30, and 60 min after volume loading in the study group, dilution volumes were calculated as the difference between predicted and observed plasma radioactivity levels. These calculations were compared to an independent measurement of PV. This method was associated with a measurement error no greater than +/- 12% in 82% of the 51 study patients. It tended to underestimate PV by 2.4%.