Pathophysiology of cardiac failure

The pathophysiologic cycle of heart failure is initiated by myocardial failure that accompanies a reduction in myocardial contractility secondary to ischemic or myopathic heart disease. Reduction in cardiac output and oxygen delivery to the tissues is followed by vasoconstriction that raises systemic vascular resistance to preserve systemic arterial pressure while maintaining regional O2 availability. As a consequence, however, impedance to left ventricular ejection is increased, creating an additional hemodynamic burden for the failing heart. A vicious cycle ensues. Hemodynamic features of acute cardiac failure include decreases in cardiac output and mixed venous O2 saturation, together with increases in left ventricular filling pressure and systemic resistance. If hypotension is present with failure, there is a markedly decreased cardiac output or an inappropriate increase in systemic resistance. If acidosis is also present with hypotension and failure, cardiac output is severely decreased and lactic acid is increased. A major objective of medical therapy in acute heart failure is to enhance ventricular emptying, thereby increasing cardiac output and O2 delivery while decreasing left ventricular filling pressure, pulmonary venous pressure and vascular resistance. Potent intravenous drugs that have a positive inotropic effect on the myocardium, including amrinone and dobutamine, have been shown to increase ventricular emptying in patients with acute heart failure. Intravenous amrinone improves pump performance without adversely raising myocardial O2 consumption, thereby enhancing myocardial efficiency. These drugs also promote a degree of vasodilation through both direct and secondary effects on the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

New strategies for the management of acute decompensated heart failure

Acute heart failure in adults is the unfolding of heart failure in minutes, hours or a few days. Low output heart failure describes a form of heart failure in which the heart pumps blood at a rate at rest or with exertion that is below the physiological range and the metabolizing tissues extract their required oxygen from blood at a lower rate, causing a proportionately smaller oxygen amount remaining in the blood. Therefore, a widened arterial-venous oxygen difference occurs. High output heart failure is characterized by pumping blood with a rate above the physiological range at rest or during exertion, resulting in an arterial-venous oxygen difference, which is normal or low. This may be caused by peripheral vasodilatation during sepsis or thyrotoxicosis, blood shunting, or reduced blood oxygen content/viscosity (Fig. 1). The differentiation between low output heart failure versus high output heart failure is of highest importance for the choice of therapy and therefore the information and the monitoring of the systemic vascular resistance. Patients who present with acute heart failure suffer from a severe complication of different cardiac disorders. Most often they have an acute injury that affects their myocardial performance (eg, myocardial infarction) or valvular/chamber integrity (mitral regurgitation, ventricular septal rupture), which leads to an acute rise in left-ventricular filling pressures resulting in pulmonary edema.     

Management of heart failure in cardiac surgical patients: amrinone and other pharmacologic agents

The pharmacologic treatment of heart failure and low cardiac output syndrome in the cardiac surgical patient continues to be a challenge in the nursing management of these patients. While the catecholamines have been of proven inotropic benefit over the years, their inherit risks of increased myocardial oxygen consumption, tachyphylaxis and poor tolerance in many patients have lead to the search for other medications to augment cardiac performance. Amrinone, the only drug available for use in the U.S. from the class of phosphodiesterase inhibitors, acts as both an inotrope and vasodilator to increase cardiac output without an increase in myocardial oxygen consumption. This paper reviews pharmacological management of heart failure in the cardiac surgical patient and nursing considerations specific to amrinone and combination inotropic therapy management.     

Catecholamines for treatment of severe heart failure (author's transl)]

In patients with severe heart failure there is increased sympathetic-adrenergic activity functioning as a compensatory mechanism. Despite of increased plasma catecholamine levels myocardial sensivity to catecholamines administered for therapeutic reasons is not diminished. The positive inotropic effect of catecholamines is more pronounced as compared to digitalis glycosides. The therapeutic efficacy of catecholamines, particularly their capability to increase cardiac output, is strongly dependent on their action on alpha- and beta2-receptors. In order to enhance cardiac performance, catecholamines are mainly used under three clinical settings: 1. severe heart failure and cardiogenic shock secondary to acute myocardial infarction, 2. 'Low cardiac output syndrome" following cardiac surgery, and 3. chronic congestive heart failure refractory to therapy with glycosides and diuretics. The use of catecholamines in the presence of acute myocardial infarction may be hazardous due to the accompanying increase of myocardial oxygen consumption. Among the available catecholamines, clinical interest recently focused on dopamine and dobutamine. Particularly with the primarily cardioselective beta-stimulating agent dobutamine a marked positive inotropic effect can be achieved in a range of dosage not significantly affecting heart rate and peripheral resistance. Positive inotropic agents may be even more effective when used in combination with vasodilators, which decrease impedance to left ventricular ejection.     

Correcting arterial hypoxemia by oxygen therapy in patients with acute myocardial infarction Effect on ventilation and hemodynamics

Hypoxemia and alveolar hyperventilation were common findings in acute myocardial infarction; they were most severe in patients with left ventricular failure or shock. Hyperventilation did not appear to be due to hypoxemia and was not abolished by administration of oxygen. Oxygen administration did not increase tissue oxygen transport in patients with arterial oxygen saturations of 90 per cent or greater because of reductions in cardiac output in excess of increases in oxygen content. Peripheral vascular resistance was increased, and heart rate, blood pressure and left ventricular minute work were unchanged. In patients with arterial oxygen saturations of less than 90 per cent, oxygen administration increased cardiac output, oxygen content and tissue oxygen transport; it had a variable effect on peripheral vascular resistance.     

Acute Heart Failure With Low Cardiac Output: Can We Develop a Short-term Inotropic Agent That Does Not Increase Adverse Events?

Acute heart failure represents an increasingly common cause of hospitalization, and may require the use of inotropic drugs in patients with low cardiac output and evidence of organ hypoperfusion. However, currently available therapies may have deleterious effects and increase mortality. An ideal inotropic drug should restore effective tissue perfusion by enhancing myocardial contractility without causing adverse effects. Such a drug is not available yet. New agents with different biological targets are under clinical development. In particular, istaroxime seems to dissociate the inotropic effect exerted by digitalis (inhibition of the membrane sodium/potassium adenosine triphosphatase) from the arrhythmic effect and to ameliorate diastolic dysfunction (via sarcoendoplasmic reticulum calcium adenosine triphosphatase activation). Additionally, the myosin activator omecamtiv mecarbil appears to have promising characteristics, while genetic therapy has been explored in animal studies only. Further investigations are needed to confirm and expand the effectiveness and safety of these agents in patients with acute heart failure and low cardiac output.     

Neurologic and cardiac benefits of therapeutic hypothermia

Numerous studies have shown the favorable effects of lowering the core temperature of the body in various conditions such as acute myocardial infarction, acute cerebrovascular disease, acute lung injury, and acute spinal cord injury. Therapeutic hypothermia (TH) works at different molecular and cellular levels. TH improves oxygen supply to ischemic areas and increases blood flow by decreasing vasoconstriction, as well as oxygen consumption, glucose utilization, lactate concentration, intracranial pressure, heart rate, cardiac output, and plasma insulin levels. TH has been shown to improve neurologic outcome in acute cerebrovascular accidents. Furthermore, recent studies revealed that TH is a useful method of neuroprotection against ischemic neuronal injury after cardiac arrest. TH in out-of-hospital cardiac arrest is becoming a standard practice nationwide. Further studies need to be performed to develop a better understanding of the benefits and detrimental effects of TH, to identify the most efficacious TH strategy, and the candidates most likely to derive benefit from the procedure. Although many animal studies have demonstrated benefit, larger human clinical trials are recommended to investigate the beneficial effect of TH on reducing myocardial infarction size and coronary reperfusion injuries.     

Use of intravenous nifedipine in the treatment of cardiac insufficiency in the acute period of myocardial infarction

The efficacy of intravenous nifedipine was examined in 42 patients with acute myocardial infarction complicated by congestive heart failure. In patients with a higher systemic arteriolar tone, its normalization caused an increase in cardiac output and tissue oxygen supply with a concomitant decrease in pressures in the lesser circulation and the right heart. In contrast, a cardiodepressive effect of the agent was shown in more than a half of the patients with para-normal values of peripheral vascular resistance. The latter is one of the determinants in selecting patients with acute heart failure to be treated with nifedipine.     

Haemodynamic effects of dobutamine in patients with congestive heart failure receiving captopril.

Treatment with captopril has proved effective in some patients with resistant heart failure. Since cardiac output responses to captopril treatment are generally small, we infused the positive inotropic agent dobutamine in six patients already receiving captopril to determine whether cardiac output could be augmented without concomitantly increasing myocardial oxygen demands. At low infusion rates of dobutamine (2.5 and 5 microgram/kg per min), a substantial rise in cardiac output was observed yet myocardial oxygen uptake remained well below baseline (pre-captopril/dobutamine) levels. At higher rates of infusion (10 and 20 microgram/kg per min) the rise in cardiac output was accompanied by a pronounced increase in myocardial oxygen uptake, and the appearance of chest pain or multifocal ventricular extrasystoles in three patients. These data indicate that captopril treatment combined with low infusion rates of dobutamine can augment cardiac output in the short term, without increasing myocardial oxygen demand.     

Acute myocardial infarction in man Comparative hemodynamic effects of norepinephrine and glucagon

The comparative hemodynamic effects of glucagon and graded doses of norepinephrine were examined in 7 subjects with acute myocardial infarction and various degrees of associated left ventricular failure. Glucagon (70 μg/kg) produced a 23 percent increase in cardiac index and a 15 percent decrease in peripheral vascular resistance, with no significant increase in tension-time index. Norepinephrine increased cardiac output 16 percent at a dose of 8 μg/min, but also produced a significant increase in the tension-time index (15 percent). The difference between these 2 agents relates to directionally opposite effects upon peripheral vascular resistance. Thus, glucagon may offer theoretical advantages over norepinephrine in the treatment of acute myocardial infarction and left ventricular failure since it produces the same increase in cardiac output for a smaller increase in tension-time index, a major determinant of myocardial oxygen consumption.     

Oxygen delivery, anoxic metabolism and hemoglobin-oxygen affinity (P50) in patients with acute myocardial infarction and shock.

Changes in systemic oxygen delivery after acute myocardial infarction were investigated in 21 patients. In seven patients with shock, circulatory failure was characterized by a significant reduction in cardiac index, a decrease in oxygen transport and oxygen consumption and an increase in concentration of blood lactate; a decrease in the affinity of hemoglobin for oxygen (increased P50) was also noted. The P50 averaged 28.8 plus or minus 0.87 (standard error of the mean) torr in patients with shock and 26.0 plus or minus 0.45 torr (P less than 0.05) in patients without circulatory failure. However, there was no significant difference in oxygen extraction from arterial blood between the two groups. The time course of the changes in P50, cardiac index and oxygen consumption was separately examined in 12 patients. In six patients with shock, P50 increased by an average of 4.6 plus or minus 2.05 torr (P less than 0.05) and this augmentation accounted for an estimated 18 percent increase in oxygen release. Maximal P50 values were observed after 24 hours of circulatory failure. In the absence of shock, no consistent changes in P50, cardiac index or oxygen consumption were observed. These data indicate that a reduction in oxygen delivery after acute myocardial infarction is followed by a compensatory increase in P50. This change in P50 accounts for increases in oxygen availability independently of changes in cardiac output.     

Levosimendan: dual mechanisms for acute heart failure...and beyond?

Levosimendan is a novel compound recently approved for the management of acute heart failure in Sweden and several European countries. Levosimendan exerts dual mechanisms of action associated with dose-dependent increases in cardiac output and decreases in pulmonary capillary wedge pressures. A positive inotropic effect is achieved through calcium sensitization, an effect of levosimendan binding to troponin C in a calcium-dependent manner. This mode of enhanced contractile force generation is achieved without an increase in myocardial oxygen consumption, intracellular calcium concentrations, or an adverse effect on diastolic function. The vasodilatory effect observed in cardiac, pulmonary and systemic vasculature occurs as a result of K-ATP channel activation, a mechanism which may also confer anti-ischemic properties. It remains unclear whether calcium sensitization or K-ATP channel activation is of greater clinical significance. Clinical studies utilizing fixed-dose infusions of 6 to 24 h in patients with left ventricular systolic dysfunction demonstrate greater safety and hemodynamic efficacy than placebo or dobutamine. This has translated into improved comparative survival at 31 days and potentially 180 days. Two additional prospective, outcome studies are being completed to confirm the beneficial effect on morbidity and mortality. Hypo-tension and decreased hematologic indices are the most common adverse effects requiring monitoring. No relevant drug interactions have been noted with chronic oral heart failure medications. Levosimendan's unique safety and efficacy profile suggests it is a rationale alternative to conventional inotropes, and potentially a useful first line agent for management of acute decompensated heart failure. Its role in other clinical scenarios, such as for cardiac surgery, diastolic dysfunction and outpatient infusion therapy, continues to evolve.     

New and traditional therapy of congestive heart failure. A European view

Our experiences with new drugs in the therapy of congestive heart failure indicate that nitroprusside infusion favorably influences acute left ventricular failure resulting from acute myocardial infarction. Although this vasodilator is beneficial in improving hemodynamic derangements in the acute phase, its effects on enhancing both short-term and long-term survival in myocardial infarction pump dysfunction remain to be ascertained. Concerning the oral vasodilators, of the agents we have evaluated, oral isosorbide dinitrate has been the most useful in achieving improved cardiac function in chronic hemodynamic overload. In contrast, although long-term administration of oral slow-release phentolamine in chronic ischemic heart disease has decreased, increased left ventricular filling pressure and tended to enhance an increase in cardiac output with exercise, serious side-effects obviate the use of the agent in longterm therapy of cardiac failure. Dobutamine infusion provides pronounced enhancement of abnormal hemodynamics in chronic coronary heart disease; however, its use appears to worsen the degree of myocardial aerobic metabolism in patients with active ischemic heart disease. Digitalis and diuretics still play an important role in the therapy of most instances of chronic congestive heart failure.     

New developments in the understanding of the actions of the digitalis glycosides

In recent years it has become clear that the fundamental action of digitalis in the relief of congestive heart failure is its ability to enhance the contractile state of the ventricle. This positive inotropic effect is a direct action of the drug and is observed in both the failing and normal heart. In patients without a lowered cardiac output, the contractile effect is not translated into an elevation of total blood flow, principally due to the direct arteriolar constrictor action of the drug which increases the resistance to ventricular ejection, and perhaps the constrictor effect on the hepatic veins which results in little change or a decline in venous return to the heart. In contrast, in patients with congestive heart failure, the glycoside produces a marked rise in the reduced cardiac output and thereby allows relaxation of the intense sympathetic-mediated vasocontriction characteristic of the heart failure state; thus, arteriolar and venous dilation due to reflex withdrawal overrides the mild direct vasoconstrictor effect of the drug. From these observations, it is concluded that the digitalis glycosides have important direct and indirect actions on the heart and peripheral circulation, and the overal effects of these agents on the cardiac output and other hemodynamic variables are dependent on the presence or absence of heart failure at the time the drugs are administered. Thus, the glycosides' enhancement of the contractile state of the heart, viewed as a muscle and considered in terms of the mechanics of contraction, is observed as an improvement of the heart examined as a pump only when there is abnormal cardiac performance.

Present evidence implies that the basic contractile action of digitalis rests upon its cellular effect of potentiating excitation-contraction coupling. This effect appears to be mediated by glycoside-induced enhancement of the intracytoplasmic concentration of calcium ions around the myofibrils during electrical activation, thereby potentiating contraction. More specifically, it is speculated that digitalis has the ability to alter the configuration of the cell membrane of cardiac muscle, thus increasing calcium and sodium influx during depolarization; these cations then are taken up by sarcoplasmic reticulum which results in the release of microsomal-bound calcium into the myoplasm surrounding the contractile machinery. It is likely that the arrhythmia-provoking properties of digitalis are related to the loss of intracellular potassium and the inhibition of the membrane pump ATPase system required for maintaining intracellular potassium concentrations. This postulation that the inotropic and certain toxic actions of digitalis are mediated by different mechanisms is important clinically, since the two properties of the glycoside can be dissociated by the administration of potassium. The increase in myocardial contractility produced by digitalis requires an increase in myocardial oxygen consumption, as it does for other inotropic agents. In the presence of heart failure, this direct effect on myocardial oxygen consumption may be masked by the drug's favorable indirect effects on certain hemodynamic variables which result in the reduction of total myocardial oxygen requirements. From the above observations, it is apparent that a thorough understanding of the hemodynamic and cellular actions of the glycosides is essential for the proper application of these extraordinarily beneficial drugs in patients.     

Treatment strategies in shock: use of oxygen transport measurements

Shock has traditionally been categorized according to its cause. Shock can result from hemorrhage, primary cardiac failure, central nervous system failure, trauma, or sepsis. Therapeutic principles have been developed for each etiologic type. End points for such therapy have included optimization of pulmonary capillary wedge pressure, cardiac output, blood pressure, and urine output. Recent investigators agree that the common denominator in each of the shock syndromes is a reduction in the amount of oxygen consumed by the cell. The logical therapeutic approach would be to increase oxygen delivery to support the increased metabolic demand of the cells. The end point of resuscitation should be optimization of oxygen delivery and oxygen consumption. These variables are easily calculated by using data obtained from pulmonary artery catheter and laboratory measurements. The physician or nurse caring for critical ill patients should have a thorough understanding of the rationale for the use of oxygen transport calculations and the methods of manipulating oxygen delivery. A simple explanation of these principles including the importance of hemoglobin, cardiac index, and percent saturation of hemoglobin and suggested treatment strategies are presented.     

Dobutamine: mechanisms of action and use in acute cardiovascular pathology

High levels of circulating catecholamines associated with heart failure down-regulate cardiac beta-receptors, with a more pronounced effect on beta-1 receptors, leading to impaired inotropic effect. The use of exogenous inotropic agents is therefore a logical therapeutic approach in heart failure. Dobutamine is a synthetic catecholamine that acts on alpha-1, beta-1 and beta-2 adrenergic receptors. In the heart, the stimulation of these receptors produces a relatively strong, additive inotropic effect and a relatively weak chronotropic effect. In the vasculature, alpha-1 agonist activity (vasoconstriction) balances the beta-2 agonist effect (vasodilatation). In clinical use, dobutamine has a rapid onset of action and a short half-life. It increases myocardial contractility, while the reflex reduction in sympathetic tone, in response to augmentation of stroke volume, leads to a decrease in total peripheral resistance. The expected hemodynamic effects are an increase in cardiac output and a decrease in systemic vascular resistance without significant change in arterial pressure or heart rate. In acute cardiac failure state with elevated afterload pressures, resulting from myocardial dysfunction, dobutamine therapy remains, nowadays, the reference.     

Selective beta-1-adrenoceptor partial agonist treatment for congestive heart failure

Xamoterol is a beta-adrenoceptor partial agonist which selectively acts at the beta 1-receptors of the heart. The partial agonist effect modestly increases myocardial contractility and appears also to improve diastolic function and cardiac output without an increase in myocardial oxygen demand. Improved myocardial performance is maintained during exercise while increased heart rate is attenuated. Partial agonist activity protects against tachyphylaxis and arrhythmogenicity. With chronic treatment, exercise duration and work capacity increase and clinical manifestations of heart failure are reduced.     

Physiological Adaptation of the Cardiovascular System to High Altitude

Altitude exposure is associated with major changes in cardiovascular function. The initial cardiovascular response to altitude is characterized by an increase in cardiac output with tachycardia, no change in stroke volume, whereas blood pressure may temporarily be slightly increased. After a few days of acclimatization, cardiac output returns to normal, but heart rate remains increased, so that stroke volume is decreased. Pulmonary artery pressure increases without change in pulmonary artery wedge pressure. This pattern is essentially unchanged with prolonged or lifelong altitude sojourns. Ventricular function is maintained, with initially increased, then preserved or slightly depressed indices of systolic function, and an altered diastolic filling pattern. Filling pressures of the heart remain unchanged. Exercise in acute as well as in chronic high-altitude exposure is associated with a brisk increase in pulmonary artery pressure. The relationships between workload, cardiac output, and oxygen uptake are preserved in all circumstances, but there is a decrease in maximal oxygen consumption, which is accompanied by a decrease in maximal cardiac output. The decrease in maximal cardiac output is minimal in acute hypoxia but becomes more pronounced with acclimatization. This is not explained by hypovolemia, acid-bases status, increased viscosity on polycythemia, autonomic nervous system changes, or depressed systolic function. Maximal oxygen uptake at high altitudes has been modeled to be determined by the matching of convective and diffusional oxygen transport systems at a lower maximal cardiac output. However, there has been recent suggestion that 10% to 25% of the loss in aerobic exercise capacity at high altitudes can be restored by specific pulmonary vasodilating interventions. Whether this is explained by an improved maximum flow output by an unloaded right ventricle remains to be confirmed. Altitude exposure carries no identified risk of myocardial ischemia in healthy subjects but has to be considered as a potential stress in patients with previous cardiovascular conditions.     

N-acetylcysteine in acute hepatic failure (non-paracetamol-induced)

BACKGROUND/AIMS: Acute liver failure is a serious condition associated with poor prognosis. It may be associated with changes in systemic hemodynamics, i.e., tissue hypoxia, which contributes to multiple-organ failure. Recent studies have shown that N-acetylcysteine administered to patients with fulminant hepatic failure (paracetamol-induced) increases oxygen delivery and improves survival. The aim of this pilot study was to evaluate N-acetylcysteine administration to patients with non-paracetamol-induced acute liver failure and assess its effect on the clinical course and outcome. METHODOLOGY: N-acetylcysteine was administered at presentation to 7 patients with non-paracetamol-induced acute liver failure. Patients were followed for changes in clinical parameters (grade of encephalopathy), coagulation factors, biochemical parameters and outcome. RESULTS: Clinically, 3 patients who initially had grade O/II encephalopathy, did not progress, and have fully recovered. The mean peak prothrombin time, serum factor V, aspartate aminotransferase and alanine aminotransferase levels, all significantly improved. Four patients (57%) have recovered fully (1 patient, although fully recovered, died later from an unrelated cause). Two patients required orthotopic liver transplantation and 1 patient died. N-acetylcysteine administration may have prevented progression to grade III/IV encephalopathy and improved serum coagulation factors. This may account for its beneficial effect on survival in patients who had poor prognostic criteria at base-line. No side effects of the drug were noted. CONCLUSIONS: This study suggests that N-acetylcysteine administration should be considered in all patients with acute liver failure.     

Haemodynamic effects of glucagon

The central and peripheral vascular haemodynamic effects of glucagon were studied in 29 patients. With a single dose method of 2 or 5 mg. glucagon intravenously the inotropic action of the drug produced immediate increased myocardial contractility with significant increase in cardiac output and enhanced cardiac performance, and lowering of pulmonary arterial pressure and pulmonary vascular resistance. No primary peripheral vascular effect was evident, and the increased systemic pressure and lowered systemic resistance appear to be secondary to the central action of the drug. With the dosage used there were no undesirable side-effects apart from a feeling of slight nausea. Though the haemodynamic effects are abrupt, reaching their maximum values in the first 10 minutes after injection, they tend to be dissipated within half an hour, presumably due to the very rapid destruction of the drug. Repeated booster doses rather than continuous infusion may be the method of choice to maintain an increased cardiac output. The positive chronotropic action of the drug may cause transient palpitations. Glucagon increased the cardiac output in the acute phase of myocardial infarction by 42 per cent. The haemodynamic effects in chronic rheumatic heart disease are more varied, and it may increase left atrial pressure in mitral stenosis, which is undesirable. Hyperglycaemia results from liver glycogenolysis but blood sugar levels rarely exceeded 200 mg./100 ml. These results warrant further study of the value of glucagon as a positive inotropic agent in low output heart failure, especially in acute myocardial infarction with cardiogenic shock, or after cardiac surgery, or in unrelieved chronic congestive heart failure.