5 the Annals of Thoracic Surgery Volume 59 Issue Supp-S1 1995 [Doi 10.1016%2F0003-4975%2894%2900916-u] Anthony R. Doyle; Achal K. Dhir; Anthony H. Moors; Raymond D. La -- Treatment

Treatment of Perioperative Low Cardiac Output Syndrome Anthony R. Doyle, MD, Achal K. Dhir, MD, Anthony H. Moors, MD, and Raymond D. Latimer, MD Department of Anaesthesia, lapworth Hospital, Papworth Everard, Cambridgeshire, England

New approaches to the treatment of perioperative low cardiac output are considered. In particular, use of the phosphodiesterase III inhibitors and their cardiovascular actions are reviewed and contrasted with those of conventional inotropic agents. The increasing recognition of right-sided dysfunction is highlighted, and appropriate

T raditionally the treatment of low cardiac output associated with a cardiac operation has concentrated on the left ventricle and the systemic vasculature. Efforts are made to optimize left ventricular function, improve oxygen supply and demand, and allow time for the ventricle to recover. This has been achieved largely with pharmacologic manipulation of the contractile state of the myocardium in conjunction with the use of vasodila- tars. Inotropic agents such as dopamine, dobutamine, and epinephrine have been used alone or in combination with mechanical support in the form of intraaortic balloon counterpulsation.

More recently, attention has focused on the vascular effects of inotropic agents. In particular the specific phosphodiesterase-III inhibitors such as enoximone, piroximone, mih-inone, and amrinone have been increasingly considered for use in this setting. These drugs combine inotropic activity with useful vascular effects that lead to a reduction in both preload and afterload, thus maintaining a favorable myocardial oxygen supply/demand ratio.

A relatively new development is the realization that the right ventricle is more important in the context of perioperative cardiac failure than once thought. Right ventricular failure, often seen with pulmonary hypertension, is associated with a poor prognosis. Attempts have been made to measure right ventricular function and to pro- vide specific treatment when it is impaired. This treatment is based on the underlying principles of optimizing preload, afterload, and contractility, which are reviewed. Consideration is also given to maintaining right coronary perfusion by maintaining aortic pressure. More specifically, right ventricular afterload reduction is examined, in particular, the increasing usage of pulmonary-specific vasodilators such as inhaled nitric oxide (NO).

Presented at the Recent Advances in Treatment of Severe Cardiac Failure Symposium, Linkijping, Sweden, March 3-4, 1994.

Address reprint requests to Dr Latimer, Department of Anaesthesia, Papworth Hospital, Papworth Everard, Cambridgeshire CB3 8RE, En- gland.

therapeutic strategies are considered. The increasing role of pulmonary-specific vasodilators such as inhaled nitric oxide is emphasized. Strategies to preserve right heart perfusion while producing pulmonary vasodilatation are discussed.

(Ann Tkoruc Surg 1995;59:S3-11)

Incidence of Perioperative Low Cardiac Output Syndrome

In patients undergoing a cardiac operation for coronary artery disease or valve replacement, myocardial dysfunction after bypass is frequently observed. This is the case even in patients with good preoperative left ventricular function. Nevertheless, patients with relatively low preoperative ejection fractions rarely require pharmacologic support in the perioperative period.

The time course of postbypass myocardial dysfunction has been shown to be remarkably consistent in many studies. There is an initial improvement in the immediate postbypass period (the first hour) followed by a decline in function (maximal at 4 to 5 hours after bypass) and then usually an improvement to preoperative levels at 24 hours after operation [l].

Royster and associates [2] have identified various preoperative and intraoperative factors that predict the need of perioperative inotropic support. In order of decreasing significance, these are as follows: low preoperative ejection fraction; old age; cardiac enlargement at catheteriza- tion; female sex; and higher baseline and postcontrast left ventricular end-diastolic pressure measurements at cath- eterization. Patients with an ejection fraction of less than 0.55 with associated wall motion abnormalities and left ventricular end-diastolic pressure changes of greater than 10 mm Hg after injection of contrast material had a higher need of inotropic support in their study.

Physiology of Cardiac Contraction

To review the pharmacologic methods of manipulating cardiac function, it is necessary to consider briefly the physiology of cardiac contraction. It is important to remember that the contractile state of the heart cannot be considered in isolation from the vascular system and that manipulation of both preload and afterload is necessary for optimal function. To consider the net effect on cardiac performance, the pharmacologic effects of inotropic

0 1995 by The Society of Thoracic Surgeons 0003-4975/95/$9.50 0003-4975(94)00916-U

s4 CARDIAC FAILURE DOYLE ET AL LOW CARDIAC OUTPUT SYNDROME

Ann Thorac Surg 1995;59:s3-11

drugs must be considered in conjunction with the vascular effects they frequently produce.

Cardiovascular Changes Associated With Congestive Heart Failure

Myocardial Stimulus-Response Coupling

Stimulus-response coupling in cardiac cells is briefly outlined to consider the sites at which inotropic drugs act.

Myocytes are enveloped by the sarcolemma, which is a phospholipid bilayer exhibiting selective ion permeabil- ity. High levels of potassium with low levels of intracellular calcium and sodium are maintained within the sarcolemma by energy-utilizing pumps. However, within the cell is found the sarcoplasmic reticulum with dilated ends called cisternae, which have relatively high concen- trations of calcium. Contraction of a myocyte is initiated by inward movement of calcium across the cell membrane through voltage-dependent calcium channels. This inward flow of activator calcium triggers the release of calcium from the sarcoplasmic reticulum. The released calcium combines with troponin C, which induces a conformational change in tropomyosin, thereby allowing the sliding of actin and myosin filaments and thus contraction. Hence, the contractile state of the myocyte is closely related to the intracellular calcium concentration.

The modulation of intracellular calcium levels is controlled by the concentration of the second messenger, cyclic adenosine monophosphate (CAMP), which thus has a direct role in controlling the contractile state of the cell. The CAMP levels can be increased by either stimu- lating the enzyme adenylate cyclase or averting its destruction by the inhibition of the enzyme phosphodiesterase III. Adenylate cyclase can be stimulated by the binding of agonists to p, and & receptors on the cell surface. The transmembrane signaling between the p receptors and the enzyme involves the guanosine 5- triphosphate (GTE)-binding regulatory proteins. One of these 9 proteins is inhibitory and one, stimulatory.

An increase in CAMP levels stimulates protein kinases, producing phosphorylation of membrane calcium channels. This augments calcium influx and thus contractility. Relaxation is induced by the sequestration of calcium into the sarcoplasmic reticulum, also an energy-consuming process driven by adenosine triphosphate- dependent calcium pumps on the sarcoplasmic reticulum. Phosphorylation of phospholamban, a regulatory protein, by CAMP in cardiac cells leads to the enhanced extrusion of ionized calcium into the sarcoplasmic reticulum. This results in an increased rate of relaxation (lusitropy). Thus, agents that increase CAMP can stimu- late both increased forced contraction (inotropism) and increased relaxation (lusitropism). Inhibition of CAMP breakdown by phosphodiesterase inhibition would be expected to have similar effects on the myocyte as p receptor activation.

Adenylate cyclase activation is also achieved by the binding of glucagon and thyroxine to their respective receptors, which are similarly linked to the enzyme. However, this mechanism of increasing CAMP levels will not be further considered.

The pathophysiology of chronic congestive heart failure needs to be considered to predict the efficacy and the desirable properties of pharmacologic agents for use in patients undergoing operation for this condition. The changes can be examined at two levels: the gross cardiovascular changes induced by complex neurohumeral mechanisms and those occurring at the cellular level in response to chronic sympathetic stimulation.

Chronic failure of ventricular function leading to impairment of peripheral perfusion induces homeostatic mechanisms, the purpose of which is to improve cardiac output and hence perfusion. The mechanisms involved are sympathetic activation and activation of the renin- angiotensin system.

Sympathetic stimulation leads to release of neural norepinephrine and also release of epinephrine from the adrenal medulla. In addition to reducing venous capaci- tance, these catecholamines have a direct inotropic and chronotropic effect on the heart, thereby increasing preload and inducing vasoconstriction. This results in an increase in systemic arterial pressure. Activation of the renin-angiotensin system induces vasoconstriction in the short term (angiotensin II and III) and an increase in circulating volume (by way of aldosterone) and hence preload, thus increasing cardiac output by the Frank- Starling mechanism.

Chronic sympathetic stimulation leads to a depletion of myocardial intraneuronal norepinephrine. The increased serum levels of epinephrine lead to a reduction in p1 but not p2 receptor density in the heart and also induces /3 receptor downregulation, possibly by increasing the levels of G inhibitory protein involved in transmembrane signaling.

Inotropic agents displaying an indirect action by re- leasing neuronal norepinephrine or inhibiting its uptake (uptake l), such as dopamine and dopexamine, respec- tively, may be less effective in the norepinephrine- depleted heart seen in patients who rely on chronically elevated sympathetic tone to maintain adequate function.

The Ideal Inotropic Drug

The ideal inotropic drug for use in the acute setting of perioperative low cardiac output should have the following characteristics: It should increase cardiac output mainly by increasing stroke volume without an appreciable increase in heart rate. It should be lusitropic and have favorable effects on the vasculature. It should lower both left ventricular afterload by inducing systemic vasodilatation and right ventricular afterload by lowering pulmonary vascular resistance (PVR). A reduction in both right and left heart filling pressures in association with increased cardiac output is desirable in the hope of maintaining a favorable myocardial oxygen supply to demand ratio.

In the context of the perioperative period, the chronically dysfunctional heart also must cope with the acute insult of surgical intervention and cardiopulmonary by-

Ann Thorac Surg 1995:59:53-11

CARDIAC FAILURE DOYLEETAL s5 LOWCARDIACOUTPUTSYNDROME

pass. The patient has to endure the ischemic insult of cardioplegia, cardioplegic arrest, and reperfusion injury. This combination increases the likelihood of postoperative myocardial dysfunction.

The failure of myocardial function after periods of hypoxic injury and reperfusion is called the stunned myocardium, and the underlying pathology may be related to reduced high-energy phosphate levels, intracellular calcium overload, and generation of superoxide radicals in addition to abnormalities in microcirculatory flow. It has been shown that the stunned myocardium responds to inotropic therapy in contrast to areas undergoing active ischemia where inotropic agents may cause further injury.

Attempted Weaning From Cardiopulmonary Bypass

It is useful to emphasize that before weaning is attempted, the patient should be warmed to an adequate temperature, should be well oxygenated with an acceptable acid-base balance, and should have a serum potassium in the upper normal range. The cardiac rate and rhythm should be adequate, and if not suitable, cardiac pacing should be instituted. Optimal preloading of both right and left ventricles by careful fluid management should be employed and acute dilatation of either ventricle avoided during the weaning process. If during these attempts under optimal conditions, weaning cannot take place, there are three options, available, which are often used in combination: (1) reinstitute cardiopulmonary bypass and allow the heart to further recover; (2) reinstitute bypass and employ intraaortic balloon counterpulsation; or (3) employ pharmacologic means of manipulating the inotropic state of the heart and the vasculature. It is this third option that will be discussed further.

Classification of Inotropic Drugs

It is convenient to classify inotropic drugs on the basis of their effect on intracellular CAMP. The CAMP- independent drugs include calcium salts, digoxin, and possibly a-adrenergic agonists.

The CAMP-dependent drugs include the familiar adrenergic agonists such as epinephrine, isoproterenol hydrochloride, dobutamine, and the dopaminergic agonists, dopamine and dopexamine. This class also includes the cyclic nucleotide phosphodiesterase inhibitors, thy- roid hormone, and glucagon.

cAMP-Independent Drugs The only commonly used drug of the CAMP-independent class in the acute perioperative situation is calcium, which is administered in an attempt to facilitate weaning from cardiopulmonary bypass. Several studies have shown that 5 mglkg of CaCl, increases mean arterial blood pressure by increasing systemic vascular resistance (SVR) but has no effect in increasing cardiac index [4]. It may, however, be detrimental by contributing to ischemic cellular injury, and it may also produce coronary artery spasm. There is some evidence that it can

increase the likelihood of postoperative pancreatitis. Thus, in the absence of proven marked hypocalcemia, severe hypokalemia, or calcium-channel blocker over- dosage, large doses of calcium (>5 mglkg of CaCl,) are not indicated.

It has also been demonstrated that calcium administration may blunt the response of patients to epinephrine and dobutamine subsequently administered. No role has been shown for the use of digoxin or (Y agonists (other than as vasopressors) in the acute perioperative setting of low cardiac output. However, it is interesting to note that (Y~ agonists increase the contractile state of the heart by a CAMP-independent mechanism that involves phospha- tidylinositol and direct calcium-channel activation.

cAtvU?-Dependent Drugs Intracellular CAMP can be elevated by &- or &- adrenergic-induced stimulation of adenylate cyclase by the appropriate agonists. Examples of the former are dobutamine, epinephrine, dopamine, and isoproterenol, and an example of the latter is dopexamine. Intracellular CAMP can also be elevated by inhibiting CAMP degrada- tion with the phosphodiesterase III-specific inhibitors milrinone, amrinone, and enoximone. The phosphodiesterase III isoenzyme is largely specific to myocardial and vascular cells, and this allows the use of drugs that lack the central nervous system and gastrointestinal side effects of nonspecific phosphodiesterase inhibitors such as aminophylzine. The increased incidence of side effects may be related to the fact that theophyllines are adenosine antagonists at high dosages.

P-ADRENERGIC AGONISTS. The archetypal & agonist is dobutamine, which has been in use for 15 years. Many studies have compared its use with that of dopamine. At low doses (0.5 to 3.0 pg. kg- . min-), dopamine is a DA, receptor agonist; at intermediate doses (3.0 to 5.0 pg. kg-l. min-I) chiefly a p, agonist; and at higher doses, increasingly an 01~ receptor and serotonergic receptor agonist. Dopamine also stimulates norepinephrine release from sympathetic nerve terminals and hence may be considered to be an indirect sympathomimetic agent. At low doses, dopaminergic stimulation results in increased splanchnic, cerebral, and coronary blood flow and particularly, renal cortical blood flow, although its role in maintaining renal function is debatable.

At doses that are active primarily on p1 receptors, dopamine increases myocardial contractility with cardiac output rising with minimal alteration in heart rate, blood pressure, or SVR. At higher doses, further increases in cardiac output are seen but with increasingly greater rises in heart rate, SVR, and blood pressure. If SVR rises excessively because of (Ye activation, cardiac output may fall.

In a comparison between dopamine and dobutamine by Salomon and co-workers [5], in patients in unstable condition undergoing aortocoronary bypass, the two drugs in equal doses produced nearly equivalent increases in cardiac output. However, dobutamine produces a greater tachycardia than dopamine, which may not be a desirable attribute. In patients whose heart rate

S6 CARDIAC FAILURE DOYLEETAL AI~J Thorac Surg LOWCARDIACOUTPUTSYNDROME 1995;59:53-11

was controlled by pacing, Fowler and colleagues [6] compared the effects of the two agents on coronary blood flow. Dopamine and dobutamine produced similar increases in myocardial oxygen consumption, but dobutamine increased coronary blood flow to a greater extent, which is an advantageous combination. It would seem that dopamine and dobutamine have been shown to exhibit minimal differences in hemodynamic variables in surgical patients.

DOPEXAMINE. Dopexamine is a relatively recently intro- duced inotropic drug. It has a unique combination of activity in that it is a potent p2 agonist in conjunction with DA, and DA, receptor agonist activity and also inhibits the uptake of norepinephrine from the synaptic cleft (uptake 1).

It has been shown that f12 receptor function and numbers are well maintained in the chronically failing heart subject to high levels of catecholamines. Consequently, dopexamine might be expected to be particularly useful as an inotropic agent in this situation.

In a study [7] comparing dopexamine with dobutamine in terms of hemodynamic response of patients with reduced cardiac output, it was demonstrated that the majority of patients receiving an equivalent dose of dopexamine had development of a sustained tachycardia (>120 beats per minute) requiring treatment with esmo- 101 hydrochloride. However, a study [S] using dopexamine after cardiac surgical intervention demonstrated a dose-dependent increase in cardiac index associated with a marked reduction in SVR. Heart rate increased significantly (89 to 117 bpm), and the mean arterial pressure remained unchanged. The study encompassed four dose regimens of 1,2,4, and 6 pg * kg-l * minP1 with a long-term infusion of 2.8 Kg * kg- . min.. (for 26 hours) that produced beneficial hemodynamic effects with an acceptable heart rate [S].

In common with the phosphodiesterase III inhibitors, dopexamine can be described as an inodilator because it produces an increase in inotropic state that is aug- mented by a reduction in SVR, thus producing little net effect on mean arterial blood pressure. This is a desirable combination of attributes, which is attenuated in the case of dopexamine by its tendency to produce a tachycardia.

EPINEPHRINE. Epinephrine is a potent agonist at &, &, and CZ~ receptors. At low infusion rates (0.005 to 0.02 pg * kg- . min?), /3 receptor stimulation predominates, resulting in increased myocardial contractility, increased heart rate, and peripheral vasodilatation. Provided circulating volume is adequate, the net hemodynamic effects are a rise in systolic pressure, a reduction in diastolic pressure, decreased SVR and PVR, and increased stroke volume, left ventricular work, and cardiac output.

Many institutions use epinephrine as a first-line drug for inotropic support after cardiopulmonary bypass. But- terworth and co-workers [9] compared epinephrine, 10 ng . kg ml * min-, with dobutamine, 2.5 and 5 pg * kg- * min-I, in patients undergoing aortocoronary bypass procedures. Epinephrine produced comparable increases in stroke volume as dobutamine with less tachycardia.

PHOSPHODIESTERASEINHIBITORS. Thisclass ofdrugsinhib- its the phosphodiesterase III isoenzyme, which is found in myocardial and vascular smooth muscle cells. Inhibi- tion of the enzyme leads to an increase in the resting level of CAMP. The increased level of CAMP produced leads to enhanced contractility and relaxation in heart muscle and relaxation in vascular smooth muscle cells, thus producing inodilatation. It also inhibits phosphodiesterase in platelets. This leads to increased levels of CAMP, which theoretically might be expected to reduce platelet aggregation and potentiate blood loss.

The actions of these agents are independent of receptor activation and are not susceptible to receptor downregulation or reduction in receptor density seen in chronic heart failure [3]. In addition, there is no demon- strable tolerance for their action when used in the short term. The phosphodiesterase III inhibitors are thought to accelerate myocardial relaxation probably as a result of CAMP-induced augmentation of calcium uptake by the sarcoplasmic reticulum.

Phosphodiesterase inhibitors have been shown to augment the action of P-adrenergic agonists with some suggestion of synergy. Evidence for this has recently become available from in vitro work on a stimulated human atria1 muscle preparation by Latimer and associates [lo]. This study demonstrated that both milrinone and piroximone markedly increased contractility of the preparation. More impressively, both potentiated the inotropic action of epinephrine in a synergistic manner. The drugs currently in use are the bipyridine derivatives amrinone and milrinone and the imidazolinic derivatives enoximone and piroximone.

This class of drugs has been found to reliably induce increases in cardiac index with decreased right and left atria1 filling pressures in association with reduced PVR and SVR. In general, they show no or little increase in oxygen consumption and have minimal effect on mean arterial blood pressure and heart rate. The observed hemodynamic effects are attenuated by the preexisting hemodynamic abnormalities. This will be discussed in more detail with reference to milrinone.

The phosphodiesterase III inhibitors are emerging as useful inotropic drugs for the perioperative treatment of low cardiac output syndrome. Their use is associated with beneficial vascular effects, namely, a decrease in filling pressures of both the left and right heart in conjunction with pulmonary and systemic vasodilatation. This has achieved increases in cardiac index associated with little or no increase in myocardial oxygen consumption. These drugs have been shown not to decrease systemic arterial pressure, particularly in patients with marked impairment of contractility. These agents have been shown to be useful in patients not responding to conventional inotropic regimens and may well be synergistic with the P,-adrenergic agonists, thus providing a further therapeutic strategy for the treatment of these problematic patients.

AMRINONE. Amrinone has been shown to increase cardiac output and reduce SVR and PVR with a reduction in both left- and right-sided filling pressures in patients with


CARDIAC FAILURE DOYLE ET AL s7 LOW CARDlAC OUTPUT SYNDROME

heart failure. The hemodynamic effects are achieved by a combination of positive inotropism and reduction in afterload manifested by a reduction in systemic arterial and left ventricular end-systolic pressures. The augmentation of cardiac output is greater than expected purely from a reduction in afterload. Amrinone reduces blood pressure less in patients with impaired left ventricular function than in those with normal function.

In a study [ll] comparing equipotent doses of amrinone and dobutamine in terms of inotropic action, amrinone produced a greater fall in ventricular filling pressures but with a slightly greater reduction in systemic arterial pressure [ll]. Myocardial oxygen consumption has not been observed to increase with amrinone usage probably because reduced preload and afterload offset the effects of increased contractility.

Dose-finding studies were carried out by Butterworth [12] in 38 patients in stable condition recovering from aortocoronary bypass grafting. The effectiveness of three increasing doses of amrinone was studied, and the results showed that amrinone significantly increased cardiac index in a dose-dependent manner. A dose of 1.5 mglkg of amrinone was found to increase stroke volume as much as 5 ,ug . kg- . rnin~l of dobutamine or 30 ng . kg- 1 + mini 1 of epinephrine [9].

The investigators showed that amrinone induced increases in heart rate and decreases in mean arterial pressure, but these changes were not dose dependent.

Further studies by the same group compared epinephrine, 30 ng . kg-r . min-, with amrinone, 1.5 mglkg, and amrinone plus epinephrine or placebo in 40 patients just weaned from cardiopulmonary bypass who were being paced at a heart rate of 90 beats per minute.

This study revealed that 1.5 mglkg of amrinone was as effective as 30 ng * kg-. . min m1 of epinephrine at improving cardiac function. The combination of amrinone and epinephrine produced results that possibly suggest a synergistic effect, which might be expected on a theoret- ical basis.

MILRINONE. Milrinone is a second-generation bipyridine derivative. Its hemodynamic profile is similar to that of amrinone, but it has a shorter half-life (2 to 4 hours) and is 20 to 30 times more potent. In common with amrinone, milrinone induces increases in cardiac output and reduces right and left ventricular filling pressures in patients with heart failure with only a slight reduction in arterial pressure. These effects are derived from a combination of inotropic augmentation and vasodilation. The positive inotropic action has been confirmed by increases in the rate of isovolumic left ventricular pressure rise at times of reduced filling pressures, shifts in the left ventricular pressure-volume and stress-shortening rela- tions, and augmentation in cardiac indices during intra- coronary infusion in doses producing minimal changes in SVR.

Milrinone has also demonstrated that it can improve left ventricular relaxation and compliance. This lusitropic action may contribute to the observed hemodynamic improvement.

Comparison of dobutamine with milrinone over 48

hours in patients with chronic congestive heart failure has shown that milrinone produces a greater reduction in pulmonary artery occlusion pressure at equivalent doses in terms of increasing cardiac output. In addition, at comparable doses, dobutamine but not milrinone was found to increase myocardial oxygen demand.

The European Milrinone Multicentre Trial Group 1131 has recently reported the hemodynamic and adverse effects of intravenous milrinone in 99 patients after myocardial revascularization and after a mitral or aortic valve procedure or both. All of the study patients had a low cardiac index (mean value, I.93 L/m*) despite adequate filling pressures (mean pulmonary capillary wedge pressure, 11.5 mm Hg). Milrinone was administered as a loading dose of 50 pglkg over 10 minutes followed by three different infusion rates. Hemodynamic measurements were made prior to the start of the study, regularly for 12 hours of treatment thereafter, and for 4 hours after discontinuation of treatment.

The loading dose produced significant increases in cardiac index, heart rate, and stroke volume index with significant falls in pulmonary capillary wedge pressure, right atria1 pressure, mean pulmonary artery pressure, and SVR. These effects were maintained by each of the three infusion regimens used, although the pulmonary vasodilator effects were less predictable and more dose dependent.

Further analysis revealed that the cardiac index before treatment affected the response to treatment; patients with a low preoperative index showed much greater enhancement than those with less impairment of contractility. Likewise, patients with a high PVR responded more to treatment than those with a lower resistance. Interestingly, patients with a low mean arterial pressure prior to treatment showed no fall in pressure after treatment but demonstrated a significant increase in cardiac index. A good therapeutic response was seen in both patients having revascularization and patients undergoing valve replacement irrespective of whether they were in sinus rhythm or atria1 fibrillation.

ENOXIMONE. Enoximone is an imidazole-derived phosphodiesterase inhibitor shown to have very similar effects to those of the bipyridine group of drugs during short-term administration. It displays a balance of inotropic and vasodilator actions and, in common with amrinone and milrinone, is unlikely to increase myocardial oxygen consumption significantly. It is expected to be proarrythmogenic and like all inotropic drugs, its use demands careful electrocardiographic monitoring.

Enoximone has been compared with amrinone recently in patients with low cardiac output syndrome after a cardiac operation. The hemodynamic indices of patients after coronary revascularization procedures, aortic valve replacement, or mitral valve replacement indicated no significant difference between amrinone-treated and enoximone-treated patients; both groups exhibited significant increases in cardiac index associated with reduced filling pressures and vascular resistances.

Enoximone has been used to treat postoperative cardiogenic shock refractory to conventional treatment with

S8 CARDIAC FAILURE DOYLE ET AL LOW CARDIAC OUTPUT SYNDROME

Ann Thorac Surg 3995;59:53-11

p agonists, vasodilators, and intraaortic balloon pump- ing. The study demonstrated a considerable improvement in all hemodynamic variables after administration of 1 mglkg of enoximone and concluded that enoximone has a useful role in this situation.

These findings have been confirmed in a study of 19 patients who could not be weaned from cardiopulmonary bypass after operation for a variety of pathologic conditions despite conventional treatment with epinephrine, dopamine, and dobutamine. After the inotropic regimen was changed to one consisting of epinephrine, dopamine, and enoximone, low cardiac output syndrome was successfully reversed in 12 of the 19 patients. In 3 patients, the use of enoximone apparently led to persistent ventricular tachycardia, which responded to discontinuation of the drug.

Despite the fact that enoximone is related to the imidazolic compounds etomidate and ketoconazole, no evidence of adrenal suppression has been demonstrated after acute administration. This was assessed by observ- ing the cortisol response to adrenocorticotropic hormone injection in healthy volunteers who received 1.25 mglkg of enoximone intravenously. All demonstrated the expected improvements in hemodynamic variables.

Right Ventricular Dysfunction

Traditionally the right ventricle has been regarded as a passive conduit between the systemic veins and the pulmonary artery. Right ventricular abnormalities were paid scant or no attention because of early animal exper- iments that showed little hemodynamic upset after extensive destruction of the free wall of the right ventricle, prolonged survival of patients with little or no right ventricular function, and the success of surgical procedures such as the Fontan operation. This view coupled with the prevalence of ischemic heart disease and systemic hypertension in which the major expression of the disease process is focused on the left ventricle has served to underestimate and perhaps misinterpret the importance of the right ventricle in clinical medicine.

Daily practice in the intensive and coronary care units and the cardiothoracic operating room indicates the important contribution of the right ventricle to the abnormal circulatory state accompanying various disorders of the heart, lungs, and circulation. Extensive right ventricular infarction can lead to cardiogenic shock and can be fatal. Mortality has been shown to be significantly higher after cardiac surgical intervention and cardiac transplantation in patients with right ventricular failure. There is an increasing number of reports of right ventricular failure after coronary artery bypass grafting, and perioperative right-sided dysfunction can have disas- trous consequences at the time of weaning from cardiopulmonary bypass. Right ventricular dysfunction is also common in other shocklike states including septic shock and postcardiotomy shock and is important in predicting survival of patients with ventricular septal defect after acute myocardial infarction.

Right Ventricular Performance: Normal Anatomy and Physiology

Compared with the left ventricle, the right ventricle is relatively thin walled and is irregular in shape. Because of the thin wall, it is highly compliant and distensible and can increase its size substantially without major changes in intracavitary filling pressure. However, the right ventricle does not have the same muscular reserve as the left ventricle; hence, even small increases in right-sided afterload result in a dramatic reduction in right ventricular stroke volume. In fact, the right ventricle is approxi- mately twice as sensitive to afterload increases as the left. Another difference between the two ventricles is that the right ventricle is perfused throughout the cardiac cycle. This is important, as systemic hypotension can lead to right ventricular failure caused by ischemia, especially if right ventricular pressures are significantly elevated (right ventricular perfusion pressure = aortic pressure - right ventricular pressure). The right ventricle has the same determinants of function as the left ventricle, namely, preload, afterload, and contractility. Right ventricular stroke volume is proportional to end-diastolic volume and inversely proportional to vascular load, ex- pressed by the PVR or pulmonary artery pressure.

The right and left ventricles are interdependent, that is, the proper functioning or malfunctioning of one ventricle affects the other. Maintenance of right ventricular function is important to ensure proper left ventricular function, as the right ventricle delivers the preload necessary for left ventricular output.

The pericardium sets the limits for the dilatation of the heart, and an increase in right ventricular volume increases the intrapericardial pressure. This external pressure decreases left ventricular distensibility. Right ventricular dilatation also causes a leftward shift of the interventricular septum with consequent impaired distensibility of the left ventricle. Right ventricular failure is evidenced by an increase in right ventricular end- diastolic pressure and a decrease in aortic pressure and cardiac output. It has been shown in dogs with experi- mental pulmonary hypertension and right ventricular failure that with increasing right ventricular systolic pressure, right ventricular myocardial blood flow fails to increase in proportion to the demand, and ischemia and failure occur. Reestablishment of myocardial perfusion pressure by pressor substances reversed the right ventricular failure.

The management of right ventricular failure includes optimization of right-sided preload, maintenance of aortic pressure (right ventricular perfusion pressure), reduction in right ventricular afterload, and increase in right heart contractility. Intravenous vasodilators are commonly used to reduce right-sided afterload. However, they must be used with caution because of their effects on systemic pressures. If right ventricular perfusion pressure becomes too low, right ventricular failure may worsen. The optimal agent for treatment of right heart failure would be a selective pulmonary vasodilator with no effects on SVR. This will be discussed later.

Ann Thorac Surg 3995:59:53-11

CARDIAC FAILURE DOYLE ET AL s9 LOW CARDIAC OUTPUT SYNDROME

Assessment of Right Ventricular Function

Because of the complex shape of the right ventricle, accurate assessment of right ventricular volume is diffi- cult (assumptions made for calculating left ventricular volume are not valid). Central venous pressure, right atria1 pressure, and right ventricular pressure have been shown to be invalid in judging right-sided ejection fraction or loading conditions. Radionucleotide angiography, thallium 201 myocardial imaging, and echocardiography, both M mode and two dimensional, have been applied to detect right ventricular dysfunction, but their lack of reproducibility and easy availability are limiting factors.

Right ventricular ejection fraction, traditionally used as an indicator of right ventricular contractility, can be effectively measured by a thermodilution technique em- ploying a fast-response thermistor catheter with two intracardiac electrocardiographic electrodes. The measurement is easily performed and is accurate for right ventricular ejection fraction and stroke volume [15]. Transesophageal echocardiography is another important intraoperative tool used effectively to assess right and left ventricular dysfunction. However, both the thermodilution and the transesophageal echocardiographic techniques have clinical limitations and are time-consuming. Measurement of right-sided pressure-volume relation- ships is another useful method of assessing right ventricular function, and pressure-volume loop recording is a good indicator of right heart dysfunction and pulmonary regurgitation in the postoperative period.

Postoperative and Acute Right Ventricular Dysfunction

Increasing numbers of patients seen for a cardiac operation are at risk for pulmonary hypertension and there- fore right ventricular dysfunction. These patients may have preexisting congestive heart failure or may have development of new ventricular dysfunction during operation. Studies using a variety of different techniques have demonstrated significant deterioration in left ventricular or biventricular function after a cardiac surgical procedure. Early postoperative right-sided dysfunction has also been shown in the previously normal right ventricle [16]. However, patients with preexisting impairment of the right ventricle show more severe and prolonged dysfunction postoperatively with profound deterioration in hemodynamics [17]. De novo right-sided failure after operation on the mitral valve, although rare, has been shown to carry a poor prognosis.

The causes of postoperative right ventricular dysfunction are multifactorial. There can be impaired contractility of the right ventricle with or without increased pressure and volume load. A poor contractile state may be due to relatively poor protection of the right side during cardiopulmonary bypass, reperfusion injury, right ventricular ischemia, and perioperative use of P-adrenergic blocking drugs. Anaphylactoid reactions to protamine sulfate, blood products, or both and inflammatory re- sponses to the extracorporeal circuit itself play an important role in increasing PVR. Intramyocardial air and kinking of the pulmonary artery have also been reported

as causes of acute right ventricular dysfunction. In- creased back pressure resulting from left ventricular failure of any cause is of major clinical relevance. There could also be pressure overload of the right ventricle because of pulmonary embolism, pulmonary disease, adult respiratory distress syndrome, pulmonary stenosis, and primary pulmonary hypertension. As the PVR rises progressively, right ventricular contractility cannot be further enhanced; this leads to intractable and irrevers- ible right ventricular failure. However, if the patient is successfully treated before that point, it may be possible to arrest and even to reverse the decline.

Principles of Managing Acute Right Ventricular Failure

Optimization of Right Ventricular Preload Most authorities believe that right ventricular preload must be optimized, but volume loading can be deleteri- ous. The optimal range of right-sided filling pressures in acute right ventricular pressure overload is not known, and treatment must be individualized. If right ventricular contractility is markedly depressed, the Frank-Starling curve is relatively flat. Volume replacement at this stage would increase right-sided filling pressures and intrapericardial pressure, subsequently reversing the trans- septal pressure gradient. Volume loading when the central venous pressure is less than 10 mm Hg should be initiated, and the cardiac output should be followed closely. Further volume loading should be avoided when the right atria1 pressure increases more than 3 mm Hg without an appreciable change in cardiac output.

Control of Heart Rate and Rhythm Establishing an atrioventricular conduction sequence is one of the most important initial therapeutic measures in patients who have not previously been in atria1 fibrillation. Electric and pharmacologic means should be used to establish an appropriate rhythm before inotropic or mechanical support is initiated. Supraventricular arrhythmias occur commonly during cardiac operations, and in patients dependent on the atria1 contribution for ventricular filling, these arrhythmias may seriously com- promise cardiac output. When pharmacologic treatment for paroxysmal supraventricular tachycardia is indicated in these circumstances, it has been shown that adenosine is a highly effective agent, as it causes rapid conversion to sinus rhythm.

Afterload Reduction Vasodilators are commonly used to attenuate the vaso- constrictive effects of catecholamines by avoiding ventricular distention and treating the elevated PVR observed in acute right ventricular pressure overload. Attention should be focused on the administration of agents that demonstrate specificity for dilating the pulmonary vasculature, ie, pulmonary versus systemic vasodilation. Currently available drug therapies for pulmonary hypertension with the exception of inhaled NO are not specifically targeted at the pulmonary vasculature. As a result, many of these drugs may also reduce SVR and

SlO CARDIAC FAILURE DOYLE ET AL LOW CARDIAC OUTPUT SYNDROME

Ann Thorac Surg 1995;59:53-11

produce systemic hypotension, thus limiting their clinical use. In addition, intravenously delivered drugs that increase pulmonary blood flow also contribute to ventilation-perfusion mismatch.

Traditionally, pulmonary vasodilation was accom- plished using NO-based dilators, ie, nitroglycerin, sodium nitroprusside, or both. Alpha-adrenergic blocking agents such as tolazoline hydrochloride and phentol- amine have been used clinically to decrease PVR, but ganglion-blocking agents have shown to be of no value in reducing PVR. There appears to be little role for the use of calcium-channel blockers in patients with acute right ventricular afterload, although in chronic pulmonary hypertension, their use has been shown to be of benefit. The use of calcium at the time of weaning from cardiopulmonary bypass has been demonstrated to have no adverse effects on PVR and right ventricular function, a finding contrary to earlier beliefs. Prostaglandin E, and prostacyclin are two potent pulmonary vasodilators. The beneficial effects of prostaglandin E, on reducing PVR have been reported, and it has been shown to be superior to isoproterenol, epinephrine, hydralazine hydrochloride, prostacyclin, or nifedipine [18]. Prostaglandin E, has also been shown to reduce the PVR in situations where nitroglycerin and nitroprusside failed in patients both before and after cardiac transplantation.

Endogenous endothelial NO release can be stimulated by a number of agents. Acetylcholine in doses of 2 to 16 mglmin reduces PVR with minimal airway and chronotropic effects, but nausea and cramps have been reported in conscious patients. Adenosine triphosphate and adenosine are currently under investigation, and adenosine has shown some promising results. Morgan and associates showed the preferential effects of adenosine on pulmonary circulation in patients with primary pulmonary hypertension. However, it should be noted that in the presence of endothelial dysfunction (as demonstrated in patients with chronic pulmonary hypertension and immediately after cardiopulmonary bypass), the endothelial-dependent agents (especially acetylcholine) may paradoxically increase the PVR.

Vascular smooth muscle relaxation can be achieved through adenylate cyclase-coupled receptor mechanisms, the most familiar way being through vascular /3 receptors. Depending on the vascular tone, fi-adrenergic stimulation will lead to a direct relaxation of vascular smooth muscle and a reduction in PVR. If the cardiac index is low, then the inotropic effects of P-adrenergic drugs (or any inotropic agent) will also lead to an effective reduction in PVR by moving the pulmonary vasculature along the pressure-flow relationship where recruitment is occurring.

Phosphodiesterase Inhibitors The role of the phosphodiesterase III-specific inhibitors in reducing IVR has been discussed, and their beneficial effects have been emphasized.

Nitric Oxide New discoveries in the biology of the endothelium have presented novel therapeutic approaches to pulmonary

vasoregulation. Nitric oxide is produced by the normal human lung and is present in exhaled gas [19]. It is an important modulator of perinatal and neonatal pulmonary vascular tone and was known previously as endothelial-derived relaxant factor. Reduction of endogenous NO activity contributes to pulmonary vasoconstriction during hypoxic gas breathing. Nitric oxide, both endogenous and exogenous (inhaled), diffuses into sub- jacent vascular smooth muscle where it activates guany- late cyclase, increases cyclic guanosine 35-monophosphate, and causes smooth muscle relaxation. When it diffuses into the intravascular space, it rapidly binds to hemoglobin to form nitrosylhemoglobin, which is rapidly oxidized to methemoglobin, which is further reduced to nitrite and nitrate prior to being excreted by the kidney [19]. It is the only known specific pulmonary vasodilator with no systemic effects and was named molecule of the year in 1992. Forty parts per million of inhaled NO has been shown to reduce the raised PVR after a cardiac surgical procedure and the transpulmonary gradient after cardiac transplantation [2O]. It has been found to decrease pulmonary hypertension from almost any cause including persistent pulmonary hypertension of the new- born. It can now be safely administered provided its inhaled concentration and that of nitrogen dioxide (a lethal by-product of NO manufacture) are continuously monitored.

Use of multiple pulmonary vasodilators to effect vascular smooth muscle relaxation at several sites can be tried. Careful choice of agents allows either a greater reduction in PVR or the use of a reduced dose of agents with an attendant reduction in side effects. Thus a phosphodiesterase inhibitor that lessens the hydrolysis of CAMP will potentiate the effects of NO, whether it comes from an endothelial cell, a gas cylinder, or a glass bottle of nitroglycerin.

Other Measures Oxygen is a useful and safe vasodilator and relieves hypoxic pulmonary vasoconstriction. It has very little effect on systemic blood pressure. Respiratory variation and ventilatory adjustments can significantly influence the PVR. Hyperventilation and hypocarbia have been shown to reduce pulmonary artery pressure. However, it is the pH, not the carbon dioxide tension, that regulates the pulmonary tone. Right ventricular ejection fraction is least affected by intermittent, mandatory, and spontane- ous modes of ventilation and most impaired by volume- controlled ventilation. A decrease in right ventricular ejection fraction is seen at positive end-expiratory pressure levels greater than 15 cm H,O. High-frequency jet ventilation has been reported to cause less hemodynamic instability and would be beneficial provided airway pressure is kept to a minimum. Control of body temperature should be given due importance, as hypothermia increases PVR. To avoid the first-pass effects on pulmonary vasculature, the use of left atria1 administration of norepinephrine may also help to increase the systemic perfusion pressure. Adequate aortic root pressure must be maintained to ensure good flow in the right coronary artery.


CARDIAC FAILURE DOYLE ET AL Sll LOW CARDIAC OUTPUT SYNDROME

Mechanical Support Devices The use of intraaortic balloon counterpulsation has been shown to improve septal motion and to improve right ventricular function indirectly by improving cardiac output. There is definitely a justification for the intraaortic balloon pump in some patients, even in the presence of normal left ventricular function where hypotension com- promises right ventricular perfusion. Left ventricular assist devices have also been shown to improve right ventricular function, and centrifugal pumps, right-sided intraaortic balloon pumps, right ventricular assist devices, and right-sided cardiomyoplasty have all been tried with varying success.

References

1. Breisblatt WM, Stein KL, Wolfe CJ, et al. Acute myocardial dysfunction and recovery: a common occurrence after coronary bypass surgery. J Am Co11 Cardiol1990;15:1261-9.

2. Royster RL, Butterworth JF IV, Prough DS, et al. Preopera- tive and intraoperative predictors of inotropic support and long-term outcome in patients having coronary artery bypass grafting. Anesth Analg 1991;72:729-36.

3. Bristow MR, Herghberg RE, Port JD, et al. Beta adrenergic pathways in non-failing and failing human ventricular myocardium. Circulation 1990;82(Suppl 1):12-25.

4. Butterworth JF IV, Strickland RA, Mark LJ, Kon ND, Zaloga GP. Calcium does not augment phenylephrines hyperten- sive effects. Crit Care Med 1990;18:603-6.

5. Salomon NW, Plachetka JR, Copeland JG. Comparison of dopamine and dobutamine following coronary artery bypass grafting. Ann Thorac Surg 1982;33:48-54.

6. Fowler MB, Alderman EL, Oesterle SN, et al. Dobutamine and dopamine after cardiac surgery: greater augmentation of myocardial blood flow with dobutamine. Circulation 1984; 70:1103-11.

7. Butterworth JF IV, Prielipp RC, Royster RL, James R, Zaloga GP. A randomized, blinded comparison of dopexamine with dobutamine in patients with reduced cardiac output after coronary artery surgery [Abstract]. Anesthesiology 1992;77: A54.

8. Friedel N, Wenzel R, Mathens G, Hetzer R. The use of dopexamine after cardiac surgery: acute and long-term ef-

fects in patients with impaired cardiac function. Thorac Cardiovasc Surg 1992;40:378-81.

9. Butterworth JF IV, Prielipp RC, Royster RL, et al. Dobut- amine increases heart rate more than epinephrine in patients recovering from aortocoronary bypass surgery. J Car- diothorac Vast Anesth 1992;6:535-41.

10. Walker IA, MacKay JH, Hardy JP, et al. The inotropic effect of milrinone and potentiation of the action of adrenoreceptor agonists. J Cardiothorac Vast Anesth 1992;6(Suppl 1):31.

11. Gage J, Rutman H, Lucid0 J, LeJemtel TH. Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure. Circulation 1986;74:367-73.

12. Butterworth JF IV. Use of amrinone in cardiac surgery patients. J Cardiothorac Vast Anesth 1993;7(Suppl2):1-7.

13. Feneck RO, and the European Multicentre Trial Group. Intravenous milrinone following cardiac surgery I and II. Effects of bolus infusion followed by variable dose maintenance infusion and influence of baseline haemodynamics and patient factors on therapeutic response. J Cardiothorac Vast Anesth 1992;6:554-67.

14. Weber KT, Janicki JS, Shroff S, et al. Contractile mechanics and interaction of the right and left ventricles. Am J Cardiol 1981;47:685.

15. Kay HK, Afshari M, Barash I, et al. Measurement of ejection fraction by thermodilution techniques. J Surg Res 1983;34: 337-46.

16. Wranne B, Pinto FJ, Hammarstrom E, St. Goar FG, Puryear J, Popp RL. Abnormal right heart filling after cardiac surgery: time course and mechanisms. Br Heart J 1991;66:435-42.

17. Fantidis P, Castejon R, Fernandez-Ruiz A, Madero-Jarabo R, Cordovilla G, Sanz-Galeote E. Does a critical haemodynamic situation develop from right ventriculotomy and free wall infarct or from small changes in dysfunctional right ventricle overload? J Cardiovasc Surg (Torino) 1992;33:229-34.

18. Prielipp RC, Rosenthal MH, Pearl RG. Haemodynamic pro- files of prostaglandin El, isoproterenol, prostacyclin and nifedipine in vasoconstrictor pulmonary hypertension in sheep. Anesth Analg 1988;67:722-9.

19. Roberts JD. Nitric oxide and the pulmonary vasculature. Society of Cardiovascular Anesthesiologists: Fifteenth An- nual Meeting book, 1993:153-6.

20. Snow DJ, Gray SJ, Ghosh S, et al. Inhaled nitric oxide in patients with normal and increased pulmonary vasculature resistance after cardiac surgery. Br J Anaesth 1994;72:185-9.

DISCUSSION

DR PATRICK M. MCCARTHY (Cleveland, Ohio): Doctor Latimer, could you tell us a little about the practical aspects of using nitric oxide. How do you monitor for toxic effects?

DR LATIMER: Major manufacturers are now developing equip- ment for both the delivery of nitric oxide and the accurate monitoring of nitric oxide and nitrogen dioxide in the inspired gas. Most delivery systems use mass flow controllers, and the one that is available in Europe was developed by Bo Kjelltoft, Sahlgrenska Hospital, Gothenburg, Sweden, and manufactured by Nomius. Initially we used the chemiluminescence analyzer for monitoring the delivered gas but it had the disadvantages of being large, noisy, and expensive and requiring a large gas flow (700 mllmin) for analysis. It also required a long warm-up time. We now are using a microfuel cell type of analyzer developed by Bedfont Scientific, Upchurch, Kent, which overcomes these problems.

The rate of oxidation of nitric oxide to nitrogen dioxide depends on the concentration of nitric oxide and oxygen at the

point of contact, the speed of mixing. and the delay in delivering the mixture. We have shown that it is potentially dangerous to add nitric oxide to the intermittent flow of gas between the ventilator and patient because there is incomplete mixing. Soda lime has been advocated to scavenge nitric oxide, but some of the available soda limes use potassium permanganate as a color indicator, which also removes the nitric oxide.

DR MCCARTHY: Does it appear that the drug becomes less effective with time?

DR LATIMER: Doctor Falkes group in Berlin gave nitric oxide for adult respiratory distress syndrome for up to 53 days. Regularly during this time, they briefly discontinued treatment during the changing of cylinders and they observed a marked deterioration in the patients condition, which recovered when treatment was recommenced. Acute withdrawal of the nitric oxide therapy is potentially hazardous, and it has been found necessary to wean the patient gradually from therapy.

Documents

5 the Annals of Thoracic Surgery Volume 59 Issue Supp-S1 1995 [Doi 10.1016%2F0003-4975%2894%2900916-u] Anthony R. Doyle; Achal K. Dhir; Anthony H. Moors; Raymond D. La -- Treatment