Cardiovascular Failure

Mary Margaret Wolfe and Fred Luchette

INTRODUCTION

Cardiovascular failure can be either the end result of multisystem organ failure (MOF) or a precursor to shock and MOF (see Chapter 61). Most often cardiovascular collapse will manifest itself with clinical signs and symptoms of cardiac failure. In trauma, the most common cause of shock is acute blood loss (hypovolemia), which results in decreased preload or decreased right heart filling volumes and manifests as tachycardia and hypotension (see Chapter 12). Although this is the most common type of shock occurring after injury, cardiogenic shock, resulting from impaired myocardial contractility, and septic shock, characterized by failure of the heart to overcome decreased vascular tone and failure of end-organ utilization of delivered oxygen, are also seen. As our population ages, the number of elderly patients in the intensive care unit (ICU) will increase. In fact, the number of elderly patients (>65 years old) is expected to double in the next three decades. With an aging population, there are age-related changes in physiology, exacerbations of chronic illnesses, and effects of therapeutic drugs, which need to be taken into consideration when caring for the traumatically injured patient.^1–3 Therapy to support the failing cardiovascular system is directed at the etiology of the shock state and includes fluid resuscitation (preload) as well as pharmacologic modulation of vascular tone (afterload), contractility (with inotropes), and heart rate (with chronotropes) (Fig. 56-1).

FIGURE 56-1 Clinical decision tree for the diagnosis and management of cardiovascular failure.

DETERMINANTS OF CARDIAC OUTPUT

Cardiac output is defined as the quantity of blood ejected into the aorta by the heart each minute and is calculated as heart rate multiplied by stroke volume (CO = HR × SV). This is the quantity of blood that flows through the circulation and is responsible for oxygen and nutrient transport to the tissues. The primary determinants of cardiac output are preload (the venous return to the heart), afterload (the resistance against which the heart must pump), contractility (the extent to which the myocardial cells can contract), and heart rate. The primary determinant of cardiac output is the filling of the heart and the ability to pump that volume effectively. Accordingly, the majority of therapeutic modalities aimed at augmenting cardiac output focus on restoring filling pressures and augmenting ineffective contractility.

Multiple studies and textbooks cite 5.6 L/min as a “normal” resting cardiac output as measured in young, healthy males. However, cardiac output varies with the level of activity of the body, and is influenced by level of metabolism, exercise state, age, size of the individual, and other factors. Accordingly, cardiac output in women is generally stated as being 10–20% lower than in men. Additionally, when factoring in age, the average cardiac output for adults is approximated as 5 L/min. Laboratory and clinical research have demonstrated that cardiac output increases in proportion to increasing body surface area. Therefore, to standardize cardiac output measurements between individuals, the parameter of cardiac index (defined as cardiac output divided by body surface area in m²) is employed.⁴

Preload

In the discussion of cardiovascular physiology, preload is the force that stretches myocardium prior to contraction. The concept of preload is derived from laboratory experiments in which strips of muscle are stretched by small weights (preload) prior to initiating contraction. In these experiments, contraction is triggered by electrical stimulation and a transducer determines the resultant force. Both in vitro experiments and in vivo correlates have revealed that increasing sarcomere length to a maximum of 0.2 m by the addition of weights results in increased force of contraction. Once stretched beyond this length, the contractility of the muscle decreases. This relationship, the Frank–Starling relationship, was described in amphibian hearts by Otto Frank in 1884 and extended to mammalian hearts by Ernest Starling in 1914. The mechanisms linking preload and contractile force are incompletely understood. Although it was initially thought that increased myocardial stretch optimized the overlap of contractile actin and myosin leading to increased force of contraction, more recent research indicates that contractile force is also dependent on sensitivity of the myocyte to ionized calcium gradients, as determined by sarcomere length.⁵

The Frank–Starling relationship provides a paradigm by which the cardiovascular system and its derangements can be approached. Hypovolemia, or decreased preload, is the result of hemorrhage, contraction of the intravascular space due to external fluid losses such as diarrhea, inappropriate polyuria, or contraction of the intravascular space due to internal sequestration as edema or third-space losses. Additionally, venous return to the heart depends on the vascular tone of the venous system. As will be discussed in the pharmacology portion of this chapter, changes in venous capacitance are often unwanted side effects of pharmacologic agents used in treating the injured patient.

Taken together, intravascular volume and venous return determine left ventricular end-diastolic volume (LVEDV), which determines the force of ventricular contraction. The Swan–Ganz catheter is used to measure the pulmonary arterial wedge pressure (PAWP), which approximates left ventricular end-diastolic pressure (LVEDP). Assuming unaltered ventricular compliance, LVEDP theoretically approximates the LVEDV. Unfortunately, in the setting of critically ill patients, factors such as myocardial ischemia, heart failure, myocardial edema, endotoxemia, cardiac hypertrophy, and circulating tumor necrosis factor (TNF) can decrease ventricular compliance, rendering measurement of PAWP as a surrogate for LVEDV unreliable. In these situations, normal or elevated PAWP may not eliminate inadequate preload as a cause of low cardiac output.

Besides changes in venous capacitance, venous return to the heart can be compromised by increased intrathoracic or intra-abdominal pressure. This is most evident with tension pneumothorax, when the shock state is immediately reversed by decompression of the pleural space. Additionally, in the mechanically ventilated patient, the use of positive-pressure ventilation coupled with positive end-expiratory pressure (PEEP) may impair venous return to the heart (see Chapter 57). In this patient population, when intravascular volume is low, the adverse effects of increased intrathoracic pressure on preload predominate and cardiac output is diminished. Importantly, when an underresuscitated patient is placed on positive-pressure ventilation, this situation may lead to cardiovascular collapse. However, in the reverse scenario, patients with normal-to-high intravascular volume may benefit from the afterload-reducing effects of elevated intrathoracic pressure seen with positive-pressure ventilation. Indeed, synchronization of positive-pressure ventilation with the cardiac cycle has been described as a method of afterload reduction and cardiac output augmentation.⁶ In the normal heart, this decrease in afterload does not usually translate into enhanced cardiac output. However, those patients with heart failure are more sensitive to the concomitant decrease in preload. There may also be a poorly understood vasodilatory reflex and changes in sympathoadrenal function.⁷ It should be noted that patients in cardiogenic shock could demonstrate sudden cardiovascular collapse upon removal of ventilatory support. This change in venous return to the heart is also seen in abdominal compartment syndrome and pregnancy (see Chapter 37). It is important to note that the net result of these physiologic changes may be hard to predict in clinical practice, but a thorough knowledge of the underlying physiology is the key to prompt diagnosis and management.

Afterload

Cardiovascular failure due to a reduction in afterload is referred to as distributive shock, and has multiple etiologies: septic shock, neurogenic shock, and anaphylactic shock. Afterload is the force that opposes ventricular contraction. Similar to preload, the concept of afterload is derived from in vitro experiments using strips of cardiac muscle. In these experiments, length is held constant while the muscle is given a variable load that must be moved (afterload). These studies have established that increasing afterload decreases the speed and force of contraction. Clinically, vascular input impedance appears to be the best in vivo correlate of ventricular afterload. Unfortunately, vascular input impedance is not a readily assessed clinical quantity, requiring right heart catheterization and continuous Doppler readings. Therefore, the clinician must rely on systemic vascular resistance (SVR) as a surrogate. SVR is calculated using the hemodynamic equivalent of Ohm’s law:

In this equation, MAP is the mean arterial blood pressure, CVP is the central venous pressure, and CO is the cardiac output. This equation provides an approximation of vascular impedance. Therefore, it is important to realize that the clinical practice of “measuring” afterload or SVR with data from the Swan–Ganz catheter actually provides a calculated value that assumes nonpulsatile flow and does not consider the viscosity of blood, the elastic properties of the arterial walls, or the changes in microvascular resistance. Finally, because SVR is inversely proportional to cardiac output, rather than directly treating an abnormally high SVR, one should first treat the low cardiac output with fluid administration to maximize preload, which will serve to increase CO and decrease SVR.

Contractility

Contractility, also known as inotropic state, is the force with which the myocardium contracts. The inotropic state of the myocardium, and the stroke work performed, can be visualized by the construction of a left ventricular pressure–volume loop (Fig. 56-2). This loop is bounded by the four phases of the cardiac cycle: isovolemic relaxation, diastolic filling, isovolemic contraction, and systolic ejection. Stroke work is defined as the area bounded by this loop.

FIGURE 56-2 The relationship between left ventricular pressure and left ventricular volume during a stylized cardiac cycle.

Instantaneous pressure–volume curves also provide a method to determine both external (stroke work) and internal (loss as heat) work performed by the heart during the cardiac cycle. As described above, the area bounded by the pressure–volume loop defines the external, or stroke work performed by the myocardium. The internal work is defined as the area of the triangle determined graphically by three lines: an extrapolation of the elastance line to the x-intercept, the isovolemic relaxation portion of the pressure–volume loop, and the diastolic filling portion of the pressure–volume loop extrapolated back to its x-intercept (Fig. 56-3). Under this system, the failing heart with low contractility will demonstrate a shallow elastance line, which translates to low efficiency (more internal work performed for the same external work). Clinically, this points toward manipulation of contractility to balance myocardial oxygen demand and delivery. Finally, the strong influence of changes in afterload are readily appreciated under this model, as increasing afterload at a given stroke volume results in increased external work performed by the heart.

FIGURE 56-3 The effect of changes in afterload on (external) ventricular stroke work at constant stroke volume. The areas inscribed by the heavy lines represent the external stroke work performed during two representative cardiac cycles. Decreasing afterload (from A to B) decreases stroke work.

Presently, the use of pressure–volume curves in patient care is limited to centers using newer generation pulmonary artery catheters (PACs) that measure ventricular volume as well as pressure.⁸ More commonly, clinicians rely on Frank–Starling curves to determine myocardial performance and estimate contractility. Finally, contractility can be estimated by angiographic or echocardiographic determination of ventricular ejection fraction, but this method is highly sensitive to changes in afterload, and may be less reliable.

Heart Rate

Heart rate is a key determinant of cardiac output. In the setting of constant stroke volume, increasing the number of cardiac ejections per unit time results in increased cardiac output. In addition, increasing the heart rate increases contractility, a phenomenon known as the Bowditch effect. This effect is due to increases in calcium concentrations. With increased heart rate, the time for reuptake of calcium decreases. The increased calcium concentrations cause upregulation of cAMP, which enhances contractility. However, in the setting of myocardial failure, it is not uncommon to observe heart rates high enough that the diastolic interval is shortened and ventricular filling is compromised, resulting in decreased cardiac output. Rapid ventricular rates that impair cardiac filling are most commonly seen in patients with preexisting or evolving myocardial ischemia. In this setting, rate control becomes paramount in ensuring matched oxygen delivery and utilization.

MYOCARDIAL DYSFUNCTION

Myocardial dysfunction can be defined on the basis of perturbed preload, afterload, contractility, or heart rate. Systemic hypovolemia (e.g., inadequate preload), secondary to hemorrhage or third-space losses, is the most common etiology in the postsurgical or trauma patient. Other causes of decreased cardiac output may arise from failing or decreased contractile function of the heart. Evolving ischemia can lead to areas of heart muscle that lose their ability to contract, leading to decreased cardiac output. The contractility of heart muscle can also become altered following any insult that results in intrinsic metabolic derangements at the cellular level. This typically occurs in the settings of sepsis, postcardiac arrest, or postcardio-pulmonary bypass. Direct physical injury to the myocardium, as occurs following blunt chest injury, may produce contused cardiac muscle, which can lead to contractile dysfunction and decreased cardiac output.

The optimal modalities to diagnose myocardial dysfunction in critically ill patients are poorly established. In this chapter we discuss the evaluation of cardiac function, focusing on measurement of CVP, the use of pulmonary artery (Swan–Ganz) catheters, echocardiography, and noninvasive techniques (see Chapter 17).

MANAGEMENT OF MYOCARDIAL DYSFUNCTION

Preload Augmentation and Rewarming

Myocardial dysfunction secondary to hypovolemia may be caused by hemorrhage or other causes of intravascular volume loss. Prior to the development of hypotension, most adult patients will demonstrate a decrease in urine output, indicative of end-organ hypoperfusion. Augmentation of preload, or restoration of intravascular volume, will reverse this dysfunction if instituted promptly. Depending on the degree of volume loss, most patients respond to simple crystalloid solutions. However, if severe or ongoing hemorrhage is present, and the patient is not responding to crystalloid administration, transfusion of blood products may be necessary. Normalization of heart rate and blood pressure, along with adequate urine output are simple and effective measurements of adequate volume restoration.

During the period of volume replacement, attention must be given to the temperature status of the patient (see Chapter 49). Multiple studies have clearly demonstrated that hypothermia induces a significant depression of both systolic and diastolic left ventricular function.⁹ The use of warmed fluids during resuscitation results in rapid restoration of left ventricular diastolic function, whereas recovery of systolic function is prolonged.¹⁰ This is likely due to long-lasting effects of hypothermia on the excitation–contraction coupling of the actin–myosin complex.

Pharmacologic

A multitude of pharmacologic agents are available for the management of myocardial dysfunction. Selection of the appropriate agent (or agents) should be tailored to the specific clinical situation. Broadly, the agents can be classified into those that act directly on the vascular system (vasodilatation or constriction) and those that augment cardiac contractility. Selected agents have multiple mechanisms of action (Table 56-1).

TABLE 56-1 Dosage, Mechanism, and Actions of Pharmacologic Agents Commonly Used in the Treatment of Cardiovascular Failure

Norepinephrine

Norepinephrine is an endogenous sympathetic neurotransmitter with α- and β-adrenergic effects. At high doses, α-adrenergic effects predominate and increased SVR and increased blood pressure result. Because of this potent vasoconstriction, norepinephrine is generally reserved for patients who are refractory to both volume resuscitation and other inotropic agents.^11,12 However, at low doses, the β-adrenergic actions of norepinephrine predominate, resulting in increased heart rate and contractility. Specifically, in the setting of right ventricular failure, low-dose norepinephrine improves cardiac function without adversely affecting visceral perfusion.¹³ De Backer et al. found no significant overall change in outcome between patients receiving norepinephrine and dopamine for shock.¹⁴ However, in those patients with cardiogenic shock, dopamine was associated with a significant increase in the rate of death. This may be due to the higher increase in heart rate seen with dopamine and subsequent ischemic events.¹⁴ Additionally, norepinephrine is widely used in the care of the head-injured patient in shock because its vasoconstrictive effects do not extend to the cerebral vasculature, making it an ideal agent for maintaining cerebral perfusion pressure.¹⁵

Vasopressin

Arginine vasopressin, or vasopressin, is a potent vasoconstrictor. This natural hormone produced by the posterior pituitary has gained widespread acceptance as a treatment for septic shock refractory to volume resuscitation and conventional pressor agents. During septic shock, the supply of endogenous vasopressin is quickly depleted, and restoration of this deficiency has shown benefits in the weaning of norepinephrine and other pressor agents and also imparts a short-term survival benefit in this group of patients. When vasopressin is combined with norepinephrine, outcomes in the treatment of catecholamine resistant cardiovascular failure in septic shock are superior to therapy with norepinephrine alone.¹⁶

Vasopressin has also emerged as a therapy for cardiac arrest and acute resuscitation.¹⁷ Current guidelines for cardiopulmonary resuscitation recommend vasopressin as an alternative to epinephrine for shock resistant ventricular fibrillation. Vasopressin is a superior agent to epinephrine in asystolic patients but is similar to epinephrine alone in the treatment of ventricular fibrillation and pulseless electrical activity.¹⁸ In the postoperative cardiotomy patient, vasopressin significantly reduces heart rate and the need for both pressor and inotropic support, with no adverse effect on the heart. A significant reduction in cardiac enzymes and cardioversion of arrhythmias into sinus rhythm has also been demonstrated with the use of vasopressin in these patients.¹⁹ Patients undergoing cardiopulmonary bypass often experience hemodynamic disturbances similar to those seen in septic patients, with characteristics of peripheral vasodilatation causing hypotension, and diminished response to conventional pressor agents. Vasopressin has been shown to correct vasodilatory shock following cardiopulmonary bypass regardless of normal circulating vasopressin levels.²⁰

Dopamine

Dopamine is an endogenous catecholamine that has several cardiovascular effects, including increased heart rate, increased contractility, and peripheral vasoconstriction. It is used primarily for inotropic support in order to maintain brain, heart, and kidney perfusion. Dopamine acts on α- and β-adrenoreceptors as well as DA1 and DA2 dopamine receptors, and its actions can be classified based on dose. At doses of 1–3 μg/kg/min, dopamine acts at primarily DA1 receptors in renal, mesenteric, coronary, and cerebral vascular beds, resulting in vasodilation.

It has long been thought that low-dose dopamine (1–3 μg/kg/min), also referred to as “renal-dose” dopamine, increases renal blood flow and maintains diuresis via the DA1 and DA2 receptors.²¹ Two meta-analyses and a large prospective, double-blinded randomized controlled trial have failed to demonstrate that dopamine protects the kidney in critically ill patients with acute renal failure.^22–24 For these reasons, there is insufficient evidence to support the use of low-dose dopamine to maintain renal perfusion in an effort to reduce the incidence of acute renal failure (see Chapter 59). At moderate doses (3–5 μg/kg/min), dopamine stimulates primarily cardiac β-adrenoreceptor, increasing contractility and thus cardiac output. At higher doses of dopamine (10 μg/kg/min), peripheral vasoconstrictive effects from stimulation of α-adrenergic receptors predominate. This can result in significant coronary vasoconstriction resulting in angina, vasospasm, and increased PAWP.²⁵ Additionally, increasing afterload from vasoconstriction coupled with an increased heart rate seen at this dose, results in increased myocardial oxygen consumption and demand. Recent investigation has revealed that individual variation in the pharmacokinetics of dopamine due to weight-based dosing typically results in poor correlation between blood levels and administered dose. Tachycardia can occur with any dose of dopamine, particularly in the hypovolemic patient. When excessive, the increased heart rate will increase myocardial oxygen demand and worsen cardiovascular failure. Due to the variable effects of dopamine, the dosage ranges used to define which receptors it affects are to be used as broad guidelines only, with the awareness that “low-dose” (1–3 μg/kg/min) dopamine may have the unwanted effects of “medium-” (3–5 μg/kg/minute) or “high-dose” (>10 μg/kg/min) dopamine on an individual patient.

Dobutamine

Dobutamine is a synthetic catecholamine with primarily β-adrenegic effects, although it does possess some α₁-adrenergic properties. It is primarily an inotrope, increasing contractility, with minimal chronotropic effects. Dobutamine also possesses mild β₂-adrenoreceptor activity, producing peripheral vasodilatation. This combination of increased contractility and reduced afterload results in improved cardiac output. Importantly, the increase in cardiac output occurs without an increase in myocardial oxygen consumption.²⁶ Because of the vasodilatory effects, dobutamine may reduce blood pressure and is ideally suited for use in low-output cardiac states. For these reasons, dobutamine should be considered the first-choice inotrope for patients with low cardiac output in the presence of adequate preload.²⁷ Two large prospective trials in critically ill patients failed to demonstrate a benefit to raising oxygen delivery to supranormal levels with the use of dobutamine,^28,29 likely due to an inability of the peripheral tissues to utilize the additional oxygen delivered.

Epinephrine

Epinephrine is an endogenous catecholamine with α- and β-adrenergic activity. At low doses, epinephrine exerts primarily β-adrenergic effects, increasing contractility and reducing SVR. Despite this, there is little evidence that epinephrine is superior to dobutamine in the treatment of low-output states (e.g., myocardial infarction [MI]). The increases in stroke volume and cardiac output seen with epinephrine have the potential of decreasing blood pressure in patients with inadequate preload. In patients with septic shock that have been adequately fluid resuscitated, epinephrine increases heart rate and stroke volume (and therefore cardiac output) and systemic oxygen delivery without altering vascular tone³⁰ At higher rates of infusion, epinephrine exerts primarily α-adrenergic effects, increasing SVR and blood pressure. It is indicated for patients with ventricular dysfunction refractory to dopamine or dobutamine.

Care must be taken when using epinephrine, as renal vasoconstriction, cardiac arrythmias, and increased myocardial oxygen consumption and demand may result. Additionally, metabolic abnormalities are common, including dyskalemias, hyperglycemia, and ketoacidosis.^31,32 Finally, epinephrine increases blood lactate levels in patients recovering from cardiopulmonary bypass or those with septic shock, likely through increases in tissue oxygen extraction in the absence of adequate delivery.^33–35

Amrinone and Milrinone

Amrinone and milrinone are synthetic bipyridines that belong to the phosphodiesterase inhibitor class, demonstrating both positive inotropic and vasodilatory actions. Although these agents inhibit phosphodiesterase III, leading to increased intracellular cAMP, their positive inotropic effects are likely related to downstream increases in intracellular calcium.³⁶

These unique cardiac drugs have the theoretical advantage of dual mechanisms of action-augmenting cardiac output while reducing cardiac work by positive inotropic actions and peripheral vasodilatation.³⁶ Both have demonstrated clinical utility in multiple low cardiac output states; however, as single-agent therapy, neither has been proven superior to single inotropes (e.g., dobutamine) in improving ventricular performance. Additionally, the longer half-lives of amrinone and milrinone as compared to that of dobutamine do not permit minute-to-minute titration of their cardiovascular effects.

In selected situations, an additive effect in myocardial function is observed when dobutamine and amrinone/milrinone are combined. The phosphodiesterase inhibitors may be used as single-agent therapy in patients with isolated systolic heart failure but are more commonly employed as secondary agents (in addition to dobutamine) in cases of refractory heart failure. In this scenario, the beneficial effects on cardiac output are additive as amrinone and milrinone do not act via the adrenergic receptors. The potent vasodilatory effect of the bypyridines requires careful attention from the clinician to avoid hypotension in hypovolemic patients.

Nitrovasodilators

The nitrovasodilators are useful agents for reducing vascular tone, allowing manipulation of both preload and afterload. The most common scenario for their use is in states of elevated SVR. Sodium nitroprusside acts primarily on arteriolar smooth muscle, reducing afterload. The onset of action of sodium nitroprusside is rapid, and its effects cease within minutes once the infusion is discontinued. When titrating the dose of sodium nitroprusside, SVR should be decreased with a concomitant increase in cardiac output, thereby maintaining a relatively constant systemic arterial pressure. Although the effects of sodium nitroprusside favor arterial dilatation, it does have mild venous dilatory effects that can lead to an increase in venous capacitance and decreased preload.

Care must be taken when using sodium nitroprusside, as cyanide toxicity is a known side effect. Briefly, the ferrous iron contained in sodium nitroprusside reacts with sulfhydryl-containing compounds in erythrocytes, producing cyanide. Toxicity results when the rate of production exceeds the capacity of the liver to metabolize cyanide to thiocyanate. This is generally seen with infusion rates in excess of 10 μg/kg/min or with prolonged therapy (several days). Toxicity manifests as an unexplained rise in mixed venous oxygen tension as a result of reduced oxygen consumption. Treatment is with sodium nitrite and is aimed at providing an alternate substrate for the cyanide ion. Sodium nitrite also converts hemoglobin to methemoglobin, producing a ferric ion that competes with the ferric ion in the cytochrome system for the cyanide ion. Methylene blue can be administered to treat the methemoglobinemia that results from sodium nitrite treatment.

Nitroglycerin, a potent arteriolar and venous smooth muscle dilator, is a useful agent when both preload and afterload are elevated. The cardiovascular effects are dose-dependent, with low doses (5–20 μg/min) primarily increasing venous capacitance and higher doses (>20 g/min) relaxing arterial tone. Side effects are generally the result of an overly rapid reduction in venous or arterial tone, and are readily reversed by cessation of the medication.

Phosphodiesterase type 5 inhibitors, such as sildenafil, have been used with success to treat primary pulmonary hypertension³⁷; however, their use in pulmonary hypertension secondary to acute respiratory distress syndrome or in the acute setting has not been studied adequately to draw conclusions on its benefit in this setting. Further studies in this specific subset of patients with secondary or acute pulmonary hypertension are warranted.

Steroids

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