Mary Margaret Wolfe and Fred Luchette
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
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.
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, 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 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 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.
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 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
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 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 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 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.36Both 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.
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.
The use of steroids as replacement therapy for insufficient adrenal production and release of corticosteroids has been proven to be a lifesaving intervention. Their role in septic shock, however, is less clear. The use of steroids in cardiovascular collapse secondary to sepsis has gained renewed interest, with new data suggesting that in adrenal-insufficient patients, low-dose glucocorticoid replacement therapy is beneficial.38,39 However, no survival benefit is seen in patients who are not adrenal-insufficient given the same therapy.
In addition to their use as a replacement therapy, steroids are known anti-inflammatory agents. Cardiopulmonary bypass produces a brisk inflammatory response, including the production oxygen free radicals, resulting in hypotension and arrythmias. The use of steroids to temper the production of free radicals in postbypass patients has been studied. In a prospective, randomized trial there was no improvement in the incidence of cardiac arrythmias.40Therefore, the use of steroids in the treatment of cardiovascular failure secondary to sepsis in nonadrenal insufficient patients, or as an anti-inflammatory agent in cardiopulmonary bypass patients cannot be recommended.
Intra-aortic Balloon Pump Counterpulsation
When myocardial failure has an underlying, surgically correctable, anatomic cause (e.g., acute mitral regurgitation, intraventricular septal defect, high-grade coronary artery stenosis) and pharmacologic methods have been ineffective in augmenting cardiac output, the use of intra-aortic balloon counterpulsation (IABP) is indicated. IABP involves placement of a balloon catheter into the proximal descending aorta (distal to the origin of the left subclavian artery) via a femoral arterial approach. The balloon catheter is connected to a pumping device that, in synchrony with the electrocardiogram, inflates the balloon during cardiac diastole and deflates it during systole. By filling during diastole, the balloon displaces ˜40 mL of blood retrograde into the coronary arterial circulation and antegrade into the descending aorta. The balloon is abruptly deflated at the beginning of systole, allowing the left ventricle to eject its stroke volume. These dual functions augment coronary arterial flow while decreasing afterload, thereby reducing myocardial oxygen consumption. Although IABP technology has improved and the risk of complications in cardiac surgical patients has decreased dramatically over the last decade,41 the utility of balloon counterpulsation in trauma patients remains unclear. The use of IABP was independently associated with survival at centers with high IABP use rates, regardless of intervention (percutaneous angioplasty [PTCA], thrombolytics, or platelet GPIIb/IIIa) in a National Registry of Myocardial Infarction trial.42 One study demonstrated improved left ventricular function in dogs sustaining blunt cardiac injury,43 but studies in humans have been limited to case reports. This device should be reserved as a method of last resort in treating myocardial failure. There have been no indications for use of IABP in penetrating trauma except in those cases that proceed to cardiac failure or as an adjunct to weaning from cardiopulmonary bypass.44
EVALUATION OF CARDIAC FUNCTION
Central Venous Pressure
CVP monitoring has been used for over four decades as a measurement of preload. In the young trauma patient with a normal functioning heart, the CVP monitor provides an adequate assessment of right-sided filling pressure or preload. Usually placed percutaneously into the superior vena cava, adequate assessment of volume status is achieved, and fluid resuscitation guided. Normal CVP is between 0 and 4 mm Hg; however, response to fluid is more useful than an absolute number. A low CVP usually indicates hypovolemia, whereas an elevated CVP may be evidence of volume overload. Increases or decreases in cardiac output/index may be further used in conjunction with CVP to assess volume status as evidenced by the Frank–Starling curve. CVP and PAWP correlate well in the normal functioning heart (EF > 50%), but this correlation is not maintained in patients with cardiac impairment (EF < 40%).45CVP measurement has its limitations and is affected by multiple variables, which may cause an inadequate assessment of true volume status. Misplacement of the catheter, congestive heart failure (CHF; right- or left-sided), pneumothorax, lung recruitment techniques or high PEEP, pulmonary embolus, cardiac tamponade, increased intrathoracic, and/or intra-abdominal pressure may all lead to increases in CVP measurements, which do not reflect the true overall volume status. Marik et al. recommends alternative measurements of fluid status to guide resuscitation.46 Magder cautions the use of CVP alone without other measurements of fluid status such as cardiac output, pulse pressure variation, or stroke volume variation.47 These will be discussed later.
Pulmonary Artery Catheters
PACs or Swan–Ganz catheters, first introduced for human use in 1970, have been widely accepted as the standard for invasive monitoring of not only volume status but also of cardiac function by measurement and approximation of left-sided cardiac pressures. Continuous monitoring of cardiac output/index along with other information provided by newer PACs may help identify cardiovascular failure early and allow treatment to be adjusted accordingly. Measurement of the PAWP is used as an indirect measurement of LVEDP and LVEDV; however, these measurements often show poor correlation and can be altered by myocardial ischemia, ventricular outflow obstruction, mitral regurgitation, vasodilator therapy or severe heart failure.48 Similar to CVP, PAWP can be affected by decreased pulmonary compliance, high PEEP (as seen in lung recruitment strategies). Commercially available PACs currently incorporate multiple calculations to derive other indices of cardiac function and tissue perfusion such as mixed venous oxygen saturation (SVO2), SVR, oxygen delivery (DO2), and consumption (VO2).49 However, a large National Heart, Lung and Blood Institute randomized clinical trial reported that PAC-guided treatment was not superior to that of CV catheter-guided treatment; mortality and ICU length of stay (LOS) were similar but the PAC group had a higher rate of complications.50 A 2006 Cochrane Review analyzing 12 studies found no difference in mortality, hospital or ICU LOS with the use of PAC and that PAC use was associated with higher costs.51
Echocardiography, transthoracic and transesophageal, has gained wide acceptance in the monitoring of cardiac function and has emerged as an effective tool in the ICU as a guide to resuscitation and fluid status. In addition, information about structural abnormalities of the heart, aorta, and main pulmonary arteries can be obtained by this method, along with assessment of ventricular dysfunction, ventricular filling, valvular abnormalities, ventricular hypertrophy, and pulmonary embolus. Transesophageal echocardiography can give accurate measurements of both right- and left-sided filling volumes of the heart and may provide a better assessment of myocardial preload when compared to CVP or PA catheter measurements.51,52 Placed in the esophagus, Doppler probes can accurately predict cardiac output using the diameter of the aorta and measurements of blood flow velocity. Findings of short mitral deceleration time (≤140 ms) is highly predictive of pulmonary capillary wedge pressure of ≥ 20 mm Hg, which is consistent with cardiogenic shock.53 These devices can provide invaluable information in the multiply injured patient with comorbidities that make readings from the PAC difficult to interpret. Transesophageal echocardiography has been found to be a safe procedure that can be done at bedside by intensivists and has been found to affect management of the critically ill patient at least one-third of the time.54
Inferior Vena Caval Ultrasound
Ultrasound evaluation of the Inferior Vena Cava (IVC) can give an estimate of the volume status of the patient and predict a beneficial response to fluid. An IVC diameter of <1.5 cm with complete inspiratory collapse is associated with a low CVP (<5) and a response to fluid bolus and volume loading. An IVC diameter of 2.5 cm with no inspiratory collapse represents a high CVP and an unlikely to response to fluid loading. In those patients on mechanical ventilation, the IVC with expand with inspiration. The need for fluid loading can be gauged by calculating the difference between the inspiratory and expiratory size of the IVC. However, the patients must be sedated enough to not be taking spontaneous breaths during the time of measurement and the ventilator should deliver 10 mg/kg of tidal volume (for the time of the measurement only, ˜30 s). A delta IVC >12% corresponded to a >15% increase in cardiac output in one study while a delta IVC >18% corresponded to fluid responsiveness with 90% specificity and sensitivity in another. Thus, ultrasound of the IVC is a good noninvasive technique for volume status measurement and fluid responsiveness.55–60
Stroke Volume Variation
As discussed above, with CVP validity in question, other measurements of fluid status should be utilized. Excessive variations in arterial blood pressure caused by the specific interactions of the heart and lungs under mechanical ventilation are a clinically well known sign of hypovolemia.61,62 Variations in pulse pressure (PPV) are exaggerated when the left ventricle (LV) is on the steep portion of the Frank–Starling curve; small preload changes cause large stroke volume changes. PPV does not measure preload but rather the responsiveness to fluid in mechanically ventilated patients. Variations in the pulse pressure >11% is indicative of fluid responsiveness.62 PPV is a surrogate of stroke volume variation (SVV).63 Pulse pressure proportional to stroke volume and inversely related to aortic compliance. Therefore, PPV may be more affected by changes in vasomotor tone. In contrast, stroke volume is a volume, not a pressure, measurement. Therefore, SVV may be more accurate than PPV. Studies of SVV have shown improve prediction of fluid responsiveness over CVP and PAWP. These studies have validated SVV and PPV as a marker of fluid responsiveness and improved cardiac output.61,64–66
Arterial pulse contour analysis has been clinically validated for continuous CO measurement and is now available for the real-time quantification of left ventricular stroke volume variation and cardiac output.63 Despite the promise of encouraging initial results in intraoperative patients, the use of stroke volume variation has its limitations. These studies have been small patient populations under the very strict conditions of nonspontaneous breathing, mechanical ventilation at high tidal volumes, and the absence of arrhythmia. In addition, there are questions of validity at high respiratory rates, with tachycardia, in the presence of β-adrenergic blockade, as well as in an over- or underdampened arterial curve.66–69
OPTIMAL ENDPOINTS OF RESUSCITATION
Mixed Venous Oxygen Saturation
Mixed venous oxygen saturation (SvO2) is a measurement of the oxygen saturation in the venous return to the heart and therefore an indirect measurement of oxygen utilization by the end organs. Normal values are approximately 75–80% and are calculated by taking the difference between measured oxygen delivery and oxygen consumption. During the septic state, the cell’s inability to utilize delivered oxygen may increase SVO2. Cellular destruction from prolonged ischemia or cellular metabolic poisoning following carbon monoxide inhalation often yield normal or increased SvO2 despite inadequate end-organ perfusion because of an inability to utilize the oxygen delivered.
Lactate and Base Deficit
Elevated serum lactate, or lactic acidosis, may be an indicator of cellular hypoxia or shock. When cells can no longer function normally due to hypoxia or decreased blood flow, the normal mechanism of ATP generation by aerobic metabolism is shifted to anaerobic metabolism. This inefficient method of ATP production yields increased amounts of pyruvate, which is converted to lactate. Therefore, increased levels of lactate may be a reflection of ongoing tissue hypoxia. Hepatic dysfunction may increase serum lactate levels due to inability of the liver to transform lactate to carbon dioxide. The use of serum lactate measurements as a guide to resuscitation is limited due to the time necessary for laboratory results to return. However, in critically ill patients past the acute resuscitation phase of treatment, serum lactate levels may be useful in determining the onset of organ dysfunction.70 In clinical practice, multiple other factors may also affect lactate production. Following severe injury, increased circulating epinephrine may cause an increase in lactate production by anaerobic glycolysis in response to increased activity of the Na+/K+-ATPase despite adequate tissue perfusion.71
The base deficit is the difference between the standard value of 24 mEq/L and the serum bicarbonate level. This value is typically negative in hemorrhagic shock and therefore the term base deficit is widely used. The magnitude of the base deficit has been used to quantify the magnitude of acidosis, with mild acidosis having a base deficit of −3 to −5 mEq/L, moderate acidosis −6 to −10 mEq/L, and severe acidosis less than 10 mEq/L.72 As the magnitude of the base deficit increases, the resuscitation volumes of both blood and fluid increases, as does mortality.73 Patients who are able to clear their base deficits in less than 48 hours have decreased mortality when compared to patients whose base deficits persist beyond this time frame.74 Persistent base deficits despite normal vital signs may be a signal of compensated shock requiring further resuscitation, and if left untreated may lead to MOF and increased morbidity and mortality. New-onset lactic acidosis and increasing base deficit in the critically ill patient may be early signs of a low flow state, cellular hypoxia, and/or end-organ injury, therefore every effort should be made to find the cause and address it as quickly as possible.
Defined as the measurement of carbon dioxide, capnography is most commonly used during endotracheal intubation to ensure proper placement of the endotracheal tube. Recent studies have reported its use to predict prognosis following cardiopulmonary arrest, to assess resuscitation efforts, to detect alveolar dead space changes, and to monitor sedation and paralytic therapy.75,76 Under normal conditions, exhaled carbon dioxide closely correlates with arterial blood CO2 levels. Due to unmatched areas of ventilation and perfusion in the lungs, the arterial PaCO2 will usually be slightly higher than the exhaled CO2.
End-tidal CO2 has been shown to predict resuscitation efforts during cardiopulmonary arrest.75 In one study higher ETCO2 levels correlated with increased survival after cardiac arrest.77 Nonsurvivors with prehospital arrests after 20 minutes of ACLS were found to have an average ETCO2 of 3.9 mm Hg, whereas survivors had ETCO2 values of 31 mm Hg.78 An ETCO2 value of 10 mm Hg has been determined to provide a 100% sensitivity to predict return of spontaneous circulation.79
Measuring tissue pH to study the adequacy of perfusion is an extremely attractive concept. Tonometric determination of mucosal carbon dioxide tension can be used to calculate pHi by use of the Hendereson–Hasselbalch equation. Although gastric tonometry and measurement of submucosal pH has its merits in determining ongoing tissue hypoxia in the ICU setting, it has not gained wide use in the initial assessment of patients due to the need for serum HCO3measurement with each tonometric reading. Gastric pHi has proven to be a remarkable reliable predictor of outcome in critically it individuals: general medical ICU patients, multiply injured trauma patients, patients with sepsis, and patients undergoing major surgical procedures. Studies have shown that sublingual CO2 (SLCO2) yielded measurements equivalent with gastric tonometry80 and is a reliable marker of tissue perfusion, with impaired circulatory blood flow correlating with high levels of SLCO2.81 In a prospective observational cohort study, SLCO2 correlated with blood loss in penetrating trauma patients and may be superior to gastric tonometry in its noninvasive nature.82
Patients at high risk for cardiac events during noncardiac surgery have been the topic of discussion for years due to the increased mortality from perioperative arrythmias and MI. MI or cardiac death occurs in 1–5% of unselected patients undergoing noncardiac surgery and is the most common reason for preoperative evaluation.83 The pathophysiology of MI in the perioperative setting differs from that seen in nonsurgical patients. In the nonsurgical setting, MI usually follows rupture of atherosclerotic plaques in the coronary arteries leading to platelet aggregation and thrombus formation.84 MI in the perioperative setting is due to plaque rupture approximately 50% of the time, with the remainder resulting from myocardial ischemia from decreased myocardial oxygen supply and increased demand in the face of atherosclerotic coronary artery disease. These demands are usually exacerbated by anemia, hypotension, hypoxia, hypertension, and tachycardia. Shifts in intravascular volume, withdrawal of anesthesia, and postoperative pain are all factors that may contribute to the increased demand of oxygen in the perioperative setting. Postoperative tachycardia, arrhythmias, and MI most commonly occur 3 days after an operation, when fluid shifts are at their greatest.85 Until recently, reduction in the occurrence of these events centered on preoperative risk assessment with clinical recommendations and often cancellation or postponement of procedures.86 Medical strategies have been proposed to reduce perioperative ischemia, as this has been linked to postoperative MI with a 21-fold increase in risk.87Mixed results have been obtained in studies using intraoperative calcium channel blockers88 and nitroglycerin.89 Two randomized controlled trials have shown that β-blocker therapy reduces perioperative cardiac complications.89,90Mangano and colleagues performed a randomized, double-blinded, placebo-controlled trial using atenolol in 200 patients with known coronary artery disease and/or risk factors for atherosclerosis who underwent noncardiac surgery. Although acute perioperative mortality did not differ between the two groups at 6 months, eight deaths occurred in the placebo group and none in the atenolol group (P < 0.001), with the difference being sustained at the 2-year follow-up period.90 In another study, patients with clinical risk factors and ischemia demonstrated by dobutamine stress echo who were to undergo major vascular procedures were randomly assigned to bisoprolol or placebo.91 The study was terminated early when investigators noted that bisoprolol markedly reduced perioperative mortality (17% vs. 3.4%; P = 0.02) and MI (17% vs. 0%; P < 0.001). A recent meta-analysis of randomized, controlled trials concluded that β-blockade may be beneficial in preventing perioperative cardiac morbidity despite the heterogeneity of the trials.92 Therefore, it seems that β-blockade reduces the risk of perioperative morbidity and mortality in patients at increased risk and is effective in patients with inducible ischemia by dobutamine stress echo.93 Subsequent studies have shown that withdrawal of β-blockers increased the risk of morbidity and mortality and that initiation of β-blockers preoperatively requires titration to blood pressure and heart rate control. Therefore, current ACCF/AHA recommendations are aimed at continuation of β-blocker therapy in the perioperative period and initiation of β-blockade should be instituted in high-risk patients and titrated to effect prior to surgery.94
CURRENT TREATMENT OF ACUTE MYOCARDIAL INFARCTION
The definition of acute MI encompasses a range of clinical entities ranging from non-ST-segment elevation MI (also known as acute coronary syndrome [ACS] or unstable angina) to acute ST-segment elevation MI. The pathophysiology for ACS differs from that of ST-segment elevation MI, as does the treatment. Whereas ACS are commonly due to a partial occlusion of the coronary arteries or transient ischemia (due to plaque rupture with platelet aggregation), in the surgical patient ACS is more commonly secondary to decreased oxygen supply or increased demand due to anemia, tachycardia, intravascular fluid shifts, hypotension, or arrhythmias. Acute ST-segment elevation MI refers to complete occlusion of the coronary arteries with myocardial injury.
Despite marked advances in diagnosis and treatment, there is still a 10% mortality associated with acute MI.95 Reduced mortality has been shown to result from adherence to three basic tenets of treatment for acute MI: (1) prompt diagnosis, (2) immediate aspirin therapy, and (3) rapid restitution of blood flow to the infarcted myocardium. Whereas prompt diagnosis and institution of aspirin therapy are relatively straight forward, the reestablishment of blood flow to the affected myocardium has evolved into two primary therapies, pharmacologic therapy with thrombolytics and interventional therapy with PTCA. With its ease of administration, early studies on the use of thrombolytic therapy consistently showed decreased mortality and improved myocardial performance compared with place-bo.96 However, thrombolytic therapy has well-documented limitations and contraindications. Intracranial bleeding resulting in death or stroke occurs in 0.6–1.4% of patients who receive thrombolytic therapy.96 Thrombolytic therapy is also associated with a reocclusion rate of 30%, resulting in reinfarction of the affected area within 3 months.97In the multiply injured patient with an increased risk of bleeding, head injury, or multivessel disease, thrombolytic therapy is contraindicated.
Patients who are not candidates for thrombolytic therapy have been shown to benefit from PTCA.98 This invasive therapy has been shown to result in better clinical outcomes when compared to thrombolysis.99 In addition to improved outcomes, PTCA offers direct visualization of the affected anatomy, gives specific hemodynamic and functional data that can be used to guide further therapy. It can also quickly identify those patients who should not undergo reperfusion therapy, which include patients with minimal residual stenosis, spontaneous reperfusion, coronary vasospasm, myocarditis, and aortic dissection involving the ostia.100 Unfortunately, PTCA is not available in all medical centers and there is wide variability in the use of PTCA even in those centers that are PTCA capable.101 Complications from PTCA include major bleeding (7%), vascular complications that require surgical repair (2%), and renal failure (13%). The incidence of renal failure rises with increasing age, volume of contrast material, decreased baseline renal function, and hypovolemia. When comparing thrombolytic therapy to PTCA, primary PTCA had been found to be more effective in reducing both short- and long-term outcomes, including death.100 Recent trials of PTCA with or without stent placement show no difference in mortality, but stented vessels had a decreased rate of restenosis and reocclusion over 6 months. The use of platelet glycoprotein (GP) IIb/IIIa inhibitors (e.g., abciximab) at the time of PTCA reduces the rates of subacute thrombosis, recurrent ischemia, and need for repeat revascularization procedures during the first month after PTCA with or without stents.102 However, clinical outcomes do not differ at 6-month follow-up. Despite the heterogeneity of these trials, including whether stents were used or not and the use of platelet GP IIb/IIIa inhibitors versus the various thrombolytic agents, the accumulated data appear to favor primary PTCA in the treatment of acute ST-segment MI. The addition of platelet GP IIb/IIIa inhibitors should be based on clinical judgment in the multiply injured trauma patient.103
For those patients with non-ST-segment elevation MI, treatment centers on the presence or absence of hemodynamic instability. In the presence of hemodynamic instability, treatment includes aspirin (ASA), vasopressors, and IABP as needed and cardiac catheterization ± PTCA. In those patients with no hemodynamic instability and minimal risk factors for recurrence, medical management with ASA, β-blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), and statins is first line. The use of statins in those patients with AMI showed reduced 1 year mortality, and statins introduced within 24 hours of AMI showed decreased early complications and in-hospital mortality.104,105For those patients with multiple risk factors, cardiac catheterization may be indicated when the patient is able to be systemically anticoagulated.106,107
MANAGEMENT OF DIASTOLIC DYSFUNCTION
The syndrome of CHF typically brings to mind an enlarged heart and decreased systolic function. However, when systolic function is normal or near-normal, as is the case in nearly 50% of patients diagnosed with CHF, and the other clinical manifestations of CHF exist, such as orthopnea, dyspnea, increased jugular venous pressure, and abnormal heart sounds on auscultation, the diagnosis of diastolic dysfunction (DD) or, more accurately, diastolic heart failure is made. DD is associated with hypertension (HTN), diabetes, female gender, coronary artery disease, and chronic atrial fibrillation. Aging itself has been associated with decreases in elastic properties of the great vessels, decreased ventricular filling, decreased relaxation, and compliance and decreased β-adrenergic receptor density. DD should be described as CHF with normal or preserved EF.108 The diagnosis of DD is generally made clinically and is often one of exclusion. Objective testing should include echocardiography or cardiac catheterization. Because the normal ejection fraction is not a standardized number, and given that systolic dysfunction often accompanies DD, the diagnosis of DD is often not clear-cut. Therefore, the diagnostic “gold standard” for DD is cardiac catheterization demonstrating increased ventricular diastolic pressure with normal systolic function and volumes. Echocardiography, being noninvasive and practical, can be used to exclude systolic dysfunction. Although the majority of clinical studies focus on systolic dysfunction, few exist that specifically target DD.
In general, the treatment principles for patients diagnosed with DD include antihypertensive therapy, reduction of volume overload, decreasing heart rate (especially those with atrial fibrillation), and the reduction of ischemia.108With hypertension being the primary predisposing factor for CHF, neurohormonal regulation has been shown to play a role in CHF and DD. The renin–angiotensin system influences CHF indirectly by causing hypertension and left ventricular hypertrophy (LVH), and directly by both angiotensin II and endothelin contributing to LVH and impaired myocardial relaxation.109,110 Blockade of the renin–angiotensin system improves diastolic distensibility in both human and animal studies.110 Volume overload can be reduced with diuretics or renal replacement therapy in renal failure patients. In DD, the use of β-adrenergic blockade or calcium channel blockade to reduce heart rate and increase left ventricular filling time reduces mortality.111 Digoxin decreases hospitalization of patients with CHF with and without systolic dysfunction; however, since digoxin is a negative chronotrope the benefit may be due to the rate-lowering effect of the drug rather than to its other properties.112 Patients with rate-altering arrhythmias such as atrial flutter or fibrillation show increased filling times once normal sinus rhythm is restored and may also benefit from rate control. Aldosterone has also been shown to contribute to CHF with detrimental effects on endothelial function as well as inducing a vasculopathy.113 Infusion of aldosterone into healthy volunteers for 1-hour results in endothelial dysfunction with a notably reduced vascular response to acetylcholine. Patients with mild CHF treated with β-blocker therapy, ACE inhibitors, and statins show an improvement in acetylcholine-mediated endothelium-dependent vasodilatation.114
Another recognized cause of right heart dysfunction is pulmonary arterial hypertension (PH). This is defined as systolic Ppa >25 mm Hg at rest and diagnosed by right heart catheterization. Other diagnostic modalities used in the workup of PH is chest radiograph, ECG, echocardiography, pulmonary function tests and arterial blood gases, V/Q scan, high-resolution computed tomography, ultrasonography of the abdomen, and biopsy. These diagnostic modalities are used not only for diagnosis of PH but also to determine etiology and functional impairment.115 Acute PH occurring in the critically ill is most commonly recognized by PAC or echocardiogram (tranthoracic or esophageal). Echocardiographic signs of PH include right ventricular dilation and hypertrophy, septal bowing into the left ventricle during late systole to early diastole (D-shaped left ventricle), right ventricular hypokinesis, tricuspid regurgitation, right atrial enlargement, and a dilated IVC.
Primary considerations when managing a critically ill patient with PH in the ICU include the diagnosis which then allows for specific treatment. Hemodynamic goals are to reduce the PVR, augment cardiac output, and resolve systemic hypotension while avoiding tachyarrhythmias. Avoidance of hypoxia and hypercapnea will minimize pulmonary vasoconstriction and thus are simple measures to avoid exacerbation of the PH. Dobutamine in doses up to 5 μg/kg/min significantly decreases PVR while slightly increasing cardiac output.116,117 Doses higher than this cause significant tachycardia without improvement in the PVR. When combined with inhaled nitric oxide (iNO), dobutamine improved cardiac index, decreased PVR and significantly increased the PaO2/FiO2 Milrinone significantly reduces PVR and improves right ventricular function. However, its use is limited due to the high incidence of systemic hypotension. Dopamine, phenylephrine, isoproterenol, epinephrine, and vasopressin cannot be recommended for use in management of PH due to the limited studies. Inhaled nitric oxide increases production of both cyclic guanosine monophosphate and cyclic adenosine monophosphate. It is the most commonly utilized pulmonary vasodilator in the critical care setting for the management of acute pulmonary hypertension. Sildenafil is a specific phosphodiesterase-5 inhibitor recently approved for treatment of PH. In stable patients, when it is used alone or in combination with iNO, the cardiac output will increase.118,119 It is contraindicated in patients receiving nitrates because of the potential for severe systemic hypotension. Although use of calcium channel blockers in the management of chronic PH is effective for control of heart rate, there are no studies of their use in the critically ill patient with PH. Because of their negative inotrophic effects, they may precipitate fatal worsening of right ventricular failure.
1. Centers for Disease Control and Prevention. Population Projections, United States 2004–2030 by state, age and sex, CDC Database, September 2005. http://wonder.cdc.gov/population-projections.html. Accessed July 8, 2010.
2. Marik PE. Management of the critically ill geriatric patient. Crit Care Med. 2006;39(suppl 9):S176–S182.
3. Kinsella K, Wan H. US Census Bureau, International Population Reports: An Aging World. 2008.
4. Belzberg H, Wo CCJ, Demetriades D, Shoemaker WC. Effects of age and obesity on hemodynamics, tissue oxygenation, and outcome after trauma. J Trauma. 2007;62:1192–1200.
5. McDonald KS, Field LJ, Parmacek MS, et al. Length dependence of Ca2 sensitivity of tension in mouse cardiac myocytes expressing skeletal troponin C. J Physiol. 1995;483:131–139.
6. Pinsky MR, Marquez J, Martin D, et al. Ventricular assist by cardiac cycle-specific increases in intrathoracic pressure. Chest. 1987;91:709–715.
7. Klinger J. Hemodynamics and positive end-expiratory pressure in critically ill patients. Crit Care Clinics North Am. 1996;12:841–864.
8. Chang MC, Mondy JS III, Meredith JW, et al. Clinical application of ventricular end-systolic elastance and the ventricular pressure-volume diagram. Shock. 1997;7:413–419.
9. Fischer UM, Cox CS, Laine GA, et al. Mild hypothermia impairs left ventricular diastolic but not systolic function. J Invest Surg. 2005;18: 291–296.
10. Tveita T, Ytrehus K, Myhre ES, et al. Left ventricular dysfunction following rewarming from experimental hypothermia. J Appl Physiol. 1998;85:2135–2139.
11. Totaro RJ, Raper RF. Epinephrine-induced lactic acidosis following cardiopulmonary bypass. Crit Care Med. 1997;25:1693–1699.
12. Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest. 1993;103: 1826–1831.
13. Levy B, Bollaert PE, Charpentier C, et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med. 1997;23:282–287.
14. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362: 779–789.
15. Angle MR, Molloy DW, Penner B, et al. The cardiopulmonary and renal hemodynamic effects of norepinephrine in canine pulmonary embolism. Chest. 1989;95:1333–1337.
16. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation. 2003;107:2313–2319.
17. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support: section 1: Introduction to ACLS 2000: overview of recommended changes in ACLS from the guidelines 2000 conference. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation. 2000;102(suppl 8):I86–I89.
18. Wenzel V, Krismer AC, Arntz HR, et al. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350:105–113.
19. Dunser MW, Mayr AJ, Stallinger A, et al. Cardiac performance during vasopressin infusion in postcardiotomy shock. Intensive Care Med. 2002;28:746–751.
20. Forrest P. Vasopressin and shock. Anaesth Intensive Care. 2001;29:463–472.
21. McDonald RH Jr, Goldberg LI, McNay JL, et al. Effect of dopamine in man: augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow. J Clin Invest. 1964;43:1116–1124.
22. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000;356(9248):2139–2143.
23. Kellum JA, Decker JM. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med. 2001;29(8):1526–1531.
24. Marik PE. Low-dose dopamine: a systematic review. Intensive Care Med. 2002;28(7):877–883.
25. Crea F, Chierchia S, Kaski JC, et al. Provocation of coronary spasm by dopamine in patients with active variant angina pectoris. Circulation. 1986;74:262–269.
26. Ko W, Zelano JA, Fahey AL, et al. The effects of amrinone versus dobutamine on myocardial mechanics and energetics after hypothermic global ischemia. J Thorac Cardiovasc Surg. 1993;105(6):1015–1024.
27. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858–873.
28. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med. 1995;333:1025–1032.
29. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994; 330:1717–1722.
30. Moran JL, O’Fathartaigh MS, Peisach AR, et al. Epinephrine as an inotropic agent in septic shock: a dose-profile analysis. Crit Care Med. 1993;21:70–77.
31. Darbar D. Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem. Am J Cardiol. 1996;77:1351–1355.
32. Le Tulzo Y. Effects of epinephrine on right ventricular function in patients with severe septic shock and right ventricular failure: a preliminary descriptive study. Intensive Care Med. 1997;23:664–670.
33. Bourgoin A, Leone M, Delmas A, et al. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med. 2005;33:780–786.
34. Meier A-Hellmann, Reinhart K, Bredle DL, et al. Epinephrine impairs splanchnic perfusion in septic shock. Crit Care Med. 1997;25:399–404.
35. Steiner LA, Johnston AJ, Czosnyka M, et al. Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients. Crit Care Med. 2004;32:1049–1054.
36. Alousi AA, Johnson DC. Pharmacology of the bipyridines: amrinone and milrinone. Circulation. 1986;73(3 pt 2):III10–III24.
37. Sastry BK, Narasimhan C, Reddy NK, et al. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol. 2004;43:1149–1153.
38. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862–871.
39. Annane D, Lipiner-Friedman D, et al. Adrenal function in sepsis: the retrospective Corticus cohort study. Crit Care Med. 2007;35: 1012–1018.
40. Volk T, Schmutzler M, Engelhardt L, et al. Effects of different steroid treatment on reperfusion-associated production of reactive oxygen species and arrhythmias during coronary surgery. Acta Anaesthesiol Scand. 2003;47:667–674.
41. Elahi MM, Chetty GK, Kirke R, et al. Complications related to intra-aortic balloon pump in cardiac surgery: a decade later. Eur J Vasc Endovasc Surg. 2005;29:591–594.
42. Chen EW. Relation between hospital intra-aortic balloon counterpulsation volume and mortality in acute myocardial infarction complicated by cardiogenic shock. Circulation. 2003;108:951–957.
43. Saunders CR, Doty DB. Myocardial contusion: effect of intra-aortic balloon counterpulsation on cardiac output. J Trauma. 1978;18:706–708.
44. Wall MJ, Mattox K L, Chen CD, Baldwin JC. Acute management of complex cardiac injuries. J Trauma. 1997;42:905–912.
45. Mangano DT. Monitoring pulmonary arterial pressure in coronary-artery disease. Anesthesiology. 1980;53:364–370.
46. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? Chest. 2008;134:172–178.
47. Madger S. Central venous pressure: a useful but not so simple measurement. Crit Care Med. 2006;34:2224–2227.
48. Raper R, Sibbald WJ. Misled by the wedge? The Swan-Ganz catheter and left ventricular preload. Chest. 1986;89:427–434.
49. Girolami A, Little RA, Foex BA, et al. Hemodynamic responses to fluid resuscitation after blunt trauma. Crit Care Med. 2002;30:385–392.
50. The NHLBI Acute Respiratory Distress Syndrome (ARDS) Clinical Trial Network. Pulmonary artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med. 2006;354:2213–2224.
51. Harvey S, Young D, Brampton W, et al. Pulmonary artery catheters for adult patients in intensive care. Cochrane Database Syst Rev. 2006;(3):CD003408. doi:10.1002-14651858.CD003408.pub2.
52. Madan AK, UyBarreta VV, Aliabadi S-Wahle, et al. Esophageal Doppler ultrasound monitor versus pulmonary artery catheter in the hemodynamic management of critically ill surgical patients. J Trauma. 1999;46: 607–611.
53. Reynolds HR, Anand SK, Fox JM, et al. Restrictive physiology in cardiogenic shock: observation from echocardiography. Am Heart J. 2006;151:890.e9–890.e15.
54. Colreavy FB, Donovan K, Lee KY, Weekes J. Transesophageal echocardiography in critically ill patients. Crit Care Med. 2002;30: 989–996.
55. Adler C, Buttner W, Veh R. Relations of the ultrasonic image of the inferior vena cava and central venous pressure. Aktuelle Gerontol. 1983; 13:209–213.
56. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol. 1990;66:493–496.
57. Simonson JS, Schiller NB. Sonospirometry: a new method for noninvasive estimation of mean right atrial pressure based on two-dimensional echographic measurements of the inferior vena cava during measured inspiration. J Am Coll Cardiol. 1988;11:557–564.
58. Minutiello L. Non-invasive evaluation of central venous pressure derived from respiratory variations in the diameter of the inferior vena cava. Minerva Cardioangiol. 1993;41:433–437.
59. Barbier C, Loubières Y, Schmit C, et al. Respiratory changes in inferior vena cava diameter are helpful in predicting fluid responsiveness in ventilated septic patients. Intensive Care Med. 2004;30:1740–1746.
60. Feissel M, Michard F, Faller JP, et al. The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med. 2004;30:1834–1837.
61. Berkenstadt H, Nevo M, Hadani M, et al. Stroke volume variation as a predictor of fluid responsiveness in patients undergoing brain surgery. Anesth Analg. 2001;92:984–989.
62. Kramer A, Zygun D, Hawes H, et al. Pulse pressure variation predicts fluid responsiveness following coronary artery bypass surgery. Chest. 2004;126:1563–1568.
63. Hofer CK, Muller SM, Zollinger A, et al. Stroke volume and pulse pressure variation for prediction of fluid responsiveness in patients undergoing off-pump coronary artery bypass grafting. Chest. 2005;128:848–854.
64. Pinsky MR. Probing the limits of arterial pulse contour analysis to predict preload responsiveness. Anesth Analg. 2003;96:1245–1247.
65. Reuter DA, Kirchner A, Felbinger TW, et al. Usefulness of left ventricular stroke volume variation to assess fluid responsiveness in patients with reduced cardiac function. Crit Care Med. 2003;31:1399–1404.
66. De Backer D, Taccone GS, Holsten R, Ibrahimi F, Vincent JL. Influence of respiratory rate on stroke volume variation in mechanically ventilated patients. Anesthesiology. 2009;110:1092–1097.
67. Michard F. Pulse contour analysis: fairy tale or new reality? Crit Care Med. 2007;35:1791–1792.
68. Kim HK, Pinsky MR. Effect of tidal volume, sampling duration and cardiac contractility on pulse pressure and stroke volume variation during positive-pressure ventilation. Crit Care Med. 2008;36:2858–2862.
69. Marik PE, Cavallazzi R, Vasu T, Harani A. Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: a systematic review of the Literature. Crit Care Med. 2009;37:2642–2647.
70. Benedict CR, Rose JA. Arterial norepinephrine changes in patients with septic shock. Circ Shock. 1992;38:165–172.
71. Luchette FA, Jenkins WA, Friend LA, et al. Hypoxia is not the sole cause of lactate production during shock. J Trauma. 2002;52:415–419.
72. Davis JW, Parks SN, Kaups KL, et al. Admission base deficit predicts transfusion requirements and risk of complications. J Trauma. 1996;41:769–774.
73. Moomey CB Jr, Melton SM, Croce MA, et al. Prognostic value of blood lactate, base deficit, and oxygen-derived variables in an LD50 model of penetrating trauma. Crit Care Med. 1999;27:154–161.
74. Davis JW, Shackford SR, Mackersie RC, et al. Base deficit as a guide to volume resuscitation. J Trauma. 1988;28:1464–1467.
75. Ahrens T, Schallom L, Bettorf K, et al. End-tidal carbon dioxide measurements as a prognostic indicator of outcome in cardiac arrest. Am J Crit Care. 2004;10:391–398.
76. Bilkovski RN, Rivers EP, Horst HM. Targeted resuscitation strategies after injury. Curr Opin Crit Care. 2004;10:529–538.
77. Sanders AB, Kern KB, Otto CW, et al. End-tidal carbon dioxide monitoring during cardiopulmonary resuscitation. A prognostic indicator for survival. JAMA. 1989; 262:1347–1351.
78. Wayne MA, Levine RL, Miller CC. Use of end-tidal carbon dioxide to predict outcome in prehospital cardiac arrest. Ann Emerg Med. 1995;25:762–767.
79. Cantineau JP, Lambert Y, Merckx P, et al. End-tidal carbon dioxide during cardiopulmonary resuscitation in humans presenting mostly with asystole: a predictor of outcome. Crit Care Med. 1996;24:791–796.
80. Povoas HP, Weil MH, Tang W, Moran B, Kamohara T, Bisera J. Comparisons between sublingual and gastric tonometry during hemorrhagic shock. Chest. 2000;118:1127–1132.
81. Rackow EC, O’Neil P, Astiz ME, et al. Sublingual capnometry and indexes of tissue perfusion in patients with circulatory failure. Chest. 2001;120:1633–1638.
82. Baron BJ, Sinert R, Zehtabchi S, et al. Diagnostic utility of sublingual PCO2 for detecting hemorrhage in penetrating trauma patients. J Trauma. 2004;57:69–74.
83. Khuri SF, Daley J, Henderson W, et al. The National Veterans Administration Surgical Risk Study: risk adjustment for the comparative assessment of the quality of surgical care. J Am Coll Surg. 1995;180: 519–531.
84. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med. 1992;326:242–250.
85. Raby KE, Barry J, Creager MA, et al. Detection and significance of intraoperative and postoperative myocardial ischemia in peripheral vascular surgery. JAMA. 1992;268:222–227.
86. Guidelines for assessing and managing the perioperative risk from coronary artery disease associated with major noncardiac surgery. American College of Physicians. Ann Intern Med. 1997;127:309–312.
87. Landesberg G, Luria MH, Cotev S, et al. Importance of long-duration postoperative ST-segment depression in cardiac morbidity after vascular surgery. Lancet. 1993;341:715–719.
88. Godet G, Coriat P, Baron JF, et al. Prevention of intraoperative myocardial ischemia during noncardiac surgery with intravenous diltiazem: a randomized trial versus placebo. Anesthesiology. 1987;66: 241–245.
89. Coriat P. Intravenous nitroglycerin dosage to prevent intraoperative myocardial ischemia during noncardiac surgery. Anesthesiology. 1986;64:409–410.
90. Mangano DT, Layug EL, Wallace A, et al. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Peri-operative Ischemia Research Group. N Engl J Med. 1996;335:1713–1720.
91. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341:1789–1794.
92. Auerbach AD, Goldman L. Beta-blockers and reduction of cardiac events in noncardiac surgery: Scientific review. JAMA. 2002;287: 1435–1444.
93. Grayburn PA, Hillis LD. Cardiac events in patients undergoing noncardiac surgery: shifting the paradigm from noninvasive risk stratification to therapy. Ann Intern Med. 2003;138:506–511.
94. Fleischmann KE. 2009 ACCF/AHA focused update on perioperative beta blockade: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation. 2009;120(21):2123–2151.
95. Rogers WJ, Canto JG, Lambrew CT, et al. Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: The National Registry of Myocardial Infarction 1, 2 and 3. J Am Coll Cardiol. 2000;36:2056–2063.
96. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Lancet. 1994;343: 311–322.
97. Gibson CM, Karha J, Murphy SA, et al. Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the thrombolysis in myocardial infarction trials. J Am Coll Cardiol. 2003;42:7–16.
98. Grzybowski M, Clements EA, Parsons L, et al. Mortality benefit of immediate revascularization of acute ST-segment elevation myocardial infarction in patients with contraindications to thrombolytic therapy: A propensity analysis. JAMA. 2003;290:1891–1898.
99. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13–20.
100. Keeley EC, Grines CL. Primary coronary intervention for acute myocardial infarction. JAMA. 2004;291:736–739.
101. Fazel, R, Krumholz HM, Bates ER, et al. Choice of reperfusion strategy at hospital with primary percutaneous coronary intervention, A National Registry of Myocardial Infarction Analysis. Circulation. 2009;120: 2455–2461.
102. Dangas G, Aymong ED, Mehran R, et al. Predictors of and outcomes of early thrombosis following balloon angioplasty versus primary stenting in acute myocardial infarction and usefulness of abciximab (the CADILLAC trial). Am J Cardiol. 2004;94:983–988.
103. Adesanya AO, de Lemos JA, Greilich NB, Whitten CW. Management of Perioperative Myocardial Infarction in Noncardiac Surgical Patients. Chest. 2006;130:584–596.
104. Stenestrand U, Wallentin L. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA. 2001;285:430–436.
105. Fonarow GC, Wright RS, Spencer FA, et al. Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality. Am J Cardiol. 2005;96:611–616.
106. Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol. 2002;39:542–553.
107. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American heart Association Task force on Practice guidelines. Circulation. 2009;120:2271–2306.
108. Wang J, Nagueh SF. Current perspectives on cardiac function in patients with diastolic heart failure. Circulation. 2009;119:1146–1157.
109. Flesch M, Schiffer F, Zolk O, et al. Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca (2)-ATPase expression in the sarcoplasmic reticulum in hypertensive cardiomyopathy. J Hypertens. 1997;15:1001–1009.
110. Friedrich SP, Lorell BH, Rousseau MF, et al. Intracardiac angiotensin-converting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis. Circulation. 1994;90:2761–2771.
111. Banerjee P, Banerjee T, Khand A, et al. Diastolic heart failure: neglected or misdiagnosed? J Am Coll Cardiol. 2002;39:138–141.
112. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med. 1997;336:525–533.
113. Struthers AD. Aldosterone: cardiovascular assault. Am Heart J. 2002; 144(suppl 5):S2–S7.
114. Farquharson CA, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond). 2002;103:425–431.
115. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. Circulation. 2009;119:2250–2294.
116. Bradford KK, Deb B, Pearl RG. Combination therapy with inhaled nitric oxide and intravenous dobutamine during pulmonary hypertension in the rabbit. J Cardiovasc Pharmacol. 2000;36:146–151.
117. Vizza CD, Rocca GD, Roma AD, et al. Acute hemodynamic effects of inhaled nitric oxide, dobutamine, and a combination of the two in patients with mild to moderate secondary pulmonary hypertension. Crit Care. 2001:5:355–361.
118. Krowka JM, Mandell MS, Ramsay MA, et al. Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant data base. Liver Transplantation. 2004;10:174–182.
119. Rafanan AL, Maurer J, Mehta AC, et al. Progressive portopulmonary hypertension after liver transplantation treated with epoprostenol. Chest. 2000;188:1497–1500.