Advanced Heart Failure and Cardiogenic Shock

2 Advanced Heart Failure and Cardiogenic Shock J. Thomas Heywood, James B. Young

KEY POINTS Introduction Definition Etiology of Cardiogenic Shock Hemodynamic Effects of Cardiogenic Shock

Neurohormonal Response to Cardiogenic Shock Inflammatory Pathways End Organ Injury Conclusion

INTRODUCTION

Sadly, Revere Osler died despite efforts to ameliorate his shock state, which was multifactorial in nature. Crile’s work subsequently led to development of “shock trousers,” which were used in the operating room when shock developed.5 It was also learned during this time that shock from blood loss could be reversed with lactated Ringer’s solution.6 The current understanding, still incomplete, of cardiogenic shock moved forward in 1927, when Alfred Blalock, prior to the creation of his eponymous shunt with Vivien Thomas and Helen Taussig, began pivotal research on the origins and classification of shock.7 He was able to show experimentally that it often was not neurologically driven. He also classified its presentation into five clinical syndromes, which form the foundation for approaching shock today, including cardiogenic shock. 1. Shock due to volume loss 2. Neurogenic shock 3. Vasogenic shock, which includes sepsis and anaphylaxis 4. Cardiogenic shock 5. Unclassified conditions What is described in the following is a current understanding of the pathophysiology of cardiogenic shock. This is by no means to suggest that cardiogenic shock is “understood,” a point that is underscored by the persistently high mortality of cardiogenic shock. We are standing on the shoulders of giants, but our vision is still woefully incomplete (Table 2.1).

The term shock first appeared in the English medical literature in a translation by John Clarke of a French treatise on gunshot wounds by Henry LeDran in 1740, Traité ou Reflexions Tirées de la Pratique sur les Playes d’armes à feu.1 In his translation, he used the English “shock” to translate the French word saisissement, which at that time might have meant “fright” or “violent emotion.”1 The description only slowly gained acceptance and described more the neurologic reaction, either torpor or agitation, to the trauma of violent injury rather than a physiologic response. The battlefield surgeons of the American Civil War were well acquainted with the condition, “Although the nervous shock accompanies the most serious wounds…. It is recognized by the sufferer becoming cold, faint and pale, with the surface bedewed with a cold sweat; the pulse is small and flickering; there is anxiety, mental depression, with at times incoherence of speech.”2 The measurement of blood pressure, at first invasively and then noninvasively, in the later part of the 19th century added reduced blood pressure to the syndrome.3,4 In the late 19th and early 20th centuries, the etiology of shock was thought to be a neurologic reflex or a result of abnormal blood pooling in the mesenteric vessels. World War I led to an intensification of medical interest on the shock syndrome, with insights added from animal models used to scientifically test models for the initiation of shock. In August 1917, George Crile led the Lakeside Unit from Cleveland into the war. These were the first US Army troops to enter the conflict. A base hospital was established to treat the wounded troops along the German-Allied lines near Rouen, France, and in Belgium’s Flanders Field. Several other units from academic medical centers were assembled, including the Harvard Unit, led by Harvey Cushing. Prior to the war, Crile developed an interest in hemorrhagic shock, developing during surgical procedures. He created a number of approaches to blood transfusion after visiting the labs of Alexis Carrel in 1902 and is sometimes credited with the first direct human blood transfusion. A poignant event is described in his autobiography when he was called by his dear friend Harvey Cushing to his outpost, also serving as a forward base hospital in the war. William Osler’s only child had been mortally wounded and Crile was called to assist with surgery and to arrange for blood transfusions in a desperate attempt to save his life.

DEFINITION Shock is a clinical syndrome, much like heart failure, that is characterized by signs and symptoms recognized by the clinician. These can be horribly apparent, as when cardiac arrest initiates cardiogenic shock with complete absence of vital signs (Fig. 2.1) or so subtle that the patient drifts into shock over the course of weeks or months and even skilled clinicians miss the transition (gradual-onset cardiogenic shock). In general, contemporary definitions of cardiogenic shock are eerily similar to battlefield depictions of severe trauma in the American Civil War, but with the addition of quantitative parameters of reduced urine output and blood pressure. Cardiogenic shock was defined in a

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CHAPTER 2  Advanced Heart Failure and Cardiogenic Shock

TABLE 2.1  INTERMACS Profiles Inform the Definitions of Cardiogenic Shock Category INTERMACS Level 1

Profile Critical cardiogenic shock

Shorthand Jargon “Crash and burn”

INTERMACS Level 2

Progressive decline

“Sliding fast on inotropes”

INTERMACS Level 3

Stable/inotrope dependent

“Inpatient/outpatient inotropes”

INTERMACS Level 4

Recurrent severe CHF

“Symptoms on oral Rx at home”

INTERMACS Level 5

Exertion Intolerant

“Housebound and sx with ADL”

INTERMACS Level 6

Exertion limited

“Walking wounded”

INTERMACS Level 7

NYHA Class IIIb

Advanced/not critical CHF

ADL, Activities of daily living; CHF, congestive heart failure; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; NYHA, New York Heart Association; Rx, medications; sx, symptoms. Source: Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant 2009;28:535–541.

Fig. 2.1  Clinical profiles and outcomes in patients presenting with cardiogenic shock. BP, Blood pressure; CO, cardiac output; CPR, cardiopulmonary resuscitation; HF, heart failure; LVAD, left ventricular assist device; MOF, multiorgan failure; PEA, pulseless electrical activity; SIRS, systemic inflammatory response; TX, cardiac transplant.

recent trial evaluating percutaneous intervention in shock as “a systolic blood pressure of less than 90 mm Hg for longer than 30 minutes or the use of catecholamine therapy to maintain a systolic pressure of at least 90 mm Hg, clinical signs of pulmonary congestion, and signs of impaired organ perfusion with at least one of the following manifestations: altered mental status, cold and clammy skin and limbs, oliguria with a urine output of less than 30 mL per hour, or an arterial lactate level of more than 2.0 mm per liter.”8

ETIOLOGY OF CARDIOGENIC SHOCK Acute myocardial infarction is a common, but by no means the only, cause of cardiogenic shock (Box 2.1), and the infarction can result in shock in a number of ways. It can be the result of a catastrophically large infarct or a relatively small infarction in the setting of an ischemic cardiomyopathy. Infarction of the right ventricle with relative sparing of the left ventricle has unique clinical features, including shock. Severe ischemia even in the absence of myocardial injury can reduce cardiac

CHAPTER 2  Advanced Heart Failure and Cardiogenic Shock

BOX 2.1  Etiologies of Cardiogenic Shock Ischemic Acute myocardial infarction Unstable angina with global ischemia Right ventricular infarction Complications of ischemic heart disease Papillary muscle rupture Acute ventricular septal defect Myocardial rupture Valvular Severe aortic stenosis or insufficiency Severe mitral regurgitation or stenosis Severe pulmonic stenosis or regurgitation Severe tricuspid regurgitation or stenosis Myocardial disease/unknown Acute myocarditis Giant cell myocarditis Takotsubo stress myocarditis Substance abuse Toxins Chemotherapeutic agents End-stage ischemic or nonischemic cardiomyopathy Extracardiac Cardiac tamponade Acute aortic dissection with aortic insufficiency, tamponade, or rupture Large pulmonary embolism End-stage congenital heart disease

output substantially with reduced blood pressure. Finally, infarction with tissue necrosis can result in papillary muscle rupture, acute ventricular septal defect, or free wall rupture with severe, often fatal, shock. In the absence of coronary artery disease, acute myocarditis and especially giant cell myocarditis can result in profound cardiogenic shock such that almost cessation of myocardial contraction can be seen and/or incessant malignant arrhythmias requiring ECMO support. Takotsubo cardiomyopathy can mimic acute myocardial infarction in the emergency room and has a reported incidence of cardiogenic shock of 9%.9 Long-standing heart failure that has been stable for decades can devolve rapidly or insidiously into end-stage heart failure with hypotension and multiorgan dysfunction. Similarly, chronic valvular abnormalities, when they become severe, can profoundly impair hemodynamics and become life-threatening. Patients with adult congenital heart disease can sink later in life into a shock state with multiorgan failure after years of relatively normal cardiovascular status following early palliative surgery. Large pulmonary emboli can present with syncope and cardiogenic shock from right heart failure, as can end-stage pulmonary arterial hypertension. Finally, long-standing alcohol abuse and illicit drug use with methamphetamines or other sympathomimetic drugs can be responsible for profound cardiac dysfunction.

HEMODYNAMIC EFFECTS OF CARDIOGENIC SHOCK Reduced Cardiac Output In general, cardiac output is reduced in cardiogenic shock, although not universally so. Cardiac output is a continuum, so there is not an absolute number below which a patient is in cardiogenic shock. The shock state exists when the output is not sufficient to meet the metabolic needs of the principle organ systems, including the kidneys, liver, central nervous system, and digestive tract. In terms of cardiac output, shock has

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been defined as a cardiac index less than 1.8 to 2.2 L/min/m2.10 That said, not all patients with this reduction in cardiac index are in shock, but it does indicate significant derangement in cardiac function. Unfortunately, cardiac output requires invasive measurements, and so there are often delays in obtaining this important determinate of shock. Beyond thermodilution estimation of cardiac output, mixed venous saturation can be an important indicator of low output states when corrected for anemia. Mixed venous saturations below 50% or, more frequently, less than 40% are indicative of cardiogenic shock.11 Echocardiographic determination of the left ventricular outflow time velocity integral can be used to calculate stroke volume and, hence, cardiac output, and extremely low values are associated with poor outcome.12 Stroke volume can also be estimated by arterial waveform analysis, although this may be less accurate in severe vasodilation or vasoconstriction states.13 In some instances of cardiogenic shock, cardiac output may be nearly normal but is associated with profound vasodilation.14 Vasodilatory shock or systemic inflammatory response, which will be discussed further in the chapter, can develop quickly or during later stages of cardiogenic shock.15 Calculation of systemic vascular resistance can quickly differentiate between vasodilatory or vasoconstrictive shock versus shock presenting with a normal or increased vascular resistance. These distinctions are vital because the pharmacologic and mechanical support approaches are quite different and initial errors in management can prolong tissue hypoperfusion. Judicious use of vasodilators can result in marked improvement of cardiac output in vasoconstriction, whereas they are absolutely contraindicated in vasodilatory states where vasopressin may be beneficial because of vasopressin depletion.16,17

Hypotension The maintenance of normal blood pressure and primarily to prevent hypotension during changes in posture and abnormal physiologic states (dehydration, hemorrhage) is a critical physiologic function in humans. In common parlance, shock and hypotension are so closely associated that they are often felt to be synonymous. When hypotension is detected by the carotid baroreceptors, this sets off a cascade of neural and hormonal responses that seek to increase cardiac output by increasing heart rate, normalize blood pressure by intense vasoconstriction, and preserve volume by changes in renal handling of salt and water.18 The degree and duration of hypotension are critical in both the ongoing pathophysiology of cardiogenic shock and its prognosis. Catastrophic shock associated with cardiac arrest must be corrected or at least ameliorated within minutes to prevent cerebral anoxic injury. Severe hypotension, that is, mean blood pressure <50 mm Hg, may not immediately cause severe brain injury but can result in acute tubular necrosis and liver injury; organ failure at this level may be survivable but complicates and exacerbates shock with poorer outcomes. Milder degrees of hypotension may be present for weeks or even months in chronic heart failure, but frequently lead to more extreme derangement.

Increased Filling Pressures As cardiogenic shock progresses, filling pressures usually rise. If the genesis of the shock is ischemic, then ischemia itself increases diastolic stiffness by interfering with calcium reuptake in the sarcoplasmic reticulum. When myocardial systolic performance is reduced, then systolic emptying falls and filling pressures rise.19 An increase in filling pressures may actually be salutary in that they increase cardiac output by the Frank Starling mechanism but, very quickly, the pressures rise to levels that are detrimental.20 Neurohormonal activation causes increased sodium reabsorption and decreased excretion of

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CHAPTER 2  Advanced Heart Failure and Cardiogenic Shock

free water. Severe prolonged hypotension can result in acute tubular necrosis, so urine output may actually stop, which exacerbates fluid retention. Fluid can shift from the mesenteric bed to the central circulation, further increasing filling pressures.21 As left atrial pressure rises, fluid moves into the lungs, increasing the work of breathing and reducing gas exchange so that ischemia may be compounded. In primarily right-sided cardiogenic shock, left-sided filling pressures are usually low and may exacerbate systemic hypotension due to inadequate left ventricular preload.

NEUROHORMONAL RESPONSE TO CARDIOGENIC SHOCK There is a marked activation of the sympathetic nervous system in response to the reduced systemic blood pressure, which is a hallmark of cardiogenic shock. This response is mainly through arterial baroreceptors located in the carotid sinus and the aortic arch.22,23 Indeed, many of the classic clinical signs of shock are mediated via profound activation of this system, whose key neurotransmitter is norepinephrine. Classical physical signs of shock, such as tachycardia, peripheral vasoconstriction, and cool, clammy skin, are the direct results of norephedrine’s effect on the sinus node, vasoconstriction of epithelial arteries near the surface of the skin, and direct effects of the sweat glands. Norepinephrine levels are elevated both in heart failure and in acute myocardial infarction, but the levels are higher and persist longer when cardiogenic shock intervenes.24 The increases in norepinephrine level are important systemic compensatory mechanisms to both protect blood pressure and increase cardiac output via heart rate increase and myocardial contractility, but this can come at the cost of exacerbating myocardial ischemia and promoting further myocardial cell death via the toxic effect of very high levels of norepinephrine on cardiac myocytes via apotosis.25 Plasma renin levels are also elevated with myocardial infarction and acute decompensated heart failure.26 These levels are especially elevated when blood pressure is significantly reduced.27 Elevated renin produces secondary increases in angiotensin II and aldosterone, whose effects include maintenance of blood pressure and sodium retention. Aldosterone levels are elevated in septic shock but have not been reported so in cardiogenic shock, although higher aldosterone levels are associated with worse long-term prognosis following myocardial infarction.28,29 NT proBNP levels may also increase after myocardial infarction, especially if shock intervenes. Extremely high levels of NT proBNP >12,000 are associated with very poor prognosis in cardiogenic shock, especially when coupled with high interleukin 6 (IL-6) levels.30 Although angiotensin II levels are elevated in severe heart failure, a recent trial suggests that pharmacologic doses of angiotensin II may improve outcome in vasodilatory shock.31 In late 2017, this formulation of angiotensin II was approved for clinical use.32

Lactic Acidosis As a consequence of decreased oxygen delivery to tissue due to hypotension and reduced cardiac output, mitochondrial production of adenosine triphosphate (ATP) is impaired and pyruvate levels increase, resulting in increased levels of lactate, a strong acid (Fig.  2.2). A reduction in intracellular and extracellular pH has important physiologic consequences that exacerbate the shock state.33 Reduced intracellular pH has negative effects on cardiac function by decreasing myofilament sensitivity to Ca++ and to adrenergic agonists.34,35 In addition, it interferes with depolarization by enhancing K+ egress from the cell, resulting in hyperpolization.17 Lactic acidosis also causes adrenoreceptor internalization so that sensitivity to norepinephrine is reduced.36,37

Finally, low intracellular PH stimulates BNIP23, which promotes apoptosis and induces nitric oxide (NO) production, which has detrimental effects.38 In smooth muscle cells, hyperpolarization occurs, so these cells critical to the maintenance of blood pressure cannot constrict normally, thus contributing to hypotension. Acidosis also reduces the sensitivity of vascular smooth muscle cells to the vasoconstrictor effects both of NE and angiotensin II.17 Clearly, in some patients with cardiogenic shock, vasoconstrictive reflexes are still functional. However, as shock is prolonged and/or a vasodilatory state appears, the vascular smooth muscle beds can no longer function normally, and irreversible shock may develop. In patients resuscitated from cardiac arrest out of hospital, presenting lactate levels were highly associated with mortality; 61% of patients survived if the initial lactate levels were <5 mmol/L, whereas only 8% survived if the levels were greater than 10 mmol/L.39 Intravascular pH and lactate levels are important indicators of both developing shock and its severity. Lactate is a key biomarker for the detection of early shock, the severity of shock, and its successful management (Box 2.2). High lactate levels correlate strongly with prognosis in cardiogenic shock and shock from other etiologies.40 Lactate is cleared by both the kidneys and the liver, and as these organs fail, lactate levels remain elevated even when corrective measures have restored blood pressure and cardiac output.41 Thus, lactate may remain elevated for many hours even though pH has been corrected.

INFLAMMATORY PATHWAYS In concert with the hemodynamic and neurohormonal abnormalities attendant with cardiogenic shock, an inflammatory response via the cytokine system plays an important role in the progressive circulatory deterioration (Fig.  2.3). IL-6 levels are increased significantly in both cardiogenic and septic shock. The actions of IL-6, which is generated and released by monocytes and T cells, contribute to the inflammatory response by an antiapoptotic effect on T cells. Geppert et  al. reported that in patients with cardiogenic shock, IL-6 levels were significantly higher than in other intensive care unit patients without shock and that very high levels of IL-6 were associated with multiorgan failure.42 IL-6, -7, -8, and -10 levels are also predictive of increased mortality.43 Tumor necrosis factor-alpha (TNF-α) is elevated in advanced heart failure and is in part responsible for cardiac cachexia; hence, it is also known as cachexin.44 Produced by activated macrophages, its release is one component of the acute phase reaction and induces fever and inhibits viral replication. Inhibition of TNF-α has proven successful in some autoimmune conditions but was not successful when applied to heart failure.45 Peak concentrations of TNF-α were higher in patients with cardiogenic shock compared to patients with acute myocardial infarctions without shock and were higher still in those whose cardiogenic shock and had a vasodilatory component.46 C-reactive protein, like TNF-α, is also involved in the acute phase reactant produced by hepatic cells and is increased in cardiogenic shock.47 While the measurement of most cytokines is not available clinically, procalcitonin is a valuable, routinely used clinical biomarker. It is the precursor of calcitonin, but it has additional biochemical effects that are similar to cytokines.48 Procalcitonin levels may be elevated in sepsis and may be useful in the early initiation of antibiotics. However, procalcitonin levels may be also elevated in cardiogenic shock without apparent bacterial infection and are indicative of a marked inflammatory response.46

CHAPTER 2  Advanced Heart Failure and Cardiogenic Shock ↓ pH

+ K+

–

+

K+ Ca

Interstitium

13

K+ channels K+ ATP channels

Ca++ –

Adenoreceptors

+

↑

Intercellular space

Cellular Hyperpolarization Troponin

–

Tropomyosin

↓ pH G-actin molecules +

↓

Myofilament Ca++ sensitivity

BNIP3 +

DNase

↑ Apoptosis

Fig. 2.2  Reduction in pH that occurs with lactic acidosis has a significant, negative impact on cellular function. Lower intracellular pH potentiates K+ egress from cells, which results in hyperpolarization. In smooth muscle cells this interferes with normal depolarization and contraction, which exacerbates hypotension. Acidosis also is associated with a decrease in adrenergic receptors. Intracellular acidosis interferes with Ca++ binding of myocytes which impairs contractility. Acidosis also activates the BNIP3 gene, which is involved in apoptosis. ATP, Adenosine triphosphate. (From Antoine Kimmoun, Emmanuel Novy, Thomas Auchet, Nicolas Ducrocq et al, Bruno Lev., Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside., Critical Care201721:40. http://creativecommons.org/licenses/by/4.0/.)

BOX 2.2  Generation and Effects of Lactic

Nitric Oxide

Lactic acidosis—key biomarker in cardiogenic shock • Elevated lactate levels indicate that oxygen delivery is inadequate to support normal metabolism. • Indicates transition from aerobic to anaerobic metabolism. • Higher lactate levels indicate more reliance on anaerobic metabolism with increased acidosis because lactate is a strong acid. • Survival declines with higher lactate levels and lower pH. • Organs with high metabolic needs (brain, heart, and kidney) are more dependent on aerobic metabolism and are thus more sensitive to hypoxia. • Acidosis has multiple detrimental cellular effects, including reduced sensitivity to norepinephrine, impaired contractility, and hyperpolarization of the smooth muscle exacerbating hypotension. • Reduction in lactate levels with shock treatment is associated with ­improved prognosis. • Lactate levels may remain elevated for some time despite reduced production and clearing acidosis because of ongoing kidney and liver disease, which impairs clearance.

NO is an important signaling molecule produced in endothelial cells, neurons, and other mammalian cell lines. The identification of NO and the elegant proof of its pivotal role in biological signaling was r­ ecognized by the awarding of the Nobel Prize to Robert Furchgott, Louis Ignarro, and Ferid Murad in 1998.49,50 It is produced from L-arginine via nitric oxide synthetase (NOS), which is present as several isoforms whose major function in vascular endothelium is to promote vasodilation and inhibit platelet adhesion and aggregation. One isoform of NOS, inducible NOS (iNOS), can be produced in large quantities in sepsis and contribute to hypotension and vasodilatory shock.51 High levels of NO produced via iNOS in addition can interfere with mitochondrial function and suppress myocardial function.52,53 The precise mechanism by which iNOS is expressed at high levels is unknown, but IL-6 may play a role.54 Inhibitors of NO synthetase exist, and early studies showed beneficial effects in cardiogenic shock.55,56 A large randomize trial, Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock (TRIUMPH), was undertaken to evaluate the effects of tilarginine in patients p ­ resenting

Acidosis in Cardiogenic Shock

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CHAPTER 2  Advanced Heart Failure and Cardiogenic Shock Pathophysiology of Cardiogenic Shock

↑Lactate Reduced Cardiac Output

Lactic Acidosis

↓pH

Nitric Oxide Interleukins (TNF-α) +/− Systemic Inflammatory Response

Severe Ventricular Valvular Dysfunction

Reduced Systemic Pressure

Reduced Renal, Liver Function

Neural Hormonal Response

↑Afterload

Increased Filling Pressures

Volume↑↑

Multiorgan Failure

DEATH

Increased Vascular Permiability

Pulmonary Edema ARDS Peripheral Edema WORSENS

Fig. 2.3  Cardiogenic shock is a complex physiology response to hypotension and/or reduced cardiac output. The primary effect of this is a shift from aerobic to anaerobic metabolism with the elaboration of lactic acid and reduce pH. Neurohormonal and inflammatory pathways are activated by hypotension and acidosis which cause fluid retention and reduce capillary integrity. Impaired oxygen delivery and volume expansion worsen organ function and can result in multiorgan failure. ARDS, Acute respiratory distress syndrome; TNF-α, tumor necrosis factor-alpha.

with myocardial infarction and cardiogenic shock.57 Although the agent did increase systolic blood pressure in the treatment group, the study was terminated for futility. Tilarginine is a nonspecific inhibitor of NOS, so all isoforms are affected; therefore, important intracellular isoforms may be inhibited along with the inducible form thought responsible for the high extracellular NO levels.58

END ORGAN INJURY A common criterion included in the clinical definition of shock is reduced urine output. Renal function may be temporarily impaired by the onset of shock or acute tubular necrosis can ensue and renal function may never recover even if the patient survives. Renal dysfunction is common in cardiogenic shock and is a marker for increased mortality.

As reported by Koreny et al. in a cohort of patients with cardiogenic shock following myocardial infarction, mortality was 87% in those who developed renal failure in the first 24 hours versus 53% in those who did not.59 Decreased urine output and worsening renal function are the end result of many factors during the initiation and evolution of shock. Hypotension and reduced cardiac output reduce glomerular filtration pressure, although the preferential shunting of blood to the central organs may forestall this. The effects of hypotension may also be mitigated by increased levels of angiotensin II, which constrict efferent arterioles and thus increase intraglomerular pressure.60 Conversely, high levels of norepinephrine and sympathetic stimulation cause generalized vasoconstriction, which may further diminish renal blood flow and even lead to renal ischemia. If the systemic vascular resistance is high enough to severely reduce cardiac output careful vasodilation

CHAPTER 2  Advanced Heart Failure and Cardiogenic Shock while scrupulously maintaining blood pressure can, in rare instances of early shock, preserve renal function. However, in most cases, blood pressure cannot be supported chemically and mechanical support is required. In any case, preservation of renal function is a critical goal in shock management. In some cases of cardiogenic shock, a vasodilatory component can occur initially or as shock becomes progressive and unrelenting. Vasodilatory shock makes maintenance of blood pressure extremely difficult as the arteriolar bed becomes resistant to pressors.17,35 Vasopressin can be useful in some instances of vasodilatory shock because stores of vasopressin are depleted as shock continues.17 As noted earlier, intravenous angiotensin II may show some benefit in high output shock.31 Renal failure is almost always seen when vasodilatory shock is present. Another important component in the setting of worsening renal function is high central venous pressure, which is rarely seen in other forms of shock but is a frequent hemodynamic finding in cardiogenic shock. The increased levels of renin, aldosterone, angiotensin II, and vasopressin all work to increase sodium and free water reabsorption when the kidneys are functioning. When they fail, volume cannot be offloaded except through dialysis and ultrafiltration. The resulting high central venous pressures cause further disruption in renal ­function by increasing interstitial and abdominal pressures.61–63 Severe tricuspid regurgitation also significantly impairs renal venous outflow and is associated with a marked reduction in survival in heart failure.64 Reduction of filling pressures to normal levels via dialysis and continuous renal replacement therapy help to maintain or restore renal function and are important components of shock management. The liver may also be severely impacted in cardiogenic shock by similar mechanisms as the kidney, that is, passive congestive and ischemic injury.65 At times, liver failure may be the chief presenting feature of cardiogenic shock; indeed, a cardiac etiology may not be detected initially.66 Passive congestion of the liver without shock can result in elevation of liver enzymes to several times the normal range and mild elevation of bilirubin. If this elevation persists for years, frank cirrhosis can result. In cardiogenic shock, ischemic hepatic necrosis can be seen. Ordinarily, the liver is resistant to hypoxic injury because hepatocytes are capable of extracting almost all the oxygen from the blood to meet its considerable metabolic needs. When shock persists and necrosis ensues, this presents histologically as centrolobular necrosis of zone 3 hepatocytes without inflammation.67 Elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 10 times above normal may be seen with much greater increases in bilirubin. Elevations in bilirubin are an independent predictor of mortality in heart failure. Unlike the kidney, where full-blown ATN develops, the liver can recover from the shock state in a matter of days if the shock is reversed quickly enough. If shock persists, liver failure can progress, with reductions in serum albumin and the development of coagulopathies, which increase the risk of mortality. Respiratory failure due to increased work of breathing and intractable pulmonary edema is a common complication of cardiogenic shock so that mechanical ventilation is extremely common. Elevated filling pressures play an important role, as does breakdown in capillary integrity, which can result in adult respiratory distress syndrome even if filling pressures are controlled by diuretics or renal replacement therapy.68 Of all the organs in the body, the central nervous system, because of its extremely high oxygen requirements, is most susceptible to hypotension in cardiogenic shock. Ordinarily, in catastrophic shock with

15

complete cessation of cardiac function, irreversible brain injury can occur unless high-quality cardiopulmonary resuscitation (CPR) is initiated in the first 1 to 2 minutes.

CONCLUSION Since the introduction of the concept of shock into the medical literature in the 18th century, our understanding of this dreadful and fascinating condition has benefited from the work of physicians on the battlefields, physiologists in the early 20th century, and basic scientists working out complex biochemical effects of neurohormones, cytokines, and apoptosis. As a result of this work, shock can now be diagnosed more quickly and reversed in some cases via well-placed balloons, appropriate pharmaceutical agents, and the rapid application of mechanical pumps. Nonetheless, many more patients are lost to cardiogenic shock than are saved each year. This is a major health care system problem with multiple causes, including inadequate CPR, lack of access to defibrillators, and poor management of shock. On a deeper level, the pathophysiology of shock is still incompletely understood, and thus, the means of reversing its pathophysiologic storm are not yet in our armamentarium.

REFERENCES 1. Millham FH. A brief history of shock. Surgery. 2010;148:1026–1037. 2. Chisolm JJ. A Manual of Military Surgery: For the Use of the Surgeons in the Confederate Army: with an Appendix of the Rules and Regulations of the Medical Department of the Confederate Army (No. 4). Norman Publishing; 1861. 3. Mansell-Moulin CW. On the Pathology of Shock. Dissertation. London: HG Saunders; 1880. 4. Booth J. A short history of the blood pressure measurement. Proc Roy Soc Med. 1977;70:793–799. 5. Crile G. George Crile: An Autobiography. 2 Lippincott; 1947. 6. Shires T, Coln D, Carrico J, Lightfoot ST. Fluid therapy in hemorrhagic shock. Arch Surg. 1964;88:688–693. 7. Blalock A. Shock and hemorrhage. Bull NY Acad of Med. 1936;11: 610–622. 8. Thiele H, Akin I, Sandri M, et al. PCI strategies in patients with acute myocardial infarction and cardiogenic shock. N Engl J Med. 2017;377:2419–2432. 9. Templin C, Ghadri J, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373:929–938. 10. Holmes DR Jr, Berger PB, Hochman JS, et al. Cardiogenic shock in patients with and without ST-segment elevation. Circulation. 1999;100:2067–2073. 11. Muir AL, Kirby BJ, King AJ, et al. Mixed venous oxygen saturation in relation to cardiac output in myocardial infarction. Br Med J. 1970;4:276–278. 12. Tan C, Rubenson D, Srivastava A, et al. Left ventricular outflow tract velocity. Cardiovasc Ultrasound 2017;15:18–26. 13. Mehta Y, Arora D. Newer methods of cardiac output monitoring. World J Cardiol. 2014;6:1022–1029. 14. Kohsaka S, Menon V, Lowe AM, et al. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch Intern Med. 2005;165:1643–1650. 15. Argenziano M, Chen JM, Choudhri AF, et al. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg. 1998;116:973–980. 16. Elkayam U, Janmohamed M, Habib M, et al. Vasodilators in the management of acute heart failure. Crit Care Med. 2008;36(1 suppl):S95–S105. 17. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001;345:588–594. 18. Creager MA. Baroreceptor reflex function in congestive heart failure. Am J Cardiol. 1992;69:10G–16G.

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CHAPTER 2  Advanced Heart Failure and Cardiogenic Shock

19. Thune JJ, Solomon SD. Left ventricular diastolic function following myocardial infarction. Curr Heart Fail Rep. 2006;3:170–174. 20. Sarnoff J. Myocardial contractility as described by ventricular function curves. Physiol Rev. 1955;35:107–122. 21. Verbrugge FH, Dupont M. Steels, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Amer Coll Cardiol. 2013;62:485–495. 22. Leimbach WN Jr, Wallin BG, Victor RG, et al. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Ciculation. 1986;73:913–919. 23. Creager MA, Creager SJ. Arterial baroreflex regulation of blood pressure in patients with congestive heart Failure. J Am Coll Cardiol. 1994;23:401–405. 24. Benedict CR, Grahame-Smith DG. Plasma adrenaline and noradrenaline concentrations and dopamine-beta-hydroxylase activity in myocardial infarction with and without cardiogenic shock. Br Heart J. 1979;42: 214–220. 25. Mann DL, Kent RL, Parsons B, et al. Adrenergic effects of the biology of the mammalian cardiocyte. Circulation. 1992;85:790–804. 26. Vaney C, Waeber B, Turini G, et al. Renin and the complications of acute myocardial infarction. Chest. 1984;86:40–43. 27. Dzau VJ, Colucci WS, Hollenberg NK, et al. Relation of the reninangiotensin-aldosterone system to clinical state in congestive heart failure. Circulation. 1981;63:645–651. 28. Moraes RB, Friedman G, Vianna MV, et al. Aldosterone secretion in patient with septic shock: a prospective study. Arq Bras Endocrinol Metab. 2013;57:636–641. 29. Palmer BR, Pilbrow AP, Frampton CM, et al. Plasma aldosterone levels during hospitalization are predictive of survival post-myocardial infarction. Eur Heart J. 2008;29:2489–2496. 30. Jarai R, Fellner B, Haoula D, et al. Early assessment of outcome in cardiogenic shock: relevance of the plasma N-terminal pro-B-type natriuretic peptide and interleukin-6 levels. Crit Care Med. 2009;37:1837–1844. 31. Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS Trial): a pilot study. Crit Care 2014;18:534–543. 32. FDA clears angiotensin II (Giapreza) for septic shock. Medscape Medical News; December 21, 2017. Accessed January 22, 2018, https://www. medscape.com/viewarticle/890494. 33. Kimmoun A, Navy E, Auchet T, et al. Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside. Crit Care 2015;19:175–187. 34. Balnave CD, Vaughan-Jones RD. Effect of intracellular pH on spontaneous Ca2+ sparks in rat ventricular myocytes. J Physiol. 2000;528:25–37. 35. Huang Y-G, Wong KC, Yip W-H, et al. Cardiovascular responses to graded doses of three catecholamines during lactic and hydrochloric acidosis in dogs. Br J Anaesth. 1995;74:583–590. 36. Ives SJ, Andtbacka RHI, Noyes RD, et al. Alpha1-adrenergic responsiveness in human skeletal muscle feed arteries: the impact of reducing extracellular pH. Exp Physiol. 2013;98:256–267. 37. Marsh JD, Margolis TI, Donghee K. Mechanism of diminished contractile response to catecholamines during acidosis. Am J Physiol. 1988;254:H20–H27. 38. Kusbasiak LA, Hernandez OM, Bishopric NH, et al. Hypoxia and acidosis activate cardiac myocyte death through the BCL-2 family protein BNIP3. Proc Natl Acad Sci USA. 2002;99:12825–12830. 39. Cocchi MN, Miller J, Hunziker S, et al. The association of lactate and vasopressor need for mortality prediction in survivors of cardiac arrest. Minerva Anestesiol. 2011;77:1063–1071. 40. Lazzeri C, Valente S, Chiostri M, et al. Clinical significance of lactate in acute cardiac patients. World J Cardiol. 2015;7:483–489. 41. Attana P, Lazzeri C, Picariello C, et al. Lactate and lactate clearance in acute cardiac care patients. Eur Heart J Acute Cardiovasc Care. 2012;1:115–121.

42. Prondzinsky R, Unverzagt S, Lemm H, et al. Interleukin-6, -7, -8 and -10 predict outcome in acute myocardial infarction complicated by cardiogenic shock. Clin Res Cardiol. 2012;101:375–384. 43. Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323:236–241. 44. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebocontrolled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate to severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation. 2003;107:3133–3140. 45. Debrunner M, Schuiki E, Minder E, et al. Proinflammatory cytokines in acute myocardial infarction with and without cardiogenic shock. Clin Res Cardiol. 2008;97:298–305. 46. Picariello C, Lazzeri C, Chiostri M, et al. Procalcitonin in patients with acute coronary syndromes and cardiogenic shock submitted to percutaneous coronary intervention. Intern Emerg Med. 2009;4: 403–408. 47. Meisner M. Update on procalcitonin measurements. Ann Lab Med. 2014;34:263–273. 48. Jin M, Khan AI. Procalcitonin: uses in the clinical laboratory and for the diagnosis of sepsis. Lab Med. 2010;41:173–177. 49. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376. 50. Ignarro LJ, Byrns RE, Buga GM, et al. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987;61:866–879. 51. Tsukahara Y, Morisaki T, Kojima A, et al. iNOS expression by activated neutrophils from patients with sepsis. ANZ J Surg. 2001;71:15–20. 52. Davidson SM, Duchen MR. Effects of NO on mitochondrial function: pathological relevance. Cardiovasc Res. 2006;71:10–21. 53. Tatsumi T, Matoba S, Kawahara A, et al. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes. J Am Coll Cardiol. 2000;35:1338–1346. 54. Dawn B, Xuan Y-T, Guo Y, et al. IL-6 places an obligatory role in late precondition via JAK-STAT signaling and upregulation of iNOS and COX-2. Cardiovasc Res. 2004;64:61–71. 55. Cotter G, Kaluski E, Milo O, et al. L-NMMA (a nitric oxide synthase inhibitor) is effective in the treatment of cardiogenic shock. Circulation. 2000;101:1358–1361. 56. Dzavik V, Cotter G, Reynolds HR, et al. Effect of nitric oxide synthase inhibition on haemodynamics and outcomes of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study. Eur Heart J. 2007;28:1109–1116. 57. The TRIUMPH Investigators. Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA. 2007;297:1657–1666. 58. Ndrepepa G, Schömig A, Kastrati A. Lack of benefit from nitric oxide synthase inhibition in patients with cardiogenic shock: looking for reasons. JAMA. 2007;297:1711–1713. 59. Koreny M, Karth GD, Geppert A, et al. Prognosis of patients who develop acute renal failure during the first 24 hours of cardiogenic shock after myocardial infarction. Am J Med. 2002;112:115–119. 60. Schoolworth. AC, Sica, DA, Ballermann, BJ, et al. Renal considerations in angiotensin converting enzyme inhibition therapy. Circulation. 2001;104:1985–1991. 61. Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet. 1988;1(8593):1035–1055. 62. Doty JM, Saggi BH, Sugerman HF, et al. Effect of increased renal venous pressure on renal function. J Trauma. 1999;47:1000–1003.

CHAPTER 2  Advanced Heart Failure and Cardiogenic Shock 63. Mullens W, Abrahams Z, Francis G, et al. Importance of venous congestion for worsening renal function in advanced decompensated heart failure. J Amer Coll Cardiol. 2008;53:589–596. 64. Iida N, Seo Y, Sai S, et al. Clinical implications of intrarenal hemodynamic evaluation by Doppler ultrasonography in heart failure. JACC Heart Fail. 2016;8:674–682. 65. Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369:2525–2534.

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66. Saner FH, Heuer M, Meyer M, et al. When the heart kills the liver: acute liver failure in congestive heart failure. Eur J Med Res. 2009;14:541–546. 67. Alvarez AM, Mukherjee D. Liver abnormalities in cardiac diseases and heart failure. Int J Angiol. 2011;20:135–142. 68. Siddall E, Khatri Minesh, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017;92:37–46.