Reconsidering Vasopressors for Cardiogenic Shock

Scientific statements and publications have recommended the use of vasoconstrictors as the first-line pharmacologic choice for most cases of cardiogenic shock (CS), without the abundance of strong clinical evidence. One challenge of guidelines is that the way recommendations are stated can potentially lead to oversimplification of complex situations. Except for acute coronary syndrome with CS, in which maintenance of coronary perfusion pressure seems logical prior to revascularization, physiologic consequences of increasing afterload by use of vasoconstrictors should be analyzed. Changing the CS conceptual frame, emphasizing inflammation and other vasodilating consequences of prolonged CS, mixes causes and consequences. Moreover, the considerable interpatient differences regarding the initial cause of CS and subsequent consequences on both macro- and microcirculation, argue for a dynamic, step-by-step, personalized therapeutic strategy. In CS, vasoconstrictors should be used only after a reasoning process, a review of other possible options, and then should be titrated to reach a reasonable pressure target, while checking cardiac output and organ perfusion. Scientific statements and publications have recommended the use of vasoconstrictors as the first-line pharmacologic choice for most cases of cardiogenic shock (CS), without the abundance of strong clinical evidence. One challenge of guidelines is that the way recommendations are stated can potentially lead to oversimplification of complex situations. Except for acute coronary syndrome with CS, in which maintenance of coronary perfusion pressure seems logical prior to revascularization, physiologic consequences of increasing afterload by use of vasoconstrictors should be analyzed. Changing the CS conceptual frame, emphasizing inflammation and other vasodilating consequences of prolonged CS, mixes causes and consequences. Moreover, the considerable interpatient differences regarding the initial cause of CS and subsequent consequences on both macro- and microcirculation, argue for a dynamic, step-by-step, personalized therapeutic strategy. In CS, vasoconstrictors should be used only after a reasoning process, a review of other possible options, and then should be titrated to reach a reasonable pressure target, while checking cardiac output and organ perfusion. Cardiogenic shock (CS) is a low cardiac output (CO) state due to heart failure, resulting in life-threatening end-organ hypoperfusion and hypoxia.1Thiele H. Ohman E.M. Desch S. Eitel I. de Waha S. Management of cardiogenic shock.Eur Heart J. 2015; 36: 1223-1230Crossref PubMed Scopus (300) Google Scholar, 2van Diepen S. Katz J.N. Albert N.M. et al.Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association.Circulation. 2017; 136: 232-268Crossref PubMed Scopus (762) Google Scholar In the setting of acute myocardial infarction, support of coronary perfusion pressure with vasoconstrictor agents as an initial step prior to revascularization seems reasonable. CS, however, occurs in many other settings, including decompensation of chronic heart failure, fulminant myocarditis, post-cardiac arrest, severe valvular heart disease, right ventricular failure, and as a component of mixed shock in lung injury, sepsis, and other inflammatory conditions. In these settings, application of an early vasoconstricting approach intended for BP support may not always be the best course of action. In the classic pathophysiologic model of CS, early compensatory systemic vasoconstriction occurs in order to maintain BP and organ perfusion. Persistence of tissue hypoxia, however, may induce inflammation with subsequent altered vasoreactivity,3Neumann F.J. Ott I. Gawaz M. et al.Cardiac release of cytokines and inflammatory responses in acute myocardial infarction.Circulation. 1995; 92: 748-755Crossref PubMed Scopus (465) Google Scholar which can change the paradigm.4Hochman J.S. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm.Circulation. 2003; 107: 2998-3002Crossref PubMed Scopus (460) Google Scholar Consequently, the choice of pharmacologic treatment may change from pure inotrope or inodilator support5Garcia-Gonzalez M.J. Dominguez-Rodriguez A. Ferrer-Hita J.J. Abreu-Gonzalez P. Munoz M.B. Cardiogenic shock after primary percutaneous coronary intervention: effects of levosimendan compared with dobutamine on haemodynamics.Eur J Heart Fail. 2006; 8: 723-728Crossref PubMed Scopus (70) Google Scholar, 6Russ M.A. Prondzinsky R. Christoph A. et al.Hemodynamic improvement following levosimendan treatment in patients with acute myocardial infarction and cardiogenic shock.Crit Care Med. 2007; 35: 2732-2739PubMed Google Scholar to a combination of inotropes and vasoconstrictors.1Thiele H. Ohman E.M. Desch S. Eitel I. de Waha S. Management of cardiogenic shock.Eur Heart J. 2015; 36: 1223-1230Crossref PubMed Scopus (300) Google Scholar, 7Reynolds H.R. Hochman J.S. Cardiogenic shock: current concepts and improving outcomes.Circulation. 2008; 117: 686-697Crossref PubMed Scopus (550) Google Scholar, 8Levy B. Perez P. Perny J. Thivilier C. Gerard A. Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock: a prospective, randomized pilot study.Crit Care Med. 2011; 39: 450-455Crossref PubMed Scopus (175) Google Scholar Although comparative studies combining different drug strategies are lacking, several scientific societies have recommended in high-impact journals that drugs with a predominantly vasoconstrictive effect—mostly norepinephrine—be used alone as the first-line treatment,2van Diepen S. Katz J.N. Albert N.M. et al.Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association.Circulation. 2017; 136: 232-268Crossref PubMed Scopus (762) Google Scholar, 9Levy B. Bastien O. Karim B. et al.Experts' recommendations for the management of adult patients with cardiogenic shock.Ann Intensive Care. 2015; 5: 52PubMed Google Scholar eventually associated with inotropes when the low-flow state persists. Although cautiously written, these recommendations tend to prioritize pressure over flow, which may initially improve BP, but present a risk of potential deterioration thereafter. Although simple messages for early management are desirable, there is a risk that oversimplification may lead to suboptimal treatment that can affect outcome. The CS context is very heterogeneous in many aspects, in part because a delay from the onset of acute hemodynamic disorders to initiation of treatment can change the clinical presentation. Thus, even if a "one-size-fits-all" approach may be logical early on, and may lead to a statistical improvement in a large population, it cannot be safely generalized to all situations and does not guarantee an optimal strategy on an individual basis. This review aims to summarize the conceptual, pathophysiologic, and therapeutic evidence arguing for a more dynamic, granular, and personalized approach, and to suggest an algorithmic process based on well-established priorities. The recommendation for using vasoconstrictors as the first choice in CS ultimately rests on a concept that prioritizes pressure over flow, essentially treating the consequences of cardiac dysfunction (hypotension) as opposed to constructing a conceptual model based on the causes of cardiac dysfunction.1Thiele H. Ohman E.M. Desch S. Eitel I. de Waha S. Management of cardiogenic shock.Eur Heart J. 2015; 36: 1223-1230Crossref PubMed Scopus (300) Google Scholar, 2van Diepen S. Katz J.N. Albert N.M. et al.Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association.Circulation. 2017; 136: 232-268Crossref PubMed Scopus (762) Google Scholar An approach based on BP seems to support symptomatic treatment more than interventions focused on mechanisms that have been understood and modeled. While the initial goal in CS is to support coronary and organ perfusion pressure, the mechanisms mediating the circulatory disorder may differ in different settings. We propose a broader conceptual model that considers tissue and coronary perfusion as a function primarily of low cardiac output, but with variable contributions from hypoxia, endothelial dysfunction, inflammation, and vasoplegia (Fig 1). The interplay of different factors results in a complex association of causes and consequences that may or may not respond adequately to vasoconstrictors. As recommendations for initial support are necessary, they should be supplemented by detailed bundles that take into account the evolution of the shock syndrome, integrating a comprehensive pathophysiologic model, as has been done with septic shock.10Coopersmith C.M. De Backer D. Deutschman C.S. et al.Surviving sepsis campaign: research priorities for sepsis and septic shock.Intensive Care Med. 2018; 44: 1400-1426Crossref PubMed Scopus (117) Google Scholar Since knowledge comes in successive layers that encompass previous concepts,11Squara P. Systematic approach: an evidence management strategy for better decision-making.J Evid Based Med. 2013; 6: 109-114Crossref PubMed Scopus (3) Google Scholar the new insights and developments in CS pathophysiology do not invalidate the past studies. A decrease in CO associated with organ congestion and hypoperfusion remains the landmark characteristic of CS, seen in combination with symptoms of acute heart failure and shock.12Mebazaa A. Tolppanen H. Mueller C. et al.Acute heart failure and cardiogenic shock: a multidisciplinary practical guidance.Intensive Care Med. 2016; 42: 147-163Crossref PubMed Scopus (116) Google Scholar, 13Harjola V.P. Mullens W. Banaszewski M. et al.Organ dysfunction, injury and failure in acute heart failure: from pathophysiology to diagnosis and management. A review on behalf of the Acute Heart Failure Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).Eur J Heart Fail. 2017; 19: 821-836Crossref PubMed Scopus (188) Google Scholar Without clear distinction between causes, consequences, time between them, and without CO and tissue perfusion assessment, replacement of the classic mechanistic model based on hemodynamic subsets14Forrester J. Diamond G. Chatterjee K. Swan H. Medical therapy of acute myocardial infarction by application of hemodynamic subsets.N Engl J Med. 1976; 295: 1356-1364Crossref PubMed Scopus (299) Google Scholar by a phenotypic classification based on BP2van Diepen S. Katz J.N. Albert N.M. et al.Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association.Circulation. 2017; 136: 232-268Crossref PubMed Scopus (762) Google Scholar is not an advance in the level of knowledge. CS is a syndrome with a conventional definition for which the key concept is shock, a circulatory disorder leading to a severe imbalance between oxygen needs and oxygen consumption (Vo2).15Squara P. Matching total body oxygen consumption and delivery: a crucial objective?.Intensive Care Med. 2004; 30: 2170-2179Crossref PubMed Scopus (29) Google Scholar All Vo2 components are interrelated to maintain Vo2 close to the oxygen needs. When a component is failing, others are stimulated to compensate.16Squara P. Central venous oxygenation: when physiology explains apparent discrepancies.Crit Care. 2014; 18: 579Crossref PubMed Scopus (25) Google Scholar Moreover, an adaptation, called the "conformance phenomenon," may reduce oxygen needs when oxygen delivery decreases.17Schumacker P.T. Chandel N. Agusti A.G. Oxygen conformance of cellular respiration in hepatocytes.Am J Physiol. 1993; 265: L395-L402PubMed Google Scholar All these mechanisms are overwhelmed when shock occurs and the oxygen deficit increases with time. As a result, both macro- and microcirculations are modified, with mutual interactions. In the early phase, the microcirculation and macrocirculation are coherently linked, but it was shown that, very rapidly, a significant proportion of patients may have incoherence between the two, with persistent tissue hypoperfusion despite improvement in macrocirculation.18Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation.Crit Care. 2015; 19: S8Crossref PubMed Scopus (241) Google Scholar This can be caused by heterogeneities in the microcirculation, decrease in the capillary density, local reduction of flow, or tissue edema, and may lead to irreversible damage. After time, in any shock state the symptoms can be dominated in different proportion by the systemic inflammatory response, adding complexity to the initial event.4Hochman J.S. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm.Circulation. 2003; 107: 2998-3002Crossref PubMed Scopus (460) Google Scholar, 19Prondzinsky 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: 375-384Crossref PubMed Scopus (74) Google Scholar As a consequence, the compensatory mechanisms to fit with oxygen needs may be less efficient, with various alterations in myocardial contraction,20Muller-Werdan U. Prondzinsky R. Werdan K. Effect of inflammatory mediators on cardiovascular function.Curr Opin Crit Care. 2016; 22: 453-463Crossref PubMed Scopus (13) Google Scholar lung function, microcirculation, and organ function.21Payen D. Luengo C. Heyer L. et al.Is thenar tissue hemoglobin oxygen saturation in septic shock related to macrohemodynamic variables and outcome?.Crit Care. 2009; 13: S6Crossref PubMed Scopus (96) Google Scholar, 22Le Dorze M. Huche F. Coelembier C. Rabuel C. Payen D. Impact of fluid challenge increase in cardiac output on the relationship between systemic and cerebral hemodynamics in severe sepsis compared to brain injury and controls.Ann Intensive Care. 2018; 8: 74Crossref PubMed Scopus (3) Google Scholar On top of these alterations, the response to vasoactive mediators and drugs can be severely altered.23Hermansen S.E. Kalstad T. How O.J. Myrmel T. Inflammation and reduced endothelial function in the course of severe acute heart failure.Translational Res. 2011; 157: 117-127Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar On an individual basis, there is considerable heterogeneity in inflammatory response depending on individual susceptibility according to age, comorbidities, genetic factors, chronic treatment, and organ damage.24Dibbs Z. Thornby J. White B.G. Mann D.L. Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: implications for clinical trials.J Am Coll Cardiol. 1999; 33: 1935-1942Crossref PubMed Scopus (123) Google Scholar, 25Hartemink K.J. Groeneveld A.B. The hemodynamics of human septic shock relate to circulating innate immunity factors.Immunol Invest. 2010; 39: 849-862Crossref PubMed Scopus (26) Google Scholar The tissue response to CS status is also influenced by the etiology and severity of shock and the delay between the onset of shock and the initiation of treatment.26Schlag G. Redl H. Hallstrom S. The cell in shock: the origin of multiple organ failure.Resuscitation. 1991; 21: 137-180Abstract Full Text PDF PubMed Scopus (111) Google Scholar The response to stress finally includes a metabolic component with hyperglycemia,27Losser M.R. Damoisel C. Payen D. Bench-to-bedside review: glucose and stress conditions in the intensive care unit.Crit Care. 2010; 14: 231Crossref PubMed Scopus (81) Google Scholar metabolic acidosis, and tissue hypercapnia, adding to the complexity of the observed symptoms.28Payen D. Haloui H. Acid-base status is an important factor for inflammation, but don't forget CO2!.Crit Care. 2014; 18: 664Crossref PubMed Scopus (4) Google Scholar All interactions and combined heterogeneities suggest an interplay between the initial circulatory disorders and the subsequent consequences that may vary largely among individuals. Inflammation-induced cell function alterations and metabolic shift may lead to irreversible damage and cell death with organ failure. In the terminal phase of shock, characterized by multiple organ failure, it becomes difficult to separate the different mechanisms responsible for the poor response to a hemodynamic treatment.29Kern J.W. Shoemaker W.C. Meta-analysis of hemodynamic optimization in high-risk patients.Crit Care Med. 2002; 30: 1686-1692Crossref PubMed Scopus (464) Google Scholar, 30den Uil C.A. Lagrand W.K. van der Ent M. et al.Impaired microcirculation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock.Eur Heart J. 2010; 31: 3032-3039Crossref PubMed Scopus (150) Google Scholar Hence, the delay between onset of shock and therapy is a major determinant of the clinical presentation and of the reversibility of organ failure. Mechanistically, the circulation is a closed-loop system with a double power generator: the right (RV) and left (LV) ventricles, with components both in series and in parallel. This approach is not simply theoretical, because it allowed the development of efficient in silico circulatory models,31Lumens J. Creating your own virtual patient with CircAdapt Simulator.Eur Heart J. 2014; 35: 335-337PubMed Google Scholar, 32Leisman S. Burkhoff D. Use of an iPad app to simulate pressure-volume loops and cardiovascular physiology.Adv Physiol Educ. 2017; 41: 415-424Crossref PubMed Scopus (7) Google Scholar commonly used for teaching and for designing and testing artificial hearts, prosthetic valves, and noninvasive technologies for CO assessment. Therefore, as a first approach, it is reasonable to see CS as a pump dysfunction with forward and backward consequences rather than as an array of phenotypic presentations. The resistance to flow is traditionally estimated at the bedside by using a transposition of Ohm's law (pressure = flow × resistance), and assuming continuous pressure and flow. This basic approach does not allow analysis of how the mechanical energy of the cardiac contraction is transformed into hydraulic energy (flow). Intuitively, it can be easily understood that the ventricle ejection would be harder if the arterial system was rigid (fixed vascular size and vasomotor tone), as compared with elastic. The analysis of the phasic interactions between two chambers with elastic properties was named ventriculoarterial coupling by Sunagawa et al,33Sunagawa K. Burkhoff D. Lim K.O. Sagawa K. Impedance loading servo pump system for excised canine ventricle.Am J Physiol. 1982; 243: H346-H350PubMed Google Scholar and requires models in the frequency domain. Any decrease in the ventricle afterload is likely to improve the ventriculoarterial coupling.34Pieragnoli P. Perego G.B. Ricciardi G. et al.Cardiac resynchronization therapy acutely improves ventricular-arterial coupling by reducing the arterial load: assessment by pressure-volume loops.Pacing Clin Electrophysiol. 2015; 38: 431-437Crossref PubMed Scopus (8) Google Scholar The ventricle afterload is therefore best evaluated by the arterial total impedance,35Monge Garcia M.I. Romero M.G. Cano A.G. Rhodes A. Grounds R.M. Cecconi M. Impact of arterial load on the agreement between pulse pressure analysis and esophageal Doppler.Crit Care. 2013; 17: R113Crossref PubMed Scopus (21) Google Scholar the equivalent of a time-varying resistance, whose main components are the arterial elastance (Ea) and the systemic vascular resistance. It has been long recognized that increasing ventricular afterload induces a rapid decrease in stroke volume when systolic ventricular function is severely limited (Fig 2).36Tarazi R.C. Levy M.N. Cardiac responses to increased afterload: state-of-the-art review.Hypertension. 1982; 4: 8-18PubMed Google Scholar, 37Weber K.T. Janicki J.S. Hunter W.C. Shroff S. Pearlman E.S. Fishman A.P. The contractile behavior of the heart and its functional coupling to the circulation.Prog Cardiovasc Dis. 1982; 24: 375-400Crossref PubMed Scopus (67) Google Scholar If the maintenance of coronary perfusion pressure is always a major goal during CS, a reduction in afterload may improve ventricular ejection38Merillon J.P. Fontenier G. Lerallut J.F. et al.Aortic input impedance in heart failure: comparison with normal subjects and its changes during vasodilator therapy.Eur Heart J. 1984; 5: 447-455Crossref PubMed Scopus (58) Google Scholar, 39Haber H.L. Simek C.L. Bergin J.D. et al.Bolus intravenous nitroglycerin predominantly reduces afterload in patients with excessive arterial elastance.J Am Coll Cardiol. 1993; 22: 251-257Crossref PubMed Scopus (39) Google Scholar and potentially reduce myocardial ischemia and organ hypoperfusion. In both RV40Bhorade S. Christenson J. O'Connor M. Lavoie A. Pohlman A. Hall J.B. Response to inhaled nitric oxide in patients with acute right heart syndrome.Am J Respir Crit Care Med. 1999; 159: 571-579Crossref PubMed Scopus (134) Google Scholar and LV failure,41Awan N.A. Evenson M.K. Needham K.E. Mason D.T. Management of refractory congestive heart failure with prazosin.Am Heart J. 1981; 102: 626-634Crossref PubMed Scopus (15) Google Scholar a decrease in ventricular afterload has been proposed as the first line of treatment. Reduction of both systemic vascular resistance and Ea combined with potentially improved systolic ventricular function leads to a modest, and most often acceptable, BP decrease. This was also the rationale for developing inodilators such as milrinone and levosimendan.42Labbene I. Arrigo M. Tavares M. et al.Decongestive effects of levosimendan in cardiogenic shock induced by postpartum cardiomyopathy.Anaesth Crit Care Pain Med. 2017; 36: 39-42Crossref PubMed Scopus (20) Google Scholar When vasoconstrictors such as norepinephrine are used, they modify the contraction efficiency and consequently, the myocardial energetic needs, as illustrated by the ventricular pressure/volume loops and areas (Fig 3).43Suga H. Total mechanical energy of a ventricle model and cardiac oxygen consumption.Am J Physiol. 1979; 236: H498-H505PubMed Google Scholar An increase in afterload (rightward shift of the Ea slope) decreases stroke volume and ventricular efficiency. This can theoretically be compensated by a proportional leftward shift of the ventricle elastance slope, which supposes a direct or indirect inotropic effect. This effect has been demonstrated with norepinephrine in animal models44Beurton A. Ducrocq N. Auchet T. et al.Beneficial effects of norepinephrine alone on cardiovascular function and tissue oxygenation in a pig model of cardiogenic shock.Shock. 2016; 46: 214-218Crossref PubMed Scopus (22) Google Scholar and in isolated human tissue.45Borthne K. Haga P. Langslet A. Lindberg H. Osnes J.B. Skomedal T. Functional characterization of an ex vivo preparation of atrial myocardium from children with congenital heart defects: sensitivity to tyramine and adrenoceptor antagonists.J Cardiovasc Pharmacol. 1994; 24: 365-371Crossref PubMed Scopus (8) Google Scholar The absence of an increase in heart rate after norepinephrine infusion suggests a modest clinical inotropic effect, but one that is usually less pronounced than the increased afterload effect.46Lakatta E.G. Beyond Bowditch: the convergence of cardiac chronotropy and inotropy.Cell Calcium. 2004; 35: 629-642Crossref PubMed Scopus (45) Google Scholar Moreover, its inotropic effect is unpredictable,47Goldberg L.I. Bloodwell R.D. Braunwald E. Morrow A.G. The direct effects of norepinephrine, epinephrine, and methoxamine on myocardial contractile force in man.Circulation. 1960; 22: 1125-1132Crossref PubMed Scopus (44) Google Scholar and seems to decrease in failing hearts.48Landzberg J.S. Parker J.D. Gauthier D.F. Colucci W.S. Effects of myocardial alpha 1-adrenergic receptor stimulation and blockade on contractility in humans.Circulation. 1991; 84: 1608-1614Crossref PubMed Scopus (76) Google Scholar In a recent study, norepinephrine did not increase CO within the first 12 hours of infusion in CS after myocardial infarction.49Levy B. Clere-Jehl R. Legras A. et al.Epinephrine versus norepinephrine for cardiogenic shock after acute myocardial infarction.J Am Coll Cardiol. 2018; 72: 173-182Crossref PubMed Scopus (170) Google Scholar In any case, even though an inotropic effect may help maintain stroke volume when a failing ventricle faces an increased afterload, the upward shift of end-systole increases the total workload and therefore the myocardial oxygen needs. In contrast, a reduction in afterload may improve cardiac reserve and ventricular metabolism. Moreover, when the LV fails, the RV afterload is increased. Since the RV is a "volume pump" and not a "pressure pump," it does not tolerate acute increases in afterload well. Hypoxic pulmonary vasoconstriction and acute systemic inflammation can further exacerbate increases in RV afterload, as can treatment with norepinephrine.50Jeon Y. Ryu J.H. Lim Y.J. et al.Comparative hemodynamic effects of vasopressin and norepinephrine after milrinone-induced hypotension in off-pump coronary artery bypass surgical patients.Eur J Cardiothorac Surg. 2006; 29: 952-956Crossref PubMed Scopus (63) Google Scholar Biventricular failure can cause global hemodynamic degradation, combining hypoperfusion and venous congestion. The cardiac power (CP = CO × mean BP) is consensually seen as the best simple prognostic indicator of compensated or decompensated cardiomyopathy, with or without CS.51Fincke R. Hochman J.S. Lowe A.M. et al.Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry.J Am Coll Cardiol. 2004; 44: 340-348Crossref PubMed Scopus (386) Google Scholar, 52Lang C.C. Karlin P. Haythe J. Lim T.K. Mancini D.M. Peak cardiac power output, measured noninvasively, is a powerful predictor of outcome in chronic heart failure.Circ Heart Fail. 2009; 2: 33-38Crossref PubMed Scopus (92) Google Scholar This indicates that any failing heart has a rather limited and invariant CP depending on myocardial oxygen delivery and global (biochemical and mechanical) heart pump efficiency. For any predetermined level of CP, increasing BP necessarily decreases CO, unless the increase in BP improves either insufficient coronary flow or heart pump efficiency (therefore CP). Insufficient coronary flow may increase when driving pressure (aortic pressure – intracardiac pressure) is augmented, improving the myocardial energetic balance. Such improvement can be obtained by an increase in BP, a decrease in intraventricular pressure, or both. For the RV, because coronary perfusion is normally present during the whole cardiac cycle, coronary blood flow depends on both systolic and diastolic perfusion pressure. In cases of severe pulmonary hypertension, RV coronary perfusion occurs predominantly in diastole, as occurs in the LV. Augmentation of aortic pressure with a vasopressor may improve RV coronary perfusion, if arterial BP increases more than pulmonary pressure and if end-diastolic RV pressure does not rise proportionally.53Klima U.P. Guerrero J.L. Vlahakes G.J. Myocardial perfusion and right ventricular function.Ann Thorac Cardiovasc Surg. 1999; 5: 74-80PubMed Google Scholar Theoretically, increasing the myocardial efficiency by increasing afterload is also possible (Fig 4).44Beurton A. Ducrocq N. Auchet T. et al.Beneficial effects of norepinephrine alone on cardiovascular function and tissue oxygenation in a pig model of cardiogenic shock.Shock. 2016; 46: 214-218Crossref PubMed Scopus (22) Google Scholar However, in the failing heart, the optimal afterload is narrow and must be tuned carefully, which mandates hemodynamic assessment with continuous and independent BP and CO measurements. Reduced CP leads to immediate heterogeneous tissue perfusion, with preferential flow regulation mediated by the vascular tone. The myocardium, brain, kidneys, and liver have protective autoregulation mechanisms (Fig 5).54Rouleau J. Boerboom L.E. Surjadhana A. Hoffman J.I. The role of autoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs.Circ Res. 1979; 45: 804-815Crossref PubMed Scopus (134) Google Scholar, 55Carlstrom M. Wilcox C.S. Arendshorst W.J. Renal autoregulation in health and disease.Physiol Rev. 2015; 95: 405-511Crossref PubMed Scopus (271) Google Scholar In other organs—targets of stimulated baroreflexes and endocrine mediators such as catecholamines, vasopressin, and angiotensin—the regional blood flow is redistributed, as can be seen by the physician (mottling and cold skin).56Cotter G. Moshkovitz Y. Kaluski E. et al.The role of cardiac power and systemic vascular resistance in the pathophysiology and diagnosis of patients with acute congestive heart failure.Eur J Heart Fail. 2003; 5: 443-451Crossref PubMed Scopus (125) Google Scholar Tissue hypoxia and inflammation may change tissue autoregulatory capabilities,22Le Dorze M. Huche F. Coelembier C. Rabuel C. Payen D. Impact of fluid challenge increase in cardiac output on the relationship between systemic and cerebral hemodynamics in severe sepsis compared to brain injury and controls.Ann Intensive Care. 2018; 8: 74Crossref PubMed Scopus (3) Google Scholar, 57Schramm P. Klein K.U. Falkenberg L. et al.Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium.Crit Care. 2012; 16: R181Crossref PubMed Scopus (83) Google Scholar with unknown consequences on the pressure/flow relationship of vasopressors,58Redfors B. Bragadottir G. Sellgren J. Sward K. Ricksten S.E. Effects of norepinephrine on renal perfusion, filtration and oxygenation in vasodilatory shock and acute kidney injury.Intensive Care Med. 2011; 37: 60-67Crossref PubMed Scopus (97) Google Scholar, 59Du