| Abstract|| |
Despite the growing body of evidence evaluating the efficacy of vasoactive agents in the management of hemodynamic instability and circulatory shock, it appears no agent is superior. This is becoming increasingly accepted as current guidelines are moving away from detailed algorithms for the management of shock, and instead succinctly state that vasoactive agents should be individualized and guided by invasive hemodynamic monitoring. This extends to the perioperative period, where vasoactive agent selection and use may still be left to the discretion of the treating physician with a goal-directed approach, consisting of close hemodynamic monitoring and administration of the lowest effective dose to achieve the hemodynamic goals. Successful therapy depends on the ability to rapidly diagnose the etiology of circulatory shock and thoroughly understand its pathophysiology as well as the pharmacology of vasoactive agents. This review focuses on the physiology and resuscitation goals in perioperative shock, as well as the pharmacology and recent advances in vasoactive agent use in its management.
Keywords: Circulatory shock; Hemodynamic instability; Perioperative period; Perioperative shock; Vasoactive agent
|How to cite this article:|
Morozowich ST, Ramakrishna H. Pharmacologic agents for acute hemodynamic instability: Recent advances in the management of perioperative shock- A systematic review. Ann Card Anaesth 2015;18:543-54
|How to cite this URL:|
Morozowich ST, Ramakrishna H. Pharmacologic agents for acute hemodynamic instability: Recent advances in the management of perioperative shock- A systematic review. Ann Card Anaesth [serial online] 2015 [cited 2021 Apr 22];18:543-54. Available from: https://www.annals.in/text.asp?2015/18/4/543/166464
| Introduction|| |
Circulatory shock is defined as inadequate oxygen delivery to the tissues, typically in the setting of hypotension.  The current definition of hypotension varies, but a systolic arterial blood pressure <90 mmHg and/or a mean arterial blood pressure (MAP) <60-70 mmHg is generally accepted. ,, If circulatory shock is not corrected rapidly, tissue hypoxia and cellular death ensue. The mortality associated with circulatory shock in the intensive care unit ranges from 16% in those with trauma/hypovolemic shock,  48% in those with cardiogenic shock,  and up to 60% in those with septic shock.  Inevitably, these patients will present perioperatively and will require ongoing management with vasoactive agents, a term collectively referring to vasopressor and inotrope medications. Conventionally, these agents are used in a supportive context with the assumption that clinical recovery will be facilitated by their temporary use. , Despite using these drugs since the 1940s, their use today remains guided largely by opinion. , In the general population of critically ill patients with circulatory shock, surveys have shown that agent selection is based on clinical experience and preference  and, interestingly, despite the growing body of evidence, this practice has recently been validated.  Similarly, perioperative studies have demonstrated significant variability in agent selection in cardiac surgery. ,, In a recently published meta-analysis of 23 randomized controlled trials comparing commonly used vasoactive agents (dopamine, norepinephrine, epinephrine, phenylephrine, vasopressin, and terlipressin), either alone or in combination with dobutamine or dopexamine for the management of hypotensive shock showed no difference in mortality based on agent use and concluded that currently, there is no sufficient evidence that any of the agents are clearly superior.  However, the presumption is that current vasoactive agent selection for the management of circulatory shock is based on correctly identifying the underlying physiologic deficit and choosing a drug with the optimal pharmacologic properties to manage it, thus a thorough understanding of these concepts is required.
| Physiology|| |
Most causes of circulatory shock are characterized by low cardiac output (CO). CO is the product of stroke volume (SV) and heart rate (HR) and is a major determinant of MAP and the delivery of oxygen (DO 2 ):
CO = SV × HR.
MAP = CO × SVR.
DO 2 = CaO 2 × CO (in dL/min).
Thus, optimizing SV and HR will improve CO, MAP, and DO 2 , keeping in mind that SV and overall myocardial performance is determined by five other factors in addition to inotropy (contractility) that requires consideration: (1) HR and rhythm (atrioventricular synchrony), (2) myocardial blood flow, (3) preload, (4) afterload, and (5) diastolic function. However, depending on the underlying cause of shock, the sympathetic nervous system compensation intended to restore normal organ perfusion pressure is manifested in different ways [Table 1]. , In the example of distributive shock, the underlying pathophysiology prevents the compensatory increase in SVR seen in most types of circulatory shock, resulting in refractory hypotension despite a normal or elevated CO and DO 2 . Although the CO and DO 2 are normal, hypotension below the normal organ autoregulatory range (e.g. MAP <60-65 mmHg) still results in impaired organ blood flow. ,, This occurs because the absolute organ perfusion pressure (or driving pressure) is too low, and the normal autoregulatory decrease in organ vascular resistance is insufficient to restore normal organ blood flow.  This relationship is expressed by relating Ohm's law to fluid flow: 
Organ blood flow =
(Organ perfusion pressure)/(organ vascular resistance)
Organ perfusion pressure is the difference between organ arterial and venous pressure. Because normal organ venous pressure is typically negligible, the organ perfusion pressure is usually equal to the organ arterial pressure, which is the MAP, thus demonstrating the direct relationship between organ blood flow and MAP:
Organ blood flow = MAP/(organ vascular resistance)
The resuscitation goals intended to preserve organ oxygen delivery in all types of circulatory shock are:
An MAP >60-65 mmHg must be achieved in primary resuscitation to maintain vital cerebral and coronary perfusion. , Because CO is a determinant of both MAP and DO 2 , further resuscitation focused on augmenting CO is preferred. , However, MAP is the product of CO and SVR, therefore transiently increasing the SVR with vasopressors to achieve an MAP >60-65 mmHg is acceptable while secondary resuscitation is ongoing. , Achieving the MAP goal of 60-65 mmHg quickly has recently been underscored by a retrospective study of critically ill patients where an MAP <50 mmHg in a subset of comorbid patients was found to result rapidly in cardiac arrest, likely as a consequence of coronary hypoperfusion.  Following successful primary resuscitation, secondary resuscitation involves first ensuring adequate volume status (correcting hypovolemia) then, subsequently administering other vasoactive agents if necessary while monitoring the resuscitation endpoints proved in goal-directed therapy (GDT). ,,
- Primary resuscitation: Rapidly reestablish normal organ perfusion pressure with an MAP >60-65 mmHg ,,
- Secondary resuscitation: Rapidly reestablish adequate DO 2 . 
| Perioperative Goal-Directed Therapy|| |
GDT, initially brought to the forefront in the management of sepsis,  has continued to evolve , and is now being expanded to the perioperative period. Although the concept in septic shock has recently been called into question , and may not be superior to clinical judgment ("usual care") and/or the utilization of other less invasive resuscitation endpoints (such as lactate),  it seems plausible that after years of integrating GDT protocols into physician education and practice that these methods now reflect "usual care," thereby potentially biasing their results. The evolving concept of perioperative GDT currently includes the use of fluids and/or vasoactive agents to achieve hemodynamic endpoints and minimize postoperative complications and has recently been reviewed.  With emerging evidence demonstrating the adverse effects of aggressive fluid resuscitation perioperatively ,,,,,, and meta-analysis favoring goal-directed versus liberal fluid therapy,  initiating perioperative GDT to optimize fluid status and hemodynamics, with the appropriate use of fluids as well as the use of earlier/preemptive inotropes and vasopressors, is likely the paradigm of the future. This is supported by recent meta-analysis suggesting that although GDT does not improve mortality, it may reduce complications and hospital length of stay  and subsequent meta-analysis found a reduction in cardiovascular complications with this practice.  However, a follow-up large, randomized trial of perioperative GDT in high-risk patients undergoing noncardiac surgery did not definitely support the practice but did demonstrate a nonsignificant trend supporting GDT.  Therefore, at this point, no consensus on the true benefit of perioperative GDT exits, but further prospective study is underway.
Regarding the end points of resuscitation used in GDT, right-sided filling pressures poorly predict preload , and although minimally invasive hemodynamic monitors are becoming widely available, most of these indirectly monitor endpoints and require further study. In contrast, intraoperative transesophageal echocardiography (IOTEE) in high-risk patients can quickly and accurately diagnose the etiology of intraoperative hypotension and allows the clinician to rapidly assess the results of intervention by monitoring cardiac volume/preload and function as well as utilizing Doppler to quantitate SV and CO. Although conclusive study demonstrating the efficacy of IOTEE in perioperative GDT is currently lacking, the early use of ITOEE in septic shock has been shown to change management by limiting fluid administration and initiating early inotropic support in patients with left ventricular (LV) systolic dysfunction, who otherwise would not have met Surviving Sepsis Campaign criteria for inotropic therapy.  Furthermore, IOTEE is considered by many as the gold standard to assess intraoperative hemodynamic instability and monitor preload, , therefore its use in perioperative GDT is plausible.
| Overview of vasoactive agents|| |
Vasopressors are primarily used in cardiopulmonary resuscitation (CPR) and in the treatment of circulatory shock, where the main clinical benefit of raising the MAP is to restore rapidly organ perfusion pressure. However, some vasopressors have inotropic properties as well, and the predominant effect is usually dose-dependent. In CPR, vasopressors cause profound systemic vasoconstriction that preferentially increases coronary perfusion pressure in an attempt to restore myocardial blood flow, oxygen delivery, and the return of spontaneous circulation. , In circulatory shock characterized by refractory hypotension, vasopressors are used in a supportive context until definitive therapy can be initiated, with the assumption that clinical recovery will be facilitated by temporarily restoring and maintaining normal organ perfusion pressure. ,
In the example of distributive shock, vasopressors correct the underlying deficit in SVR, thus restoring organ perfusion pressure. , The importance of organ perfusion pressure has recently been emphasized as vasopressors are now being recommended as secondary agents where the indication is less obvious - Circulatory shock characterized by low CO and persistent hypotension that is refractory to conventional treatment. Historically, vasopressors have been used with extreme caution in this setting to avoid the complications associated with excessive vasoconstriction (increasing systemic and organ vascular resistance beyond normal physiologic values) such as further impairment of CO, DO 2 , and organ blood flow, together possibly increasing mortality. , However, excessive vasoconstriction primarily occurs when these agents are given in the setting of inadequate volume resuscitation with or without preexisting low CO.  Considering this, patients receiving vasoactive agents require careful monitoring and frequent reevaluation, so these agents can be titrated to the minimal effective dose.
Vasopressor agents are broadly classified below by their clinical effect as: (1) Pure vasoconstrictors or (2) inoconstrictors (vasoconstrictors with inotropic properties). Further classification of these agents is illustrated in [Figure 1] and their standard dosing, receptor binding, and adverse effects are listed in [Table 2].  Although some adrenergic agents stimulate many receptors producing various cardiovascular effects, their vasopressor actions are mediated via alpha-1 receptors resulting in arterial and venous vascular smooth muscle contraction and an increase in systemic and pulmonary vascular resistance and venous return. ,, The nonadrenergic agents such as vasopressin, exerts its vasopressor effects through V1 receptor stimulation resulting in vascular smooth muscle contraction,  and methylene blue scavenges nitric oxide and inhibits nitric oxide synthesis, thus reversing the vasodilatory effects of nitric oxide on the endothelium and vascular smooth muscle.
|Figure 1: Vasopressor classification[8,91] a: Adrenergic agents mimic sympathetic nervous system stimulation and are also termed "sympathomimetics;" b: Catecholamines structurally contain a catechol group and are rapidly metabolized by catechol-O-methyltransferase and monoamine oxidase corresponding to their short duration of action (1-2 min), making them ideal agents for titration; c: Noncatecholamines have longer durations of action (approximately 5-15 min) since they are not metabolized by catechol-O-methyltransferase|
Click here to view
|Table 2: Standard dosing of vasoactive agents, their receptor binding (or mechanism of action), and major adverse effects |
Click here to view
Inotropy (contractility) refers to the force and velocity of cardiac muscle contraction, and the term inotrope generally refers to a drug that produces positive inotropy (increased contractility). Inotropes differ from vasopressors, which primarily produce vasoconstriction and a subsequent rise in MAP. As with vasopressors, some inotropes have vasopressor properties as well, and the predominant effect is usually dose-dependent. In circulatory shock characterized by low CO (e.g., cardiogenic and obstructive shock), the main clinical benefit of increasing contractility with inotropes is to increase SV and CO to restore adequate DO 2 to vital organs until definitive therapy can be initiated. ,
All inotropes increase CO by increasing the force of contraction of cardiac muscle, but the other determinants of myocardial performance are variably affected. For example, some inotropes directly increase HR, some indirectly decrease HR (reflex), while others have no effect, some inotropes increase venous tone (venoconstriction) and arterial tone (afterload) while others decrease these through vasodilation, and some improve diastolic function. Therefore, any given agent may have multiple and dose-dependent effects to be considered. In cardiogenic shock, the failing ventricle is very sensitive to afterload, so inotropes that produce systemic vasodilation (inodilators) should be first-line agents as long as systemic hypotension does not occur. Although supraphysiologic goals for CO have not shown benefit and may cause harm, ,, maximal doses of a first agent are inadequate to meet goals, then a second drug should be added, with consideration given to agents with different mechanisms of action to maximize effects.
Inotropes are broadly classified below by their clinical effects as: (1) Inodilators agents that produce inotropy and vasodilation or  inoconstrictors agents that produce inotropy and vasoconstriction. Further classification of these agents is illustrated in [Figure 2].  The commonly used adrenergic agents stimulate the adrenergic receptors as listed in [Table 3] to produce their cardiovascular effects.  The standard dosing of inotropes, their receptor binding (or mechanism of action), and adverse effects are listed in [Table 2]. ,
|Figure 2: Inotrope classification.[8,91] a: Adrenergic agents mimic sympathetic nervous system stimulation and are also termed "sympathomimetics;" b: Catecholamines structurally contain a catechol group and are rapidly metabolized by catechol-O-methyltransferase and monoamine oxidase corresponding to their short duration of action (1-2 min), making them ideal agents for titration; c: Noncatecholamines have longer durations of action (approximately 5-15 min) since they are not metabolized by catechol-O-methyltransferase|
Click here to view
| Common vasoactive agents and literature review|| |
- Phenylephrine stimulates only alpha receptors resulting in arterial and venous vasoconstriction, clinically producing an increase in SVR, MAP, venous return, and baroreceptor-mediated reflex bradycardia. The increase in SVR (afterload) and reflex bradycardia may decrease CO, so phenylephrine should only be used transiently in general and with caution in patients with preexisting cardiac dysfunction (low CO). , Perioperatively, phenylephrine is used to correct hypotension, improve venous return, and decrease the HR in patients with various cardiac conditions (e.g. aortic stenosis and hypertrophic cardiomyopathy).  In addition, the use of phenylephrine to maintain hemodynamic stability during liver transplantation has demonstrated less blood loss and lower lactate levels compared to inotropes, an effect attributable to its ability to increase vascular resistance and thus reduce portal blood flow.  Phenylephrine is considered a first-line agent in hyperdynamic (normal CO) septic shock as it restores SVR and organ perfusion pressure. , Also, phenylephrine's reflex bradycardia may prove useful in the treatment of hypotension caused by tachyarrhythmias or when tachyarrhythmias occur in response to other vasoactive agents used in the treatment of circulatory shock 
- Vasopressin (antidiuretic hormone) levels are increased in response to early shock to maintain organ perfusion,  but levels fall dramatically as shock progresses. , Unlike the adrenergic agents, vasopressin does not stimulate adrenergic receptors and is not associated with their adverse effects,  and its vasopressor effects are relatively preserved during hypoxemic and acidemic conditions, making it useful in refractory circulatory shock and CPR, ,,,,,,, specifically asystole.  Vasopressin, due to its alternate mechanism of action, not only improves hemodynamics but also improves the vascular response to adrenergic agents, allowing a reduction in their dosing ,, which may reduce the adverse effects seen with adrenergic agents, this is commonly referred to as an adrenergic sparing effect. Vasopressin is primarily indicated in distributive shock, usually as a secondary agent,  but its ability to increase MAP and not adversely impact CO has recently been demonstrated in refractory cardiogenic shock,  underscoring the physiologic importance of maintaining organ (myocardial) perfusion pressure.  Considering this, the use of vasopressin has shown utility perioperatively, where its preemptive use in high-risk patients undergoing cardiac surgery has demonstrated hemodynamic stability after cardiopulmonary bypass and an adrenergic agent sparing effect.  Moreover, recent in vitro study  supports the emerging clinical observations  that compared to adrenergic agents such as norepinephrine, vasopressin produces selective systemic vasoconstriction, with minimal effect on the pulmonary vasculature. This has significant application, particularly in cardiac surgery, where vasopressin would improve right ventricular (RV) function by increasing coronary perfusion without altering RV afterload, suggesting it may be the drug of choice to improve MAP in the setting of RV failure. Its 30-60 min duration of action is much longer than adrenergic agents, making titration more challenging
- Methylene blue inhibits the vasodilatory effects of nitric oxide on the endothelium and vascular smooth muscle. Historically, methylene blue has not been considered a vasoactive agent, but its expanding use in vasoplegic syndrome prompted its inclusion here. Vasoplegic syndrome is generally defined as an MAP <50 mmHg with a low SVR (<600-800 dynes/s/cm 5 ) despite vasoactive agent administration. , The syndrome is also typically accompanied by low filling pressures (central venous pressure <5-10 mmHg, pulmonary capillary wedge pressure <10 mmHg). , The incidence of vasoplegic syndrome in cardiac surgery varies but has been reported as high as 42% in comorbid patients undergoing ventricular assist device placement  and the mortality may be as high as 25%.  Methylene blue has been used as a rescue agent for perioperative vasoplegic syndrome in multiple clinical scenarios including cardiac surgery, protamine reaction, sepsis, and anaphylaxis. ,,, It has even been used prophylactically in high-risk patients undergoing cardiac surgery.  Suggested risk factors for perioperative vasoplegic syndrome in cardiac surgery have been reviewed, and include preoperative LV ejection fraction <35%, ventricular assist device implantation, prolonged CPB, and the preoperative use of intravenous heparin, angiotensin-converting enzyme inhibitors, calcium channel blockers, and beta-blockers.  The dose of methylene blue varies in the literature but in cardiac surgery, a dose of 1.5-2.0 mg/kg IV infused over 1 h is generally acceptable. , In some cases, this initial bolus is followed by a continuous infusion. Methylene blue has a rapid onset, but unlike most vasoactive agents, it has a long half-life of approximately 5.25 h.  It is eliminated by the kidney and is contraindicated in renal failure and should be avoided in patients with known glucose-6-phosphate dehydrogenase deficiency.  Adverse effects have been reviewed and include transient color change of the skin and urine to greenish-blue, cardiac arrhythmias (transient nodal rhythm and ventricular ectopy), coronary vasoconstriction, decreased CO, increased PVR, and decreased renal and mesenteric blood flow; however, these effects were transient and dose dependent (usually at doses >2 mg/kg).  Although the use of perioperative methylene blue is currently controversial,  a recent meta-analysis of randomized controlled trials in hypotensive patients demonstrated no harm.  Therefore, due to the high mortality associated with perioperative vasoplegic syndrome, the use of methylene blue as a rescue agent should be considered in the setting of refractory hypotension.
- Epinephrine, in low doses, increases CO because beta-1 inotropic and chronotropic effects predominate, while the minimal alpha-1 vasoconstriction is offset by beta-2 vasodilation, resulting in increased CO with decreased SVR and variable effects on the MAP.  At higher doses, alpha-1 vasoconstrictive effects predominate, producing increased SVR, MAP, and CO.  Thus, in the acutely failing ventricle (e.g., low CO syndrome after cardiac surgery), epinephrine maintains coronary perfusion pressure and CO. Epinephrine is used in CPR to restore coronary perfusion pressure and in the management of symptomatic bradycardia unresponsive to atropine or a temporizing measure while awaiting the availability of a pacemaker.  It is a second-line agent in septic  or refractory circulatory shock and is the drug of choice in anaphylaxis because of its efficacy to maintain MAP, partly due to its superior recruitment of splanchnic reserve (about 800 mL), compared to other vasoactive agents, which helps to restore venous return and CO.  Consequently, the degree of splanchnic vasoconstriction appears to be greater than with equipotent doses of norepinephrine or dopamine in patients with severe shock,  thus limiting its liberal use among clinicians. However, recent prospective study in critically ill patients demonstrated no difference in 28 and 90 days mortality compared to norepinephrine when using MAP as the sole endpoint, thus tempering the theoretical safety concerns held by many 
- Norepinephrine has potent alpha-1, modest beta-1, and minimal beta-2 activity.  Thus, norepinephrine produces powerful vasoconstriction and a reliable increase in SVR and MAP, but a less pronounced increase in HR and CO, compared to epinephrine.  Therefore, caution must be used in the setting of the failing ventricle. Reflex bradycardia usually occurs in response to the increased MAP, such that its modest beta-1 chronotropic effect is mitigated, and the HR remains relatively unchanged. Because norepinephrine is the predominant endogenous adrenergic agent and sepsis can lead to its depletion, its use as the first-line agent in septic shock has been argued as intuitive. , Current Surviving Sepsis Campaign guidelines support its use as the first-line agent,  especially in hyperdynamic (normal CO) septic shock because of its ability to increase SVR and MAP, thus correcting the physiologic deficit in organ perfusion pressure, compared to other agents that instead increase MAP by increasing CO (e.g., dopamine). ,, Although its recommendation in cardiogenic shock no longer formally exists, it may still be useful in the presence of severe hypotension (systolic blood pressure <70 mmHg) in the setting of LV systolic dysfunction due to its ability to improve MAP, thereby restoring coronary and organ perfusion pressure 
- Dopamine is the immediate precursor to norepinephrine and is characterized by dose-dependent effects that are due to both direct receptor stimulation and indirect effects  due to norepinephrine conversion and release.  Doses <5 mcg/kg/min stimulate dopamine receptors and have minimal cardiovascular effects. At moderate doses between 5 and 10 mcg/kg/min, dopamine weakly binds to beta-1 receptors, promotes norepinephrine release, and inhibits norepinephrine reuptake in presynaptic sympathetic nerve terminals, resulting in increased inotropy and chronotropy, and a mild increase in SVR via alpha-1 adrenergic receptor stimulation.  At higher doses of 10-20 mcg/kg/min, alpha-1 receptor-mediated vasoconstriction dominates.  Dopamine remains the treatment for symptomatic bradycardia unresponsive to atropine or as a temporizing measure while awaiting the availability of a pacemaker.  Otherwise, the clinical use of dopamine continues to decline due to its indirect effects, significant variations in plasma concentrations in patients receiving the same dose, and recent study demonstrating a higher incidence of arrhythmia and higher mortality in cardiogenic  and septic shock.  Consequently, previous recommendations for its use in cardiogenic shock with SBP 70-100 mmHg with signs or symptoms of end-organ compromise,  based on its alpha-1 activity to correct the deficit in organ perfusion pressure, have been removed.  Also citing this evidence, dopamine is no longer a first-line treatment for septic shock, but may be reserved for select patients with a low risk of arrhythmia who present with hypodynamic (low CO) septic shock and/or bradycardia,  as dopamine increases inotropy and chronotropy (thereby increasing CO and MAP) with a minimal increase in SVR
- Ephedrine acts primarily on alpha and beta receptors,  similar to epinephrine but with less potency. Ephedrine also releases endogenous norepinephrine from sympathetic neurons and inhibits norepinephrine reuptake, accounting for additional indirect alpha and beta receptor effects. Ephedrine's combined effects result in an increased HR, CO, and MAP. Ephedrine is a noncatecholamine and because of its longer duration of action, its dependence on endogenous norepinephrine for its indirect effects and its potential to therefore deplete norepinephrine, it is not ideal for infusion and is therefore rarely used except in the setting of transient anesthesia-related hypotension.
- Isoproterenol has potent beta-1 and beta-2 activity with virtually no alpha activity. Its principal actions are inotropy, chronotropy, and systemic and pulmonary vasodilation.  Despite its inotropy, the systemic vasodilation decreases venous return, resulting in a minimal increase in CO and a drop in MAP.  Because of this, isoproterenol is limited to situations where hypotension and shock result from bradycardia or heart block 
- Dobutamine primarily stimulates beta-1 and beta-2 receptors resulting in increased chronotropy, inotropy, and systemic and pulmonary vasodilation. The net result is increased HR, CO, and decreased SVR with or without a small reduction in MAP. Dobutamine is frequently used to treat low CO following cardiac surgery primarily due to its inotropic and pulmonary vasodilatory effects.  Although its recommendation in cardiogenic shock no longer formally exists, it may still be useful in early cardiogenic shock without evidence of organ hypoperfusion.  However, if organ hypoperfusion is present, an inoconstrictor should be chosen to restore organ perfusion pressure.  Dobutamine remains recommended therapy in septic shock with low CO 
- Milrinone, a nonadrenergic phosphodiasterase inhibitor, increases intracellular levels of myocardial and vascular smooth muscle cAMP by inhibiting its breakdown, leading to increased myocardial contractility and smooth muscle relaxation resulting in pulmonary and systemic vasodilation. Thus, milrinone improves RV function in the setting of pulmonary hypertension,  more so than the adrenergic inodilators. In addition, milrinone uniquely improves diastolic relaxation (lusitropy). Being a nonadrenergic agent, it has the advantage of not being affected by beta-blocker use or the characteristic diminished beta receptor responses seen in chronic heart failure and does not produce the adverse effects associated with beta-receptor stimulation. , Milrinone's vasodilatory properties limit its use in hypotensive patients,  and its 30-60 min half-life is significantly longer than the adrenergic inodilators 
- Levosimendan is a nonadrenergic calcium-sensitizing agent that produces inotropy by calcium sensitization of myocardial contractile proteins, without increasing intracellular calcium, and vasodilatation within the systemic and pulmonary circulation, by activation of adenosine triphosphate-sensitive potassium channels.  Levosimendan produces similar clinical effects to milrinone, , but is also limited by hypotension and a long duration of action (80 h due to active metabolites). Levosimendan is a relatively new agent and is not currently approved for use in the United States.
| Conclusion|| |
Despite the growing body of evidence evaluating the efficacy of vasoactive agents in the management of circulatory shock, it appears no agent is superior, and the recent meta-analysis of 23 randomized controlled trials comparing commonly used agents supports this.  This is becoming increasingly accepted as current guidelines from the American College of Cardiology and the American Heart Association no longer publish detailed algorithms for the management of cardiogenic shock,  and have instead replaced them with a single statement: Vasoactive agents should be individualized and guided by invasive hemodynamic monitoring.  Based on this, vasoactive agent selection may currently be individualized and left to the discretion of the treating physician with a goal-directed approach. However, circulatory shock in the comorbid patient is a complex process; therefore, the ability to rapidly diagnose the etiology and firmly understand its pathophysiology as well as the pharmacology of vasoactive agents is ultimately paramount importance to guide successful therapy.
In summary, the following recommendations can be made regarding the current management of perioperative circulatory shock: (1) Vasoactive agent selection should be based on correcting the underlying physiologic deficits and the agent ultimately chosen probably does not matter as long as the hemodynamic goals are achieved; , (2) achieving supraphysiologic goals for CO has not been shown benefit patients and may cause harm, ,, but if maximal doses of a first agent are inadequate to meet goals, then a second drug should be added, with consideration given to agents with different mechanisms of action to maximize effects; and (3) patients receiving vasoactive agents require careful monitoring and frequent reevaluation so these agents can be titrated to the minimal effective dose to avoid potential adverse effects.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Vincent JL, De Backer D. Circulatory shock. N Engl J Med 2013;369:1726-34.
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al
. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580-637.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al
. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 2003;31:1250-6.
Cannon CM, Braxton CC, Kling-Smith M, Mahnken JD, Carlton E, Moncure M. Utility of the shock index in predicting mortality in traumatically injured patients. J Trauma 2009;67:1426-30.
Babaev A, Frederick PD, Pasta DJ, Every N, Sichrovsky T, Hochman JS; NRMI Investigators. Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005;294:448-54.
Alberti C, Brun-Buisson C, Chevret S, Antonelli M, Goodman SV, Martin C, et al.
Systemic inflammatory response and progression to severe sepsis in critically ill infected patients. Am J Respir Crit Care Med 2005;171:461-8.
Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al.
Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589-96.
Overgaard CB, Dzavík V. Inotropes and vasopressors: Review of physiology and clinical use in cardiovascular disease. Circulation 2008;118:1047-56.
Müllner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors for shock. Cochrane Database Syst Rev 2004 ;(3):CD003709.
Leone M, Vallet B, Teboul JL, Mateo J, Bastien O, Martin C. Survey of the use of catecholamines by French physicians. Intensive Care Med 2004;30:984-8.
Havel C, Arrich J, Losert H, Gamper G, Müllner M, Herkner H. Vasopressors for hypotensive shock. Cochrane Database Syst Rev 2011;(5):CD003709.
Hernandez AF, Li S, Dokholyan RS, O'Brien SM, Ferguson TB, Peterson ED. Variation in perioperative vasoactive therapy in cardiovascular surgical care: Data from the Society of Thoracic Surgeons. Am Heart J 2009;158:47-52.
Nielsen DV, Johnsen SP, Madsen M, Jakobsen CJ. Variation in use of peroperative inotropic support therapy in cardiac surgery: Time for reflection? Acta Anaesthesiol Scand 2011;55:352-8.
Complex information for anesthesiologists presented quickly and clearly: Vasopressor variation: Intra- and international variation in perioperative utilization of vasopressors and inotropes in cardiac surgery. Anesthesiology 2014;120:A29.
Massie BM. Heart failure: Pathophysiology and diagnosis. In: Goldman L, Ausiello D, editors. Cecil Medicine. 23 rd
ed., Ch. 57. Philadelphia: Saunders Elsevier; 2008.
Pinsky MR. Hemodynamic evaluation and monitoring in the ICU. Chest 2007;132:2020-9.
Bourgoin A, Leone M, Delmas A, Garnier F, Albanèse J, Martin C. Increasing mean arterial pressure in patients with septic shock: Effects on oxygen variables and renal function. Crit Care Med 2005;33:780-6.
Johnson PC. Autoregulation of blood flow. Circ Res 1986;59:483-95.
LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med 2000;28:2729-32.
Polanco PM, Pinsky MR. Practical issues of hemodynamic monitoring at the bedside. Surg Clin North Am 2006;86:1431-56.
Pinsky MR. Both perfusion pressure and flow are essential for adequate resuscitation. Sepsis 2000;4:143.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al.
Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717-22.
Martin C, Papazian L, Perrin G, Saux P, Gouin F. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993;103:1826-31.
Herget-Rosenthal S, Saner F, Chawla LS. Approach to hemodynamic shock and vasopressors. Clin J Am Soc Nephrol 2008;3:546-53.
Pinsky MR. Goals of resuscitation from circulatory shock. Contrib Nephrol 2004;144:94-104.
Brunauer A, Koköfer A, Bataar O, Gradwohl-Matis I, Dankl D, Dünser MW. The arterial blood pressure associated with terminal cardiovascular collapse in critically ill patients: A retrospective cohort study. Crit Care 2014;18:719.
Pinsky MR, Vincent JL. Let us use the pulmonary artery catheter correctly and only when we need it. Crit Care Med 2005;33:1119-22.
Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992;20:80-93.
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al
. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327.
ARISE Investigators; ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, et al.
Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-506.
ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, et al.
A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93.
Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: A randomized clinical trial. JAMA 2010;303:739-46.
Lobo SM, Mendes CL, Rezende E, Dias FS. Optimizing perioperative hemodynamics: What is new? Curr Opin Crit Care 2013;19:346-52.
Bickell WH, Wall MJ Jr, Pepe PE, Martin RR, Ginger VF, Allen MK, et al.
Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994;331:1105-9.
Roberts I, Evans P, Bunn F, Kwan I, Crowhurst E. Is the normalisation of blood pressure in bleeding trauma patients harmful? Lancet 2001;357:385-7.
Ley EJ, Clond MA, Srour MK, Barnajian M, Mirocha J, Margulies DR, et al.
Emergency department crystalloid resuscitation of 1.5 L or more is associated with increased mortality in elderly and nonelderly trauma patients. J Trauma 2011;70:398-400.
Cordemans C, De Laet I, Van Regenmortel N, Schoonheydt K, Dits H, Huber W, et al.
Fluid management in critically ill patients: The role of extravascular lung water, abdominal hypertension, capillary leak, and fluid balance. Ann Intensive Care 2012;2 Suppl 1:S1.
Lowell JA, Schifferdecker C, Driscoll DF, Benotti PN, Bistrian BR. Postoperative fluid overload: Not a benign problem. Crit Care Med 1990;18:728-33.
Solomonov E, Hirsh M, Yahiya A, Krausz MM. The effect of vigorous fluid resuscitation in uncontrolled hemorrhagic shock after massive splenic injury. Crit Care Med 2000;28:749-54.
Shoemaker WC, Peitzman AB, Bellamy R, Bellomo R, Bruttig SP, Capone A, et al.
Resuscitation from severe hemorrhage. Crit Care Med 1996;24 2 Suppl: S12-23.
Corcoran T, Rhodes JE, Clarke S, Myles PS, Ho KM. Perioperative fluid management strategies in major surgery: A stratified meta-analysis. Anesth Analg 2012;114:640-51.
Grocott MP, Dushianthan A, Hamilton MA, Mythen MG, Harrison D, Rowan K; Optimisation Systematic Review Steering Group. Perioperative increase in global blood flow to explicit defined goals and outcomes after surgery: A Cochrane Systematic Review. Br J Anaesth 2013;111:535-48.
Arulkumaran N, Corredor C, Hamilton MA, Ball J, Grounds RM, Rhodes A, et al.
Cardiac complications associated with goal-directed therapy in high-risk surgical patients: A meta-analysis. Br J Anaesth 2014;112:648-59.
Pearse RM, Harrison DA, MacDonald N, Gillies MA, Blunt M, Ackland G, et al.
Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: A randomized clinical trial and systematic review. JAMA 2014;311:2181-90.
Kumar A, Anel R, Bunnell E, Habet K, Zanotti S, Marshall S, et al
. Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects. Crit Care Med 2004;32:691-9.
Cheung AT, Savino JS, Weiss SJ, Aukburg SJ, Berlin JA. Echocardiographic and hemodynamic indexes of left ventricular preload in patients with normal and abnormal ventricular function. Anesthesiology 1994;81:376-87.
Bouferrache K, Amiel JB, Chimot L, Caille V, Charron C, Vignon P, et al
. Initial resuscitation guided by the Surviving Sepsis Campaign recommendations and early echocardiographic assessment of hemodynamics in intensive care unit septic patients: A pilot study. Crit Care Med 2012;40:2821-7.
Tousignant CP, Walsh F, Mazer CD. The use of transesophageal echocardiography for preload assessment in critically ill patients. Anesth Analg 2000;90:351-5.
ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112 24 Suppl: IV1-203.
Zhong JQ, Dorian P. Epinephrine and vasopressin during cardiopulmonary resuscitation. Resuscitation 2005;66:263-9.
Gregory JS, Bonfiglio MF, Dasta JF, Reilley TE, Townsend MC, Flancbaum L. Experience with phenylephrine as a component of the pharmacologic support of septic shock. Crit Care Med 1991;19:1395-400.
Morelli A, Ertmer C, Lange M, Westphal M. Continuous terlipressin infusion in patients with septic shock: Less may be best, and the earlier the better? Intensive Care Med 2007;33:1669-70.
Azarov N, Milbrandt EB, Pinsky MR. Could dopamine be a silent killer? Crit Care 2007;11:302.
Currigan DA, Hughes RJ, Wright CE, Angus JA, Soeding PF. Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries: An in vitro
study. Anesthesiology 2014;121:930-6.
Stedman's Electronic Medical Dictonary. Ver. 6.0; 2004.
Alía I, Esteban A, Gordo F, Lorente JA, Diaz C, Rodriguez JA, et al.
A randomized and controlled trial of the effect of treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic shock. Chest 1999;115:453-61.
Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, et al.
A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med 1995;333:1025-32.
Williamson AP, Seifen E, Lindemann JP, Kennedy RH. WB4101- and CEC-sensitive positive inotropic actions of phenylephrine in rat cardiac muscle. Am J Physiol 1994;266 (6 Pt 2):H2462-7.
Yamazaki T, Shimada Y, Taenaka N, Oshumi H, Takezawa J, Yoshiya I. Circulatory responses to afterloading with phenylephrine in hyperdynamic sepsis. Crit Care Med 1982;10:432-5.
Hong SH, Park CS, Jung HS, Choi H, Lee SR, Lee J, et al.
A comparison of intra-operative blood loss and acid-base balance between vasopressor and inotrope strategy during living donor liver transplantation: A randomised, controlled study. Anaesthesia 2012;67:1091-100.
Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med 2001;345:588-95.
Day TA, Randle JC, Renaud LP. Opposing alpha- and beta-adrenergic mechanisms mediate dose-dependent actions of noradrenaline on supraoptic vasopressin neurones in vivo
. Brain Res 1985;358:171-9.
Sharshar T, Carlier R, Blanchard A, Feydy A, Gray F, Paillard M, et al.
Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med 2002;30:497-500.
Dünser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G, Pajk W, et al.
Arginine vasopressin in advanced vasodilatory shock: A prospective, randomized, controlled study. Circulation 2003;107:2313-9.
Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D'Alessandro D, et al.
Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997;95:1122-5.
Landry DW, Levin HR, Gallant EM, Seo S, D'Alessandro D, Oz MC, et al.
Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997;25:1279-82.
Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999;47:699-703.
Mutlu GM, Factor P. Role of vasopressin in the management of septic shock. Intensive Care Med 2004;30:1276-91.
Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002;96:576-82.
Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D. Circulating vasopressin levels in septic shock. Crit Care Med 2003;31:1752-8.
Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA 3 rd
. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 2001;29:487-93.
Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH; European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350:105-13.
Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al.
Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87.
Jolly S, Newton G, Horlick E, Seidelin PH, Ross HJ, Husain M, et al.
Effect of vasopressin on hemodynamics in patients with refractory cardiogenic shock complicating acute myocardial infarction. Am J Cardiol 2005;96:1617-20.
Morales DL, Garrido MJ, Madigan JD, Helman DN, Faber J, Williams MR, et al.
A double-blind randomized trial: Prophylactic vasopressin reduces hypotension after cardiopulmonary bypass. Ann Thorac Surg 2003;75:926-30.
Park SY, Kim DH, Kim JS, Lim SH, Hong YW. Comparative effects of norepinephrine and vasopressin on internal thoracic arterial graft flow after off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg 2011;141:151-4.
Ozal E, Kuralay E, Yildirim V, Kilic S, Bolcal C, Kücükarslan N, et al.
Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg 2005;79:1615-9.
Maslow AD, Stearns G, Butala P, Schwartz CS, Gough J, Singh AK. The hemodynamic effects of methylene blue when administered at the onset of cardiopulmonary bypass. Anesth Analg 2006;103:2-8.
Argenziano M, Chen JM, Choudhri AF, Cullinane S, Garfein E, Weinberg AD, 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;116:973-80.
Andritsos MJ. Con: Methylene blue should not be used routinely for vasoplegia perioperatively. J Cardiothorac Vasc Anesth 2011;25:739-43.
Beloncle F, Meziani F, Lerolle N, Radermacher P, Asfar P. Does vasopressor therapy have an indication in hemorrhagic shock? Ann Intensive Care 2013;3:13.
Kwok ES, Howes D. Use of methylene blue in sepsis: A systematic review. J Intensive Care Med 2006;21:359-63.
Viaro F, Dalio MB, Evora PR. Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: Should methylene blue be the treatment of choice? Chest 2002;122:1061-6.
Evora PR, Ribeiro PJ, Vicente WV, Reis CL, Rodrigues AJ, Menardi AC, et al.
Methylene blue for vasoplegic syndrome treatment in heart surgery: Fifteen years of questions, answers, doubts and certainties. Rev Bras Cir Cardiovasc 2009;24:279-88.
Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, et al.
Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg 2004;77:496-9.
Peter C, Hongwan D, Küpfer A, Lauterburg BH. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol 2000;56:247-50.
Weiner MM, Lin HM, Danforth D, Rao S, Hosseinian L, Fischer GW. Methylene blue is associated with poor outcomes in vasoplegic shock. J Cardiothorac Vasc Anesth 2013;27:1233-8.
Pasin L, Umbrello M, Greco T, Zambon M, Pappalardo F, Crivellari M, et al.
Methylene blue as a vasopressor: A meta-analysis of randomised trials. Crit Care Resusc 2013;15:42-8.
Allwood MJ, Cobbold AF, Ginsburg J. Peripheral vascular effects of noradrenaline, isopropylnoradrenaline and dopamine. Br Med Bull 1963;19:132-6.
Sidebotham DA, editor. Cardiothoraic Critical Care. Butterworth-Heinemann; 2007. p. 34.
Field JM, Hazinski MF, Sayre MR, Chameides L, Schexnayder SM, Hemphill R, et al.
Part 1: Executive summary: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122 18 Suppl 3:S640-56.
Gelman S, Mushlin PS. Catecholamine-induced changes in the splanchnic circulation affecting systemic hemodynamics. Anesthesiology 2004;100:434-9.
De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best? Crit Care Med 2003;31:1659-67.
Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J; CAT Study Investigators. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008;34:2226-34.
Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine. Crit Care Med 1999;27:639-60.
Myburgh J. Norepinephrine: More of a neurohormone than a vasopressor. Crit Care 2010;14:196.
Myburgh JA. An appraisal of selection and use of catecholamines in septic shock-old becomes new again. Crit Care Resusc 2006;8:353-60.
Marik PE, Mohedin M. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994;272:1354-7.
Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al
. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:E1-211.
Goldberg LI. Dopamine - Clinical uses of an endogenous catecholamine. N Engl J Med 1974;291:707-10.
De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al.
Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-89.
De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis*. Crit Care Med 2012;40:725-30.
O'Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al
. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127:e362-425.
Ramanathan S, Grant GJ. Vasopressor therapy for hypotension due to epidural anesthesia for cesarean section. Acta Anaesthesiol Scand 1988;32:559-65.
Gillies M, Bellomo R, Doolan L, Buxton B. Bench-to-bedside review: Inotropic drug therapy after adult cardiac surgery - A systematic literature review. Crit Care 2005;9:266-79.
Löllgen H, Drexler H. Use of inotropes in the critical care setting. Crit Care Med 1990;18 (1 Pt 2):S56-60.
Morelli A, Teboul JL, Maggiore SM, Vieillard-Baron A, Rocco M, Conti G, et al.
Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: A pilot study. Crit Care Med 2006;34:2287-93.
Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, et al
. Levosimendan vs dobutamine for patients with acute decompensated heart failure: The SURVIVE randomized trial. JAMA 2007;297:1883-91.
Mebazaa A, Nieminen MS, Filippatos GS, Cleland JG, Salon JE, Thakkar R, et al
. Levosimendan vs. dobutamine: Outcomes for acute heart failure patients on beta-blockers in SURVIVE. Eur J Heart Fail 2009;11:304-11.
Mayo Clinic College of Medicine, Department of Anesthesiology, Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, Phoenix, Arizona
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]