2014 Pharmacologic Therapies for Acute Cardiogenic Shock

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CURRENTOPINION Pharmacologic therapies for acute cardiogenicshock

Jose Nativi-Nicolaua,b

, Craig H. Selzmanc

, James C. Fanga

, andJosef Stehlika,b

Purpose of review

The natural history of cardiogenic shock has improved significantly with the utilization of revascularizationand mechanical circulatory support. Despite the interest in identifying new pharmacological agents, themedical therapy to restore perfusion is limited by their side-effects and no solid evidence about improvingoutcomes. In this article, we review the current pharmacological agents utilized during cardiogenic shock.

Recent findings

Inotropes and vasopressors are widely used to improve hemodynamics acutely; however, reliable

information regarding comparative efficacy of individual agents is lacking. A subanalysis of a prospectiverandomized trial suggested that norepinephrine may be preferred over dopamine in patients withcardiogenic shock. Levosimendan is a new inotrope with calcium sensitization properties that improvesacute hemodynamics, but with uncertain effects in mortality. Diuretics are used to decongest patients;however, mortality data are not available. Inhibition of inflammation during cardiogenic shock seems to bea potential therapeutic target; however, initial clinical studies in this area have not shown benefit.

Summary

The current pharmacological treatment for cardiogenic shock includes inotropes, vasopressors anddiuretics. The information about comparative effective outcomes is limited and their use should be limited asa temporary measure as a bridge to recovery, mechanical circulatory support or heart transplantation.

Keywords

inotropes, shock, vasopressors

INTRODUCTION

Cardiogenic shock is a stage of heart failure charac-terized by decreased tissue perfusion from cardiacpump failure. Clinically, cardiogenic shock presentswith an evidence of congestion (dyspnea, ortho-pnea, high jugular venous pressure, rales, edema,ascites) and low perfusion (hypotension, narrowpulse pressure, pulsus alternans, cool forearms andlegs, obtunded mental status, oliguria), a clinical

scenario commonly described as a wet and coldpatient[1]. Hemodynamically, cardiogenic shock isdefined as persistent hypotension (systolic bloodpressure


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(b) 18 mmHg or(b) Right ventricular end-diastolic pressure

>10 15 mmHg (Adapted from [2&&

])

This general definition includes a fairly largespectrum of patients as far as acuity of onset ofhemodynamic derangements, treatment consider-ations and expected prognosis. Therefore, for heartfailure patients, who are failing optimal medicaltherapy, additional clinical stratification into the

Interagency Registry for Mechanically Assisted Cir-culatory Support INTERMACS profiles has beenproposed [3

&&

]. Patients with cardiogenic shock areassigned profiles 1 3: INTERMACS Profile 1 encom-passes patients with life-threatening hypotensiondespite rapidly escalating inotropic support andcritical organ hypoperfusion, often confirmed byworsening acidosis; INTERMACS Profile 2 is charac-terized by a progressive decline despite inotropicsupport, and INTERMAC Profile 3 designates a morestable but inotrope-dependent patient [3

&&

].Any reversible cause of cardiogenic shock should

be treated emergently, for example revascularizationin acute coronary syndromes, pericardial drainage intamponade, or surgery for acute valvular heart dis-ease or mechanical complications of myocardialinfarction. Medical management to restore tissueperfusion is limited by potential complications ofpharmacologic therapies and the lack of evidenceof improved survival with medical managementalone. In the absence of a reversible underlying causeof cardiogenic shock, the role of medical manage-ment is mainly supportive, serving as a bridge torecovery, mechanical circulatory support or heart

transplantation. In this article, we will review thecurrent pharmacological strategies available for thetreatment of acute cardiogenic shock.

INOTROPES AND VASOPRESSORS

Inotropes and vasopressors increase myocardial

contractility and modify vascular tone throughthe activation of adrenergic pathways. The effectsvary depending on the interaction with the specificreceptors in the myocardium and the smoothmuscle (Table 1). Table 2 provides a summary ofthe inotropes and vasopressors commonly used incardiogenic shock.

Dobutamine

Dobutamine is a predominantly b1-adrenergicagonist, with weak b2 and a1 activity. In patientswith heart failure, dobutamine increases the heart

rate, stroke volume and cardiac output with a con-comitant decrease in the left ventricular fillingpressures, and a modest decrease in blood pressureand systemic vascular resistance (SVR) [4]. Thepositive effects on the cardiac output and fillingpressures make dobutamine an ideal medicationfor cardiogenic shock. However, the beneficialeffects are limited by an increase in heart rate andmyocardial oxygen consumption [4], which canprecipitate and accelerate tachyarrhythmias, worsenmyocardial ischemia and increase mortality. Ananalysis from the Acute Decompensated Heart

Failure National Registry demonstrated that, in4226 patients with decompensated heart failuretreated with dobutamine, the inhospital mortalitywas 14%, raising significant concerns about safety[5]. The mortality is also high in other clinical

KEY POINTS

Medical therapies for cardiogenic shock includeinotropes, vasopressors and diuretics.

There is limited information about comparative efficacyamong pharmacological agents.

The utilization of inotropes, vasopressors and diureticsis limited by their adverse event profile and limitedimprovement in outcomes.

The utilization of inotropes and vasopressors isrecommended as a temporary measure as a bridge torecovery, mechanical circulatory support or hearttransplantation.

Table 1. Adrenergic receptors location and responses

Receptor Location Response to activation

b1 Heart Increase force and rateof contraction

Increase AV nodal

conduction velocityb2 Smooth muscle

(vascular, bronchial,GI and GU)

Relaxation

a1 Vascular smooth muscle Contraction

Heart Increase force of contraction

a2 Vascular smooth muscle Contraction

D1 Vascular smoothmuscle (renal)

Relaxation

AV, atrio-ventricular; GI, gastrointestinal; GU, genitourinary.Adapted from[25].

Pharmacologic therapy for cardiogenic shock Nativi-Nicolau et al.

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scenarios, including intermittent [6] and continu-ous intravenous (i.v.) infusions [7]. The recom-mended dose is from 2 to 15 mg/kg/min [8] anddoes not require renal adjustment.

Milrinone

Milrinone is a phosphodiesterase-3 inhibitor thatprevents the degradation of cyclic adenosine mono-phosphate (cAMP). In the myocardium, elevatedlevels of cAMP activate protein kinase A, which thenphosphorylates calcium channels, increasing theinflux of calcium into the cardiomyocyte, and pro-motes contractility. In the smooth muscle, elevatedcAMP inhibits myosin light chain kinase, producingarterial and venous vasodilation. In patients withheart failure, milrinone increases heart rate, stroke

volume and cardiac output. It is also likely todecrease mean arterial pressures, SVR and leftventricular filling pressures[4]. Milrinone increasesmyocardial oxygen consumption, but to a lesserdegree than dobutamine (Fig. 1) Although milri-none improves hemodynamics acutely, there areconcerns regarding its safety as far as longer-termoutcomes. The Outcomes of a Prospective Trial ofIntravenous Milrinone for Exacerbations of ChronicHeart Failure study randomized 951 patients withdecompensated heart failure (not in shock) tomilrinone vs. placebo for a total of 48h. There

was no significant difference in the primary end-point of cumulative days of hospitalisation;however, there was a nonsignificant increase ininhospital mortality in the milrinone group vs.the placebo group (3.8 vs. 2.3%, P 0.19). Therewere also more adverse events in the milrinonegroup compared with placebo, including new atrialfibrillation or flutter (4.6 vs. 1.5%, P 0.004) andsustained hypotension (10.7 vs. 3.2%, Pb2>a 215mg/kg/min # " "" #

Milrinone PDE-3 inhibitor 0.375 0.75mg/kg/min ## " "" ##

Levosimendan Calcium sensitizer 0.050.2mg/kg/min 0 0 "" ##

Epinephrine b1 b2>a 0.010.03mg/kg/min, max 0.1 0.3mg/kg/min " " """ #

Norepinephrine b1>a>b2 0.010.03mg/kg/min, max 0.1mg/kg/min "" 0 or # 0 ""

Dopamine Moderate dose b 2 5mg/kg/min "" " "" 0 or #

Dopamine High dose a 515mg/kg/min "" "" " ""

Phenylephrine a1 4060mg/min "" # # "

Vasopressin V1 0.010.04 units/min "" 0 0 ""

BP, blood pressure; CO, cardiac output; HR, heart rate; PDE, phosphodiesterase; SVR, systemic vascular resistance.

Cardiac failure

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or blood pressure. There was a small and nonsigni-ficant decrease in the pulmonary capillary wedgepressure and pulmonary vascular resistance. Six ofthe 10 patients died, four from refractory cardio-genic shock, one from intracerebral bleed and onefrom mesenteric embolization.

The role of levosimendan in cardiogenic shock

remains unclear. The recommended dose is 0.050.2mg/kg/min, but levosimendan is not recom-mended in systolic blood pressures


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Norepinephrine increases systemic blood pressure,pulse pressure, peripheral vascular resistance andstroke volume. In response to norepinephrinetherapy, the cardiac output is unchanged ordecreased, and there is a compensatory vagal reflexthat slows the heart rate [20]. In clinical practice,norepinephrine is commonly used as a first-line

agent to provide blood pressure support in hypo-tension, and it is suggested as a better choice thandopamine for the initial management of hypoten-sion [22

&&

]. The recommended starting dose is from0.01 to 0.03mg/kg/min; maximum suggested dose is0.1mg/kg/min [8].

Dopamine

Dopamine is an endogenous catecholamine withcardiovascular effects that are dose-dependent. Atlow doses (2mg/kg), it causes vasodilation by stim-ulating dopaminergic receptors on smooth muscleand by stimulating D2 receptors, which are domi-nant in splanchnic and renal artery beds. At inter-mediate doses (25 mg/kg/min), it stimulates breceptors in the heart and on vascular sympatheticneurons. At higher doses (515 mg/kg/min), alphaadrenergic stimulation occurs, with peripheral arte-rial and venous constriction [20]. The effects ofdopamine in cardiogenic shock include an elevationin the heart rate (11%), cardiac output (40%),stroke volume (30%) and left ventricular end dias-tolic pressures (2.4 mm Hg), with a reduction inSVR (20%)[20]. In animal models, high doses of

dopamine increase mean pulmonary artery press-ures without changes in pulmonary vascular resist-ance[23].

The effects of dopamine and norepinephrine inthe treatment of shock of different causes wererecently examined in a randomized trial. Patientsassigned to dopamine and norepinephrine hadsimilar mortality during intensive care (50 vs.46%, P 0.07), during overall hospital stay (59 vs.57%, P 0.24) and at 12 months (66 vs. 63%,P 0.34). Patients assigned to dopamine had higherrate of arrhythmias compared with patients on

norepinephrine, including atrial fibrillation (20.5vs. 11%, P 0.001), ventricular tachycardia (2.4vs. 1.0%, P


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Cardiogenic shock is more often associatedwith hypervolemia, and diuretics are used todecrease the elevated filling pressures and relievepulmonary and peripheral edema. Acute kidneyinjury is a common complication of cardiogenicshock from a ST-elevation myocardial infarction[36

&&

,37], and results in diuretic resistance and

increased need for renal replacement therapy. Inthe setting of hypotension with clear signs of con-gestion, efforts should be made to restore adequateperfusion of the kidneys.

Loop diuretics

Furosemide is a loop diuretic that blocks thesodium-potassium-chloride transporter, and there-fore increases urinary excretion of Na and Cl.Furosemide also acutely increases the systemicvenous capacitance, decreasing left ventricularfilling pressures independently of its diuretic effect[3840]. The oral bioavailability of furosemide canbe markedly reduced during congestion, makingthe i.v. route preferred in cardiogenic shock. Theresponse to furosemide is decreased when under-lying renal function is abnormal. There are noclinical trials of diuretics in cardiogenic shock, butthe Diuretic Strategies in Patients with AcuteDecompensated Heart Failure trial evaluated theoutcomes of high (2.5 outpatient oral dose) vs.low dose (outpatient oral dose) and intermittent vs.continuous infusion of furosemide in patientswith decompensated heart failure. After 72 h, there

were no differences in the co-primary end-point ofglobal assessment of symptoms and change inserum creatinine level when diuretics were admin-istered by bolus compared with continuous infusionor at high dose compared with a low dose. However,the higher dose group compared with the low dosegroup was associated with greater weight loss(8.7 vs. 6.1 pounds, P 0.011), and greater netvolume loss at 72 h (4.8 vs. 3.6 l,P 0.001) but witha transient increase in serum creatinine (23 vs. 14%,P 0.041) [41]. Bumetanide and torsemide are othercommonly used loop diuretics.

Sequential nephron blockade

Diuretic resistance is common in advanced heartfailure. In cardiogenic shock, it can be related to lowcardiac output, low renal perfusion pressure andacute kidney injury. It can also be related to thebraking phenomenon a decrease in the efficacyof loop diuretics due to multiple dosing [42]. Thiscan sometimes be overcome by increasing the doseor frequency of the loop diuretic. Another strategy issequential nephron blockade combining loop and

a thiazide diuretic which results in a synergisticblocking of sodium absorption in different sectionsof the nephron. The only randomized clinical trialof sequential nephron blockade compared additionof metolazone 10 mg daily or bendrofluazide 10 mgdaily to furosemide 80 mg i.v. twice daily. Bothtreatment arms achieved similar median weight

loss (5.6 vs. 5.1 kg), but patients on metolazonehad higher loss of potassium compared with bend-rofluazide (0.7 vs. 0.3 mmol/l) [43]. Because ofthe risk of hypokalemia and acute kidney injurywith the combination therapy, low doses of thia-zides are recommended.

ANTI-INFLAMMATORY AGENTS

SVR is typically elevated in cardiogenic shock. How-ever, some patients present with profound hypo-tension and normal or decreased SVR. The proposedmechanisms for this vasoplegic state include acti-vation of KATP channels in the vascular smoothmuscle, vasopressin deficiency and the release ofcytokines and nitric oxide due to an underlyinginflammatory process[44,45]. Inflammatory modu-lators have been identified as potential targets fortherapy.

Tilarginine

Nitric oxide is a proinflammatory mediatorthat stimulates guanylate cyclase, increasingcyclic guanosine monophosphatase (cGMP) and

smooth muscle relaxation. It has been shownthat nitric oxide synthase (NOS) is upregulatedin acute myocardial infarction [46,47]. As thevasodilatory effect of NOS can contribute to hypo-tension in shock, NOS inhibition has been pro-posed as a therapeutic target. In the TilarginineAcetate Injection in a Randomized InternationalStudy in Unstable Acute Myocardial InfarctionPatients with Cardiogenic Shock trial, 398 patientswith acute coronary syndrome, percutaneousrevascularization and cardiogenic shock refractoryto vasopressor therapy were randomized to NOS

inhibitor tilarginine (1 mg/kg bolus 1 mg/kg/h5-h infusion) vs. placebo. Enrolment was termi-nated early, however, after an interim analysisshowed no differences between the treatmentgroups in 30-day and 6-month mortality, shockduration and resolution[48].

Methylene blue

Methylene blue is a guanylate cyclase inhibitor thatdecreases cGMP and circumvents its vasodilatoryeffects in the smooth muscle[49]. In patients with




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catecholamine-refractory vasoplegia, methyleneblue administered at 2 mg/kg i.v. for 20minincreases mean arterial pressure and SVR, with aconsequent decrease in cardiac output. The meanpulmonary artery pressure and the right atrial andleft atrial pressures remain unchanged [50]. Meth-ylene blue has been suggested to improve morbidity

and mortality in vasoplegic syndrome after cardio-pulmonary bypass, defined as mean arterial pressurelower than 50 mmHg, cardiac index higher than2.5 l/min/m2, right atrial pressure lower than5 mmHg, left atrial pressure lower than 10 mmHgand SVR less than 800 dynes/s/cm5 during norepi-nephrine infusion (0.5mg/kg/min) [49,51]. Meth-ylene blue is, in general, avoided in cardiogenicshock of other causes due to its negative effect oncardiac output.

CONCLUSION

There has been limited progress in pharmacologicalapproaches in the treatment of cardiogenic shock.Vasoactive medications inotropes and vasopres-sors are widely used to acutely improve hemody-namics; however, reliable information regardingcomparative efficacy of individual agents is lacking.A common clinical practice in the setting of cardio-genic shock is to initiate therapy with inotropes andto add, or transition to, vasopressors, if hypotensionpersists. Nevertheless, this approach has not beentested in prospective trials. A subanalysis of a loneprospective randomized trial suggested that norepi-

nephrine may be preferred over dopamine inpatients with cardiogenic shock [22

&&

]. Diureticsare used to decongest patients in cardiogenic shockand volume overload; however, mortality data arealso not available for this group of medications.Inhibition of inflammation during cardiogenicshock seems to be a potential therapeutic target;however, initial clinical studies in this area havenot shown benefit.

In summary, vasoactive therapies have predict-able favorable acute effect on hemodynamics inmost patients; however, their use is accompanied

by significant adverse events and possibly increasedmortality. Other strategies, including early intro-duction of mechanical circulatory support, mayimprove survival in cardiogenic shock, and thishypothesis should be tested in clinical trials. Inthe meantime, the use of vasoactive agents shouldbe limited to the dose and time necessary to restoretissue perfusion before recovery of myocardial func-tion takes place (where this can be accomplished), orbefore advanced therapies, including mechanicalcirculatory support or heart transplantation, canbe implemented.

Acknowledgements

None.

Conflicts of interest

There are no conflicts of interest.

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2014 Pharmacologic Therapies for Acute Cardiogenic Shock