病理生理学病理生理学 (7).pdf
Send Orders for Reprints to 102 Current Cardiology Reviews,2019,15,102-113 REVIEW ARTICLE 1573-403X/19$58.00+.00 2019 Bentham Science Publishers Shock Classification and Pathophysiological Principles of Therapeutics Olga N.Kislitsina1,2,*,Jonathan D.Rich2,Jane E.Wilcox2,Duc T.Pham1,Andrei Churyla1,Esther B.Vorovich2,Kambiz Ghafourian2 and Clyde W.Yancy2 1Department of Cardiac Surgery Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center,Chicago,Illinois,IL,USA;2Department of Cardiology Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center,Chicago,Illinois,IL,USA A R T I C L E H I S T O R Y Received:April 17,2018 Revised:October 11,2018 Accepted:December 10,2018 DOI:10.2174/1573403X15666181212125024 Abstract:The management of patients with shock is extremely challenging because of the myriad of possible clinical presentations in cardiogenic shock,septic shock and hypovolemic shock and the limitations of contemporary therapeutic options.The treatment of shock includes the administration of endogenous catecholamines(epinephrine,norepinephrine,and dopamine)as well as various vasopressor agents that have shown efficacy in the treatment of the various types of shock.In addi-tion to the endogenous catecholamines,dobutamine,isoproterenol,phenylephrine,and milrinone have served as the mainstays of shock therapy for several decades.Recently,experimental studies have suggested that newer agents such as vasopressin,selepressin,calcium-sensitizing agents like levosimendan,cardiac-specific myosin activators like omecamtiv mecarbil(OM),istaroxime,and natriuretic peptides like nesiritide can enhance shock therapy,especially when shock presents a more complex clinical picture than normal.However,their ability to improve clinical outcomes re-mains to be proven.It is the purpose of this review to describe the mechanism of action,dosage re-quirements,advantages and disadvantages,and specific indications and contraindications for the use of each of these catecholamines and vasopressors,as well as to elucidate the most important clinical trials that serve as the basis of contemporary shock therapy.Keywords:Shock,cardiogenic shock,septic shock,shock therapy,endogenous catecholamines,exogenous catecholamines,inotropes,vasopressors.1.INTRODUCTION The treatment of cardiogenic shock,septic shock,and hypovolemic shock include the administration of endoge-nous catecholamines(epinephrine,norepinephrine,and do-pamine)as well as various vasopressor agents that have shown efficacy in the treatment of the various types of shock.In addition to the endogenous catecholamines,exoge-nous catecholamines like Dobutamine,isoproterenol,phen-ylephrine,and milrinone have served as the mainstays of shock therapy for several decades.Vasopressin,selepressin,calcium-sensitizing agents like levosimendan,cardiac-specific myosin activators like omecamtiv mecarbil(OM),istaroxime,and natriuretic peptides like nesiritide can en-hance therapy when shock is especially complex.It is the purpose of this communication to describe the mechanisms of action,dosage requirements,advantages/disadvantages,and indications/contraindications for the use of each of these catecholamines and vasopressors and to discuss the impor-tance of the major clinical trials that serve as the basis of contemporary shock therapy.*Address correspondence to this author at the Center for Heart Failure,Bluhm Cardiovascular Institute Feinberg School of Medicine,Galter Pavil-ion 11-140,Northwestern University,Chicago,Illinois 60611,IL,USA;Tel:312-476-8093;Fax:312-696-1903;E-mail:olga.kislitsinanm.org 2.CLASSIFICATION OF SHOCK AND GENERAL PRINCIPLES OF TREATING SHOCK Shock is defined as inadequate organ and peripheral tis-sue perfusion and is categorized on the basis of its etiology as being either hypovolemic,cardiogenic,or restrictive(vasodilatory/distributive).In hypovolemic shock,the addition of intravascular vol-ume(preload)combined with drugs specifically capable of increasing LV contractility and stroke volume(SV)can be used to improve cardiac output(CO).Unfortunately,the de-gree to which the SV can be enhanced pharmacologically is limited by the fact that these drugs also increase the heart rate.Cardiogenic shock is most commonly caused by an acute myocardial infarction but it can also result from hindrances to adequate cardiac filling such as pericardial tamponade or valvar stenosis.It is characterized by initial hypotension that triggers a vasoconstrictor release to re-establish normal blood pressure(Fig.1).However,despite the restoration of normal mean arterial pressure(MAP)in both hypovolemic and cardiogenic shock by these compensatory measures,the MVO2 is often decreased in both of these types of“cold shock”.If cardiogenic shock is due to pericardial tamponade,immediate physical intervention to relieve the tamponade is required.However,if cardiogenic shock is due to acute myo-Shock Classification and Pathophysiological Principles of Therapeutics Current Cardiology Reviews,2019,Vol.15,No.2 103 cardial infarction,therapy can vary widely depending upon the hemodynamic sequelae of the infarction.Both hypo-volemic shock(inadequate preload)and cardiogenic shock(impaired cardiac contractility)are characterized by low left ventricular stroke volume,though unlike hypovolemic shock,cardiogenic shock is often accompanied by an inap-propriately slow heart rate.Vasodilatory/distributive,shock is characterized by ex-cessive arteriolar vasodilatation that causes a decrease in systemic vascular resistance(SVR)with resultant hypoten-sion that leads to inadequate peripheral perfusion in the pres-ence of warm extremities,hence the term“warm shock”.Septic shock(Fig.2)is the most common cause of“warm shock”and it is also the most common type of shock overall 1,2.Restoration of mean arterial pressure(MAP)is most often achieved by using drugs that increase the SVR.How-ever,initial therapy aimed solely at increasing the SVR may result in only a modest increase in the CO.Hypovolemic shock is usually the simplest form of shock to treat but many of its treatment strategies do not apply for the other types of shock.Thus,the therapy of shock,regard-less of its etiology,demands a thorough knowledge of car-diovascular physiology and the pharmacology of the drugs that are used to treat its derangements.Fig.(1).Simplified scheme of cardiogenic shock.Fig.(2).Simplified scheme of septic shock.Left Panel:Gram-positive and gram-negative bacteria,viruses,and fungi have unique cell-wall molecules called pathogen-associated mo-lecular patterns that bind to pattern-recognition receptors(toll-like receptors TLRs)on the surface of immune cells.The lipopolysaccharide of gram-negative bacilli binds to lipopolysaccharide-binding protein,CD14 complex.The gram-positive bacteria and the lipopolysaccharide of gram-negative bacteria bind to TLR-2 and TLR-4.Those are proinflammatory cytokines that activate the adaptive immune and both direct and indirect host injury.Sepsis increases the activity of inducible nitric oxide synthase(iNOS),which increases the synthesis of nitric oxide(NO),a potent vasodilator.Cytokines activate endothelial cells,injure endothelial cells by inducing neutrophils,monocytes,macrophages,and platelets to bind to endothelial cells and also activate the coagulation cascade.Right Panel:Simplified scheme of septic shock described in the text above.104 Current Cardiology Reviews,2019,Vol.15,No.2 Kislitsina et al.3.ENDOGENOUS CATECHOLAMINES The endogenous catecholamines epinephrine,norepi-nephrine,and dopamine all display variable physiologic ef-fects across the dosing range and substantial patient variabil-ity in doseresponse 1,3.4.EPINEPHRINE Epinephrine(“adrenalin”)is a nonselective agonist of all adrenergic receptors,including the major subtypes 1,2,1,2,and 3.Epinephrine increases SVR via 1 receptor-dependent vasoconstriction(Fig.3)and increases cardiac output via its binding to 1 receptors.As a result,epinephrine is especially useful for the treatment of acute LV fail-ure during cardiac surgery because it predictably increases cardiac output.It is most useful as an inotrope in patients who are hypotensive with no myocardial ischemia,espe-cially following cardiac surgery 3-7.Epinephrine doses above 0.3-0.5 mcg/kg/min are consid-ered high,but there is no defined maximum epinephrine dose for refractory shock 8,9.Unfortunately,the use of epi-nephrine may be limited because it promotes the develop-ment of atrial and ventricular arrhythmias.Another reason for avoiding epinephrine is concern that it may cause ele-vated lactate levels that could not only be directly harmful but might also confound the serial trending of serum lactate levels 10.The mechanism of hyperlactemia in sepsis is multifactorial and results from factors beyond hypoxic tissue injury alone 11-13.Indeed,serum lactic acid levels can be elevated in the presence of adequate systemic perfusion,MAP,and peripheral oxygen delivery 14.Ven Genderen et al.showed that septic shock behaves differently from other forms of shock in that even when cardiac output and other systemic parameters are optimized,there continues to be a regional microvascular oxygen mismatch 15.Thus,Rivers et al.warn against using lactate clearance as the only marker of sepsis recovery and state that lactate clearance,central venous oxygen saturation(ScvO2),and other markers repre-sent complementary end points that are not mutually exclu-sive 16,17.However,much like vasopressor-induced sinus tachycardia,elevated lactate may be a beneficial compensa-tory mechanism 18 by providing a dual action of epineph-rine on the heart.Randomized controlled clinical trials have shown that concentrated sodium lactate improves cardiac output among post-CABG and heart failure patients 19,20.5.NOREPINEPHRINE Norepinephrine(“noradrenalin”)is an 1-adrenergic re-ceptor agonist with modest-agonist activity that makes it a vasoconstrictor but a less potent inotrope.Since norepineph-rine is virtually a“pure”vasoconstrictor it may actually re-duce CO in patients with cardiac dysfunction because of the strong increase in afterload,although many patients with cardiogenic shock can maintain CO during norepinephrine therapy 21,22.Because norepinephrine has minimal chro-notropic effects,it is useful in settings in which heart rate Fig.(3).Schematic of the postulated mechanism of intracellular actions of adrenergic agonists.Alpha-adrenoceptor agonists(-agonists)bind to-receptors on vascular smooth muscle and induce smooth contraction and vasoconstriction,thus mimicking the effects of sympa-thetic adrenergic nerve activation to the blood vessels.The-adrenergic receptor,activates a different regulatory G protein(Gq),which acts through the IP3 signal transduction pathway activates the release of calcium from the sarcoplasmic reticulum(SR)which by itself and through the calciumcalmodulin dependent protein kinases(CaMKII)influences cellular processes,which in vascular smooth muscle leads to vaso-constriction.Shock Classification and Pathophysiological Principles of Therapeutics Current Cardiology Reviews,2019,Vol.15,No.2 105 stimulation may be undesirable.Norepinephrine increases both systolic and diastolic blood pressures so it increases coronary blood flow and thus,may improve cardiac function indirectly 23.Norepinephrine is the first-line vasopressor for all forms of shock with severe hypotension 1,3,24.6.DOPAMINE Dopamine binds weakly to 1-adrenergic receptors but has a high binding affinity at dopamine receptors and at trace amine-associated receptor 1(TAAR1)25.At low doses,dopamine inhibits the release of norepinephrine in peripheral blood vessels,thereby acting as a mild vasodilator.It also inhibits the re-uptake of norepinephrine in presynaptic sym-pathetic nerve terminals resulting in an indirect increase in cardiac contractility and heart rate.The direct vasodilator effect of dopamine tends to offset the indirect vasoconstric-tion effect of the secondary increase in norepinephrine so there is usually only a mild increase in SVR.The net effect of the combination of increased contractility,heart rate and only a slight increase in SVR is to improve CO,dramatically in some cases 26.At higher infusion rates(10-20 mcg/kg/min),1-adrenergic receptormediated vasoconstric-tion dominates the peripheral response and further increases blood pressure 26,27 but the CO and peripheral tissue per-fusion may not continue to improve.At low doses,dopamine promotes vasodilation and in-creased blood flow in the coronary,renal,mesenteric and cerebral vascular beds by acting on D1 postsynaptic dopa-minergic receptors and it provides additional blood flow to the kidneys by stimulating their D2 presynaptic receptors.Low doses of dopamine(below 4 mcg/kg/min)cause renal vasodilation and natriuretic effects that increase urine output but the impact on creatinine clearance and renal blood flow varies 28-32 and the clinical significance of“renal-dose”dopamine remains unclear.As a result,dopamine is no longer recommended for vasopressor support in septic shock except in patients with bradycardia who have a low risk of developing tachyarrhythmias 24.7.COMPARISON OF ENDOGENOUS CATECHO-LAMINES Epinephrine and norepinephrine have equal affinity at both alpha1 and alpha2 receptors.Norepinephrine is slightly lower in potency than epinephrine and approximately 100-fold more potent than dopamine for raising MAP 21,27,33,34.Epinephrine is more effective than norepinephrine or dopamine in increasing CO in septic shock 7.In patients with septic shock and a MAP 70 mm Hg despite norepi-nephrine infusion,adding epinephrine increases MAP,HR,and cardiac index more than adding dobutamine does.Nore-pinephrine carries a lower tachyarrhythmia risk than either dopamine or epinephrine when used for vasopressor support 27,34-37.However,prolonged norepinephrine infusion can have a direct toxic effect on cardiac myocytes by induc-ing apoptosis via protein kinase A activation and increased cytosolic calcium influx 38.Likewise,the use of epineph-rine in high doses for long periods of time is toxic to arterial walls and causes focal regions of myocardial contraction-band necrosis and myocyte apoptosis 39.8.EXOGENOUS CATECHOLAMINES 8.1.Dobutamine Dobutamine directly stimulates 1-receptors and 1 receptors but has a weak affinity for 2 activity,leading to a substantial increase in SV and CO,a moderate increase in HR,and an inconsistent effect on MAP(Fig.4)3.This means that dobutamine is a potent inotrope whose use is less hampered by induced sinus tachycardia than other inotropes.Fig.(4).Simplified schematic of postulated intracellular actions of-adrenergic agonist.-Receptor stimulation,through a stimulatory Gs-GTP unit activates the adenyl cyclase system,which results in increased concentrations of cAMP.In cardiac myocytes,1-receptor activation through increased cAMP concentration activates Ca2 ch
