Intensive Care Med https://doi.org/10.1007/s00134-018-5242-5 REVIEW A global perspective on vasoactive agents in shock Djillali Annane1*, Lamia Ouanes‑Besbes2, Daniel de Backer3, Bin DU4, Anthony C. Gordon5, Glenn Hernández6, Keith M. Olsen7, Tifany M. Osborn8, Sandra Peake9,10, James A. Russell11 and Sergio Zanotti Cavazzoni12 © 2018 Springer-Verlag GmbH Germany, part of Springer Nature and ESICM Abstract Purpose: We set out to summarize the current knowledge on vasoactive drugs and their use in the management of shock to inform physicians’ practices. Methods: This is a narrative review by a multidisciplinary, multinational—from six continents—panel of experts including physicians, a pharmacist, trialists, and scientists. Results and conclusions: Vasoactive drugs are an essential part of shock management. Catecholamines are the most commonly used vasoactive agents in the intensive care unit, and among them norepinephrine is the frst-line therapy in most clinical conditions. Inotropes are indicated when myocardial function is depressed and dobutamine remains the frst-line therapy. Vasoactive drugs have a narrow therapeutic spectrum and expose the patients to potentially lethal complications. Thus, these agents require precise therapeutic targets, close monitoring with titration to the minimal efcacious dose and should be weaned as promptly as possible. Moreover, the use of vasoactive drugs in shock requires an individualized approach. Vasopressin and possibly angiotensin II may be useful owing to their norepinephrine-sparing efects. Keywords: Shock, Cardiovascular system, Adrenergic agonists, Clinical trials, Practice guidelines Introduction review provides a summary of current knowledge about Acute illnesses are often characterized by a loss in cardio- vasopressors and inotropes to guide intensive care physi- vascular homeostasis. Underlying mechanisms may include cians’ practices when managing patients with shock. multiple factors altering blood volume (actual or efective), cardiac (diastolic and/or systolic) function or the vessels Pharmacological basis (large vessels and/or microvasculature). Vasopressors and Catecholamines inotropes are vasoactive drugs that have been developed Vasoactive agents are classifed into sympathomimet- to act on the vessels and the heart. In practice, a number ics, vasopressin analogues, and angiotensin II. Catecho- of drugs are available with heterogeneous mechanisms of lamines are further subdivided in categories of indirect, action and varying beneft to risk balance. Tis narrative mixed-acting, and direct acting. Only the direct acting agents have a role in shock. Direct agents are further *Correspondence: [email protected] delineated by their selective nature (e.g., dobutamine, 1 General ICU, Raymond Poincaré Hospital (APHP), School of Medicine phenylephrine) or non-selective activity (e.g., epineph- Simone Veil U1173 Laboratory of Infection and Infammation (University of Versailles SQY, University Paris Saclay/INSERM), CRICS-TRIGERSEP rine, norepinephrine) on α1, α2, β1, β2, and β3 receptors [1]. Network (F-CRIN), 104 boulevard Raymond Poincaré, 92380 Garches, Catecholamines are most often linked to clinical improve- France ment in shock states [1, 2]. Catecholamines act by stimu- Full author information is available at the end of the article lation of either α or β receptors, exerting excitatory action All authors have equally contributed to this manuscript. on smooth muscle and resulting in vasoconstrictive or vasodilatory efects in skin, kidney, and lung. Intravenous decreased lung oedema and fuid balance more than vaso- (IV) administration of epinephrine or norepinephrine pressin and control groups with concomitant mitigation of results in increasing blood pressure with increasing dose. decreased plasma total protein concentration and oncotic Te rise in blood pressure is due to vasoconstriction and pressure [16]. β receptor stimulation. β-stimulation directly increases inotropy and heart rate. Although receptor responses Calcium sensitizers have classically been presented as linear, all responses fol- Calcium sensitizers produce their inotropic efect by low a sigmoidal type curve resulting in a pharmacological sensitizing the myocardium to existing calcium, rather response to increasing doses followed by a plateau afect. than increasing intracellular concentrations. Tis has the Dopamine receptors include at least fve subtypes that advantage of producing increased myocardial contraction are broadly distributed in the central nervous system, in (inotropy) without the same increases in oxygen demand pulmonary and systemic blood vessels, cardiac tissues as other inotropes. Furthermore, as calcium levels fall in and the kidneys [1]. Te impact on receptors provides the diastole, calcium sensitizers do not impair relaxation in pharmacologic basis for catecholamine therapy in shock. the same way as other inotropes. Clinicians should also be aware of their efects on glycog- Levosimendan is the only calcium sensitizer in clinical enolysis in the liver and smooth muscle, free fatty acid use [17]. Opening of ATP-sensitive potassium channels release from adipose tissue, modulation of insulin release in vascular smooth muscle results in vasodilatation and and uptake, immune modulation, and psychomotor activ- through actions in the mitochondria of cardiomyocytes, ity in the central nervous system. it is reported as cardioprotective in ischaemic episodes. At higher doses it also exhibits phosphodiesterase III Vasopressin and analogues inhibitor efects. Although the parent drug has a short Vasopressin is a potent nonapeptide vasopressor hormone half-life of about 1 h, an active metabolite, OR1896, has released by the posterior pituitary gland in response to a long half-life and therefore a 24-h infusion of levo- hypotension and hypernatremia [3]. Vasopressin stimu- simendan can have haemodynamic efects for about lates a family of receptors—V1a (vasoconstriction), V1b 1 week. (ACTH release), V2 (anti-diuretic efects), oxytocin (vaso- dilator) and purinergic receptors (of limited relevance to Selective beta‑1 antagonists septic shock). Vasopressin paradoxically induces synthesis Although sympathetic stimulation is an appropriate phys- of nitric oxide (NO) [4]. NO may limit vasopressin’s vaso- iological response to sepsis there is evidence that if exces- constriction, while preserving renal perfusion [5]. How- sive this can become pathological [18]. Both high levels ever, it may also contribute to vasopressin/NO-induced of circulating catecholamines and tachycardia have been cardiac depression. Notably, V1a-receptor activation of associated with increased mortality in septic shock [19]. vascular smooth muscle induced vasoconstriction is cat- Although myocardial dysfunction is common in sepsis, echolamine-independent and may explain why vasopressin short-acting β1 antagonists may have benefcial cardio- complements norepinephrine in septic shock. Te main vascular efects through slowing heart rate, improving rationale for vasopressin infusion in septic shock is well- diastolic function and coronary perfusion [20]. Esmolol is established. Vasopressin defciency in early septic shock a cardioselective β1 receptor antagonist with rapid onset [6] is due to depletion of vasopressin stores and inadequate and very short duration of action [21]. Landiolol is an synthesis and release from the hypothalamic-pituitary ultra-short acting β blocker about eight times more selec- axis. Low dose vasopressin infusion of 0.01–0.04 units/ tive for the β1 receptor than esmolol [22]. min, increased blood pressure and decreased norepineph- rine requirements [6–10]. Vasopressin defciency and its Others anti-diuretic efects only become apparent later, during Historically, angiotensin was recognized as a potent vaso- septic shock recovery with about 60% of patients having constrictor [23]. Angiotensin increases blood pressure inadequate vasopressin responses to an osmotic challenge mainly by stimulating NADH/NADPH membrane bound 5 days post recovery from septic shock [11]. Highly selec- oxidase with subsequent oxygen production by vascu- tive V1a agonists could have better efects in septic shock lar smooth muscles [24]. Recently, a synthetic human than vasopressin because of the narrow focus on the V1a angiotensin II was shown to act synergistically with nor- receptor [12]. In addition to minimizing V2 anti-diuresis, epinephrine to increase blood pressure in patients with less or no von Willebrand factor release is reported (V2 vasodilator shock [25]. Methylene blue and non-selective mediated) and there is some evidence in animal models of inhibitors of NO synthase induced vasoconstriction by less vascular leak with V1a agonists compared to vasopres- modulating endothelial vascular relaxation, and phos- sin [13–16]. Te highly selective V1a agonist selepressin phodiesterase type III inhibitors exert inotropic efects and vasodilation by modulating cyclic AMP metabolism pressure [1]. Norepinephrine also increases stroke vol- [26]. ume and coronary blood fow partly by stimulating cor- onary vessel β2-receptors [32]. Tese potential positive Cardiovascular efects efects of norepinephrine on cardiac function are often Efects of catecholamines on the cardiovascular system transient. Epinephrine is a much more powerful stimu- are summarized in Fig. 1. lant of cardiac function than norepinephrine, i.e., has more β-adrenergic efects. Epinephrine accelerates heart Efects on the heart rate, improves cardiac conduction, stimulates the