1 a Global Perspective on Vasoactive Agents in Shock

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1 A global perspective on vasoactive agents in shock Authors*: Djillali Annane, Lamia Ouanes-Besbes, 1 2 2 Daniel de Backer, Bin DU, Anthony C Gordon, Glenn Hernández, Keith M. Olsen, Tiffany M. Osborn, Sandra 3 4 3 Peake, James A. Russell, Sergio Zanotti Cavazzoni 5 6 4 *All authors have equally contributed to this manuscript 7 8 5 Address: 9 10 6 Djillali Annane, MD, PhD 11 12 7 General ICU, Raymond Poincaré hospital (APHP), School of medicine Simone Veil, U1173 Laboratory of 13 14 8 Infection& Inflammation (University of Versailles SQY- University Paris Saclay / INSERM) – CRICS- 15 16 9 TRIGERSEP network (F-CRIN), 104 boulevard Raymond Poincaré, 92380 Garches, France 17 18 10 Lamia Ouanes-Besbes, MD 19 20 11 Intensive Care Unit, CHU F. Bourguiba ; Monastir, Tunisia 21 22 12 Daniel de Backer, MD,PhD 23 24 13 Department of intensive Care, CHIREC Hospitals, Université Libre de Bruxelles, Brussels, Belgium 25 26 14 Bin DU, MD 27 28 15 Medical ICU, Peking Union Medical College Hospital; 1 Shuai Fu Yuan, Beijing 100730; China 29 30 16 Anthony C Gordon, MD, FRCA, FFICM 31 32 17 Section of Anaesthetics, Pain Medicine & Intensive Care, Imperial College London, UK 33 34 18 Glenn Hernández, MD, PhD 35 36 Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Chile 37 19 38 39 20 Keith M. Olsen, PharmD, FCCP, FCCM 40 41 21 UAMS College of Pharmacy. Little Rock, AR, USA 42 43 22 Tiffany M. Osborn, MD, MPH 44 45 23 Section of Acute Care Surgical Services; Surgical/Trauma Critical Care; Barnes Jewish Hospital, USA 46 47 24 Sandra Peake, BM BS BSc(Hons) FCICM PhD 48 49 25 Department of Intensive Care; The Queen Elizabeth Hospital; School of Medicine; University of Adelaide; 50 51 26 Adelaide, South Australia; School of Epidemiology and Preventive Medicine; Monash University; Victoria; 52 53 27 Australia 54 55 28 James A. Russell AB, MD, FRCPC 56 57 29 Centre for Heart Lung Innovation, St. Paul's Hospital and University of British Columbia,1081 Burrard Street, 58 59 30 Vancouver, BC, Canada 60 61 62 1 63 64 65 31 Sergio Zanotti Cavazzoni, MD, FCCM, 1 2 32 Sound Critical Care, Sound Physicians; Houston, Texas, USA 3 4 33 Correspondence to: Djillali ANNANE, General ICU, Raymond Poincaré hospital (APHP), School of medicine 5 6 34 Simone Veil (University of Versailles SQY- University Paris Saclay) 7 8 35 104 boulevard Raymond Poincaré, 92380 Garches, France 9 10 36 Phone: 331 47107786 11 12 37 [email protected] 13 14 38 15 16 39 Word count: 4969 17 18 19 40 Competing financial interests: 20 21 41 DA reports having received a grant from the French ministry of health to conduct a trial comparing epinephrine 22 23 42 to norepinephrine plus dobutamine for septic shock (CATS) . 24 25 43 DDB reports that he acts as a consultant to and material for studies by Edwards Lifesciences 26 27 28 44 ACG reports that outside of this work he has received speaker fees from Orion Corporation Orion Pharma and 29 30 45 Amomed Pharma. He has consulted for Ferring Pharmaceuticals, Tenax Therapeutics, Baxter Healthcare, 31 32 46 Bristol-Myers Squibb and GSK, and received grant support from Orion Corporation Orion Pharma, Tenax 33 34 47 Therapeutics and HCA International with funds paid to his institution. 35 36 37 48 GH reports no financial conflict of interest. 38 39 49 JR reports patents owned by the University of British Columbia (UBC) that are related to PCSK9 inhibitor(s) and 40 41 50 sepsis and related to the use of vasopressin in septic shock. JR is an inventor on these patents. JR is a founder, 42 43 51 Director and shareholder in Cyon Therapeutics Inc. (developing a sepsis therapy (PCSK9 inhibitor)). JR has share 44 45 52 options in Leading Biosciences Inc. JR is a shareholder in Molecular You Corp. JR reports receiving consulting 46 47 48 53 fees in the last 3 years from: 1)Asahi Kesai Pharmaceuticals of America (AKPA)(developing recombinant 49 50 54 thrombomodulin in sepsis). 2) La Jolla Pharmaceuticals (developing angiotensin II; JR chaired the DSMB of a 51 52 55 trial of angiotensin II from 2015 - 2017) - no longer actively consulting. 3) Ferring Pharmaceuticals 53 54 56 (manufactures vasopressin and was developing selepressin) - no longer actively consulting. 4) Cubist 55 56 57 Pharmaceuticals (now owned by Merck; formerly was Trius Pharmaceuticals; developing antibiotics) – no 57 58 58 longer actively consulting. 5) Leading Biosciences (was developing a sepsis therapeutic that is no longer in 59 60 61 62 2 63 64 65 59 development) – no longer actively consulting. 6) Grifols (sells albumin) - no longer actively consulting. 1 2 60 7)CytoVale Inc. (developing a sepsis diagnostic) - no longer actively consulting. JR reports having received an 3 4 61 investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic 5 6 62 shock?”) that is provided to and administered by UBC. 7 8 9 63 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 3 63 64 65 64 Abstract 1 2 Purpose 3 65 4 5 66 We aimed to summarize the current knowledge on vasoactive drugs and their use in the management of shock to 6 7 67 inform physicians’ practices. 8 9 10 68 Methods 11 12 13 69 This was a narrative review from a multidisciplinary, multinational – from the six continents- panel of experts 14 15 70 including physicians, pharmacist, trialists, and scientists. 16 17 18 71 Conclusions 19 20 21 72 Vasoactive drugs are an essential part of shock management. Catecholamines are the most commonly used 22 23 73 vasoactive agents in the intensive care unit, and among them norepinephrine is the first-line therapy in most 24 25 74 clinical conditions. Inotropes are indicated when myocardial function is depressed and dobutamine remains the 26 27 75 first-line therapy. Vasoactive drugs have a tight therapeutic margin and expose the patients to potentially lethal 28 29 76 complications. Thus, these agents require precise therapeutic targets, close monitoring with titration to the 30 31 77 minimum efficacious dose and should be weaned as promptly as possible. Moreover, the use of vasoactive drugs 32 33 78 in shock requires an individualized approach. Vasopressin and possibly angiotensin II may be useful owing to 34 35 79 their norepinephrine sparing effects. 36 37 80 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 4 63 64 65 81 Acute illnesses are often characterized by a loss in cardiovascular homeostasis. Underlying mechanisms may 1 2 82 include multiple factors altering blood volume (actual or effective), cardiac (diastolic and/or systolic) function or 3 4 83 the vessels (large vessels and/or microvasculature). Vasopressors and inotropes are vasoactive drugs that have 5 6 84 been developed to act on the vessels and the heart. In practice, a number of drugs are available with 7 8 85 heterogeneous mechanisms of action and varying benefit to risk balance. This narrative review provides a 9 10 86 summary of current knowledge about vasopressors and inotropes to guide intensive care physicians’ practices 11 12 87 when managing patients with shock. 13 14 15 88 Pharmacological basis 16 17 18 89 Catecholamines 19 20 90 Vasoactive agents are classified into sympathomimetics, vasopressin analogues, and angiotensin II. 21 22 91 Catecholamines are further subdivided in categories of indirect, mixed-acting, and direct acting. Only the direct 23 24 92 acting agents have a role in shock. Direct agents are further delineated by their selective nature (e.g. dobutamine, 25 26 phenylephrine) or non-selective activity (e.g. epinephrine, norepinephrine) on , , , , and receptors [1]. 27 93 1 2 1 2 3 28 29 94 Catecholamines are most often linked to clinical improvement in shock states [1,2]. Catecholamines act by 30 31 95 stimulation of either or receptors, exerting excitatory action on smooth muscle and resulting in 32 33 96 vasoconstrictive or vasodilatory effects in skin, kidney, and lung. Intravenous (IV) administration of epinephrine 34 35 97 or norepinephrine results in increasing blood pressure with increasing dose. The rise in blood pressure is due to 36 37 98 vasoconstriction and receptor stimulation. -stimulation directly increases inotropy and heart rate. Although 38 39 99 receptor responses have classically been presented as linear, all responses follow a sigmoidal type curve 40 41 100 resulting in a pharmacological response to increasing doses followed by a plateau affect. Dopamine receptors 42 43 101 include at least five subtypes that are broadly distributed in the central nervous system, in pulmonary and 44 45 102 systemic blood vessels, cardiac tissues and the kidneys [1]. The impact on receptors provides the pharmacologic 46 47 103 basis for catecholamine therapy in shock. Clinicians should also be aware of their effects on glycogenolysis in 48 49 104 the liver and smooth muscle, free fatty acid release from adipose tissue, modulation of insulin release and 50 51 105 uptake, immune modulation, and psychomotor activity in the central nervous system. 52 53 106 54 55 107 56 57 108 58 59 109 Vasopressin and analogues 60 61 62 5 63 64 65 110 Vasopressin is a potent nonapeptide vasopressor hormone released by the posterior pituitary gland in response to 1 2 111 hypotension and hypernatremia [3]. Vasopressin stimulates a family of receptors – V1a (vasoconstriction), V1b 3 4 112 (ACTH release), V2 (anti-diuretic effects), oxytocin (vasodilator) and purinergic receptors (of limited relevance 5 6 113 to septic shock). Vasopressin paradoxically induces synthesis of nitric oxide (NO) [4]. NO may limit 7 8 114 vasopressin’s vasoconstriction, while preserving renal perfusion [5]. However, it may also contribute to 9 10 115 vasopressin/NO-induced cardiac depression. Notably, V1a-receptor activation of vascular smooth muscle 11 12 116 induced vasoconstriction is catecholamine-independent and may explain why vasopressin complements 13 14 117 norepinephrine in septic shock. The main rationale for vasopressin infusion in septic shock is well-established. 15 16 118 Vasopressin deficiency in early septic shock [6] is due to depletion of vasopressin stores and inadequate 17 18 119 synthesis and release from the hypothalamic-pituitary axis. Low dose vasopressin infusion of 0.01–0.04 19 20 120 units/min. increased blood pressure and decreased norepinephrine requirements [6-10]. Vasopressin deficiency 21 22 121 and its anti-diuretic effects only become apparent later, during septic shock recovery with about 60% of patients 23 24 122 having inadequate vasopressin responses to an osmotic challenge 5 days post recovery from septic shock [11]. 25 26 123 Highly selective V1a agonists could have better effects in septic shock than vasopressin because of the narrow 27 28 124 focus on the V1a receptor [12]. In addition to minimizing V2 anti-diuresis, less or no von Willebrand factor 29 30 125 release is reported (V2 mediated) and there is some evidence in animal models of less vascular leak with V1a 31 32 126 agonists compared to vasopressin [13-16]. The highly selective V1a agonist selepressin decreased lung oedema 33 34 127 and fluid balance more than vasopressin and control groups with concomitant mitigation of decreased plasma 35 36 128 total protein concentration and oncotic pressure [16]. 37 38 129 Calcium Sensitizers 39 40 130 Calcium sensitizers produce their inotropic effect by sensitizing the myocardium to existing calcium, rather than 41 42 131 increasing intracellular concentrations. This has the advantage of producing increased myocardial contraction 43 44 132 (inotropy) without the same increases in oxygen demand as other inotropes. Furthermore, as calcium levels fall 45 46 133 in diastole, calcium sensitizers do not impair relaxation in the same way as other inotropes. 47 48 134 Levosimendan is the only calcium sensitizer in clinical use [17]. Opening of ATP-sensitive potassium channels 49 50 135 in vascular smooth muscle results in vasodilatation and through actions in the mitochondria of cardiomyocytes, it 51 52 136 is reported as cardioprotective in ischaemic episodes. At higher doses it also exhibits phosphodiesterase III 53 54 137 inhibitor effects. Although the parent drug has a short half-life of about 1 hour, an active metabolite, OR1896, 55 56 138 has a long half-life and therefore a 24-hour infusion of levosimendan can have haemodynamic effects for about 57 58 one week. 59 139 60 61 62 6 63 64 65 140 Selective beta-1 antagonists 1 2 141 Although sympathetic stimulation is an appropriate physiological response to sepsis there is evidence that if 3 4 142 excessive this can become pathological [18]. Both high levels of circulating catecholamines and tachycardia 5 6 143 have been associated with increased mortality in septic shock [19]. Although myocardial dysfunction is common 7 8 144 in sepsis, short-acting 1 antagonists may have beneficial cardiovascular effects through slowing heart rate, 9 10 145 improving diastolic function and coronary perfusion [20]. Esmolol is a cardioselective 1 receptor antagonist 11 12 146 with rapid onset and very short duration of action [21]. Landiolol is an ultra-short acting blocker about 8 times 13 14 147 more selective for the 1 receptor than esmolol [22]. 15 16 148 Others 17 18 149 Historically, angiotensin was recognized as a potent vasoconstrictor [23]. Angiotensin increases blood pressure 19 20 150 mainly by stimulating NADH/NADPH membrane bound oxidase with subsequent oxygen production by 21 22 vascular smooth muscles [24]. Recently, a synthetic human angiotensin II was shown to act synergistically with 23 151 24 norepinephrine to increase blood pressure in patients with vasodilator shock [25]. Methylene blue and non- 25 152 26 27 153 selective inhibitors of NO synthase induced vasoconstriction by modulating endothelial vascular relaxation, and 28 29 154 phosphodiesterase type III inhibitors exert inotropic effects and vasodilation by modulating cyclic AMP 30 31 155 metabolism [26]. 32 33 34 156 Cardiovascular effects 35 36 37 157 Effects of catecholamines on the cardiovascular system are summarized in figure 1. 38 39 40 158 Effects on the heart 41 42 159 Catecholamines 43 44 160 Vasoactive agents are utilized in shock with the intent of counteracting vasoplegia, myocardial depression or a 45 46 161 combination of both. Potential benefits are balanced against the possible negative impact on cardiac output (CO), 47 48 162 myocardial oxygen consumption, myocardial perfusion and cardiac rhythm. Norepinephrine effects on cardiac 49 50 163 function and CO are inconsistent and time-dependent [27-29], which may be related to baseline cardiovascular 51 52 164 state, ventriculo-arterial coupling [30] and potential unmasking of myocardial depression with increased 53 54 165 afterload [31]. Usually the direct positive chronotropic effects of norepinephrine are counterbalanced by the 55 56 166 vagal reflex activity of the increased blood pressure [1]. Norepinephrine also increases stroke volume and 57 58 167 coronary blood flow partly by stimulating coronary vessel 2-receptors [32]. These potential positive effects of 59 60 61 62 7 63 64 65 168 norepinephrine on cardiac function are often transient. Epinephrine is a much more powerful stimulant of cardiac 1 2 169 function than norepinephrine, i.e. has more β-adrenergic effects. Epinephrine accelerates heart rate, improves 3 4 170 cardiac conduction, stimulates the rate of relaxation, and reinforces systolic efficiency, with subsequent increase 5 6 171 in CO at the cost of dramatic increase in cardiac work and oxygen consumption [1]. Epinephrine does not 7 8 172 shorten diastole as a result of increased end diastolic time by shortening systole, decreased the resistance of the 9 10 173 myocardium during diastole, accelerating relaxation after contraction, or increasing filling pressure [1]. 11 12 174 Epinephrine may be associated with a higher risk of tachycardia and arrhythmias than norepinephrine [29, 13 14 175 33,34]. Dopamine acts through several receptors; at infusion rates of 2-15μg/kg/min, this drug stimulates β1- 15 16 176 receptors with increased myocardial contractility at the cost of tachycardia and increased risk of arrhythmias 17 18 177 [2,26,35,36]. The clinical effects in shock, of stimulation of cardiac dopamine receptors remain unclear. 19 20 178 Phenylephrine is a pure α-agonist, which increases afterload and reduces heart rate and CO [37]. 21 22 179 Vasopressin and analogues 23 24 180 Vasopressin and its analogues may impair cardiac contractility via vasopressin V1a receptor–mediated decreased 25 26 181 -adrenergic receptor sensitivity [38]. Likewise, angiotensin may impair CO via increased afterload. 27 28 182 Inotropes 29 30 183 Inotropes are used in patients with myocardial depression, to improve CO through enhanced cardiac myofibril 31 32 184 contractility [39]. Although dobutamine may initially decrease vascular tone, MAP is usually improved with the 33 34 185 increased CO except in condition of low systemic vascular resistance. Phosphodiesterase III inhibitors also 35 36 186 increase myocardial contractility (possibly synergistically with dobutamine) but are often associated with 37 38 187 hypotension and arrhythmias. While these agents are potentially interesting for right ventricular failure due to 39 40 188 their effects on right ventricular afterload, great caution should be observed in preserving coronary perfusion. 41 42 189 Levosimendan increases contractility and CO with minimal tachycardia and without increasing myocardial 43 44 190 oxygen consumption but often with significant decrease in MAP (especially with loading dose). In cardiogenic 45 46 191 shock, as compared to dobutamine, levosimendan may result in higher CO and lower cardiac preload [40]. 47 48 49 192 Selective 1-antagonists 50 51 193 Administration of short-acting selective 1-antagonists increased systolic function and left ventricle end- 52 53 194 diastolic volume, reduced myocardial oxygen consumption, and restored cardiac variability during both 54 55 195 experimental sepsis and heart failure [20]. These drugs showed substantial improvement in stroke volume and 56 57 196 CO in patients with severe septic shock and tachycardia [41]. 58 59 197 Effects on systemic and pulmonary circulations 60 61 62 8 63 64 65 198 Norepinephrine and epinephrine are equipotent with regard to their effects on systemic blood pressure and 1 2 199 systemic vascular resistance [33,34]. Low dose epinephrine may lower systemic blood pressure, via activation of 3 4 200 vascular 2 adrenergic receptors, an effect not seen with norepinephrine [1]. Norepinephrine and epinephrine 5 6 201 similarly increase pulmonary artery pressure and pulmonary vascular resistance with little effects on pulmonary 7 8 202 capillary wedge pressure [42]. Norepinephrine also decreases preload dependency [43] possibly by increasing 9 10 203 venous return via a shift of unstressed to stressed volume, with subsequent transient increase in CO [44]. High 11 12 204 dose dopamine (10-20μg/kg/min) stimulates α-adrenergic receptors and increase systemic vascular resistance. 13 14 205 However, clinically it increases MAP through increased CO with little to no peripheral vasoconstriction 15 16 206 [2,35,36]. Dobutamine decreases systemic and pulmonary vascular resistance with little change in systemic 17 18 207 blood pressure owing to increased CO. Vasopressin is usually used for its norepinephrine sparing effects. This 19 20 208 drug increases afterload without pulmonary vasoconstriction (8). Vasopressin may have beneficial effects for 21 22 209 right heart function [9,10]. However, conflicting reports regarding its use as a primary agent in post-cardiac 23 24 210 surgery vasoplegic syndrome include dysrhythmia and myocardial infarction [45-47]. In septic shock, 25 26 211 selepressin decreased norepinephrine requirements and limited positive fluid balance [14]. This drug has been 27 28 212 investigated in a Phase IIB/III trial which is now completed after the recruitment of 868 patients [48]. In adults 29 30 213 with vasoplegic shock, a new synthetic human angiotensin II substantially increased systemic vascular resistance 31 32 214 without alteration in CO, and subsequently increased blood pressure [25]. In septic shock, infusion of 33 34 215 levosimendan was associated with significant reduction in systemic vascular resistance necessitating increased 35 36 216 doses of norepinephrine [49]. Interestingly, levosimendan may decrease pulmonary vascular resistance, and may 37 38 217 improve right ventricular function when pulmonary artery pressure is high |17]. 39 40 41 218 Effects on regional circulation 42 43 219 In general, -adrenergic agents, phosphodiesterase III inhibitors and levosimendan increase splanchnic perfusion 44 45 220 while -adrenergic agents and vasopressin have more variable effects. Several studies have shown that 46 47 221 dobutamine usually increases splanchnic perfusion but with high individual variability [50,51]. The effects were 48 49 222 observed at low doses (5µg/kg/min), and dose escalation did not affect splanchnic perfusion further. 50 51 223 Vasoactive drugs can improve splanchnic perfusion by restoring organ perfusion pressure. Pressures higher than 52 53 224 autoregulation pressure can be either neutral or detrimental. Two factors need to be taken into account: both the 54 55 225 nature of the agent and that dose may affect the response. At low doses, adrenergic agents have relatively similar 56 57 226 and neutral effects; while at high doses can impair splanchnic perfusion and metabolism [52]. Similarly, 58 59 60 61 62 9 63 64 65 227 vasopressin has modest effects on the splanchnic circulation at low doses but markedly impaired it at high doses 1 2 228 [53]. 3 4 229 Inotropic agents improve renal perfusion only in the setting of low CO. Vasoactive drugs improve renal 5 6 230 perfusion when correcting hypotension during euvolemia. Vasopressin may have a greater impact on glomerular 7 8 231 filtration pressure through a preferential effect on efferent arteriole, explaining the greater urine output and 9 10 232 creatinine clearance obtained at the same blood pressure, compared to norepinephrine [10]. 11 12 233 Effects on the microcirculation 13 14 234 When mean arterial pressure decreases below an autoregulatory threshold of 60-65 mm Hg, organ perfusion 15 16 235 becomes pressure-dependent. In this setting, increasing MAP with vasopressors might improve microcirculatory 17 18 236 flow in severely hypotensive septic shock patients [54]. On the other hand, above the autoregulation threshold, 19 20 237 vasopressor-induced excessive vasoconstriction could also be deleterious [55]. In septic shock, increasing MAP 21 22 238 above 65 mm Hg with incremental doses of norepinephrine showed considerable variations in individual 23 24 239 responses depending on basal microcirculatory status, timing, or other factors [56-58]. Phenylephrine has 25 26 240 detrimental effects on microvasculature perfusion in shock patients [59,60]. Vasopressin (or analogues) has 27 28 variable effects on microcirculation [61-64]. Recent studies suggest comparable effects to norepinephrine [65- 29 241 30 67]. In clinical practice with refractory hypotension, increasing MAP with norepinephrine improves 31 242 32 33 243 microcirculatory perfusion. Nevertheless, the optimal MAP and dose of vasoactive drug for an optimal 34 35 244 microcirculatory perfusion are fairly variable, should be tailored to individuals and whenever possible 36 37 245 monitored. 38 39 246 The microcirculatory response to dobutamine had a high individual variability, resulting in different results 40 41 247 between trials [51,68-70]. Dobutamine improved the microcirculation mainly in patients in whom it was severely 42 43 248 altered via unclear mechanisms that are independent of its effects on the macro-circulation [68,69]. The effects 44 45 249 of levosimendan and phosphodiesterase III inhibitors are still uncertain with beneficial effects in experimental 46 47 250 models and scarce data in humans [71-73]. 48 49 50 251 Metabolic and endocrine effects 51 52 53 252 Effects on metabolism 54 55 253 Non-cardiovascular effects of vasoactive drugs are summarised in table 1. Stimulation of adrenergic-receptors 56 57 254 results in reduced insulin release by B cells of the pancreas, reduced pituitary function, and inhibited lipolysis in 58 59 255 adipose tissues [1]. Stimulation of -adrenergic receptors in the liver increases glucose production and glycogen 60 61 62 10 63 64 65 256 breakdown via formation of cyclic AMP. In skeletal muscles, owing to the absence of glucose 6 phosphatase, - 1 2 257 adrenergic stimulation activates glycogenolysis and lactate production [74]. In practice, compared to 3 4 258 norepinephrine, epinephrine infusion was associated with a transient, non-clinically relevant, increase in serum 5 6 259 lactate levels and decrease in arterial pH [29,33,34]. There is no evidence of any metabolic effects of vasopressin 7 8 260 or its analogues, human synthetic angiotensin II, and levosimendan when administered to critically ill patients. 9 10 11 261 Effects on hormones 12 13 262 Dopamine decreases serum concentrations of all anterior pituitary hormones (prolactin, thyrotrophic releasing 14

15 263 hormone, growth hormone, and luteinizing hormone) via D2 receptors in the anterior pituitary and the 16

17 264 hypothalamic median eminence [75]. Dopamine can also induce or aggravate the low-T3 syndrome by 18 19 265 suppressing thyroid stimulating hormone secretion and decreasing thyroxin and tri-iodo-thyroxin levels. 20 21 266 Moreover, dopamine may suppress serum dehydroepiandrosterone sulphate, an effect mediated by low levels of 22 23 267 prolactin or thyroid hormones. Moreover, dopamine blunts pulsatile growth hormone secretion and decreases 24 25 268 concentrations of insulin-like growth factor-1, which is implicated in peripheral tissue and bone anabolism. 26 27 269 Vasopressin modulates ACTH release by the hypothalamus-pituitary axis via V1b receptors and cortisol release 28 29 270 by the adrenal cortex via V1a receptors [76]. 30 31 32 33 271 Immune effects 34 35 36 272 Immune dysfunction during critical illness varies from excessive inflammatory response to immune paralysis. 37 38 273 Sepsis may be characterized by defective antigen presentation, T and B cell mediated immunity, and defective 39 40 274 Natural killer cell mediated immunity, relative increase in T-regs, activation of PD-1, decreased immunoglobulin 41 42 275 levels, quantitative and qualitative alterations in neutrophils, hypercytokinaemia, complement consumption, and 43 44 276 defective bacterial killing/persistence of neutrophil extracellular traps [77]. Catecholamines may aggravate 45 46 277 sepsis associated immune paralysis [20]. Dopamine decreases serum levels of prolactin that triggers a transient 47 48 278 T-cell hyporesponsiveness and may reduce lymphocyte count, although decreased serum 49 50 279 dehydroepiandrosterone may also play a role. In addition, dopamine may also inhibit the transformation of 51 52 280 lymphocytes by mitogens. Epinephrine and norepinephrine may downregulate endotoxin induced immune cells 53 54 281 release of proinflammatory cytokines and upregulate anti-inflammatory cytokines (e.g. IL-10). They may also 55 56 282 stimulate bacterial growth by removal of iron from lactoferrin and transferrin by the catechol moiety and its 57 58 283 subsequent acquisition by bacteria. By contrast, selective 1 blockade may decrease the concentrations of 59 60 61 62 11 63 64 65 284 circulating and tissue inflammatory cytokines, may inhibit bacterial growth, and may improve fibrinolysis [20]. 1 2 285 In patients with decompensated heart failure, levosimendan reduced significantly circulating levels of 3 4 286 proinflammatory cytokines (IL-6, TNF, and TNF/IL-10 ratio) and soluble apoptosis mediators (soluble Fas 5 6 287 and Fas ligand), partly as a result of improved haemodynamics [78]. Vasopressin decreased plasma cytokines 7 8 288 more than norepinephrine [79], especially in patients with less severe shock and vasopressin has other complex 9 10 289 immune effects [80]. Selepressin-induced reduction of IL-6 and nitrite/nitrate levels may limit vascular 11 12 290 permeability associated with vasodilatory shock [15]. 13 14 15 291 16 17 18

19 292 20 21 22 293 Effects on survival 23 24 25 294 The extent to which vasoactive drugs can improve haemodynamic parameters in shock is influenced by the 26 27 295 choice, dose and timing of individual and/or combinations of agents. Unfortunately, a definitive survival benefit 28 29 296 for the commonest agents administered is lacking. A Cochrane review of high quality randomised trials found no 30 31 297 survival advantage related to the choice of the vasoactive drugs [81]. Accordingly, recommendations are made 32 33 298 based on organ dysfunction effects and safety issues, not survival benefits [2]. 34 35 36 299 Septic shock 37 38 300 Norepinephrine is the recommended first-line vasoactive drug [2]. Epinephrine, phenylephrine and vasopressin 39 40 301 are usually considered second-line agents, with dopamine reserved for bradycardic patients [2]. Norepinephrine 41 42 302 and epinephrine achieve similar shock reversal and no randomised trial demonstrates survival advantage when 43 44 303 using one agent over the other [81]. Likewise, 28-day survival when combining norepinephrine and dobutamine 45 46 304 is similar to epinephrine alone [33]. Notably, kidney failure-free days and mortality were not different in the 47 48 305 VANISH trial comparing early vasopressin versus norepinephrine [82]. The addition of low-dose vasopressin to 49 50 306 norepinephrine did not improve survival in a large, double-blind trial of vasopressor-dependent shock, although 51 52 307 a potential benefit for patients with less severe shock (norepinephrine <15 µg/min) was not excluded [83]. In this 53 54 308 trial, there was a synergic effect of vasopressin and hydrocortisone on survival [84]. However these beneficial 55 56 309 effects were not confirmed in the VANISH trial [82]. Similarly, there are no large-scale trials with mortality as 57 58 310 the primary outcome comparing norepinephrine and either phenylephrine or other V1a agonists such as 59 60 311 terlipressin or selepressin. Finally, a large blinded trial comparing norepinephrine versus dopamine in 61 62 12 63 64 65 312 generalised shock (SOAP II) reported an increase in arrhythmic events with dopamine as first-line therapy, but 1 2 313 no difference in survival either overall (primary endpoint) or in the pre-defined sub-group with septic shock [85]. 3 4 314 Moreover, mortality rates increased during a 6 month period of norepinephrine shortage in 26 US hospitals 5 6 315 (during that period norepinephrine was mostly replaced by phenylephrine and dopamine) [86]. 7 8 316 Inotropes such as dobutamine and levosimendan have also been suggested as second-line agents for the 9 10 317 management of refractory shock [2]. A network meta-analysis of 33 randomised trials of vasoactive agents in 11 12 318 septic shock reported that levosimendan, dobutamine, epinephrine, vasopressin and norepinephrine with 13 14 319 dobutamine were all significantly associated with survival, with levosimendan and dobutamine affording the 15 16 320 greatest benefit [87]. In contrast, a multicentre, double-blind trial in vasopressor-dependent shock reported 17 18 321 increased arrhythmias and ventilator weaning difficulties with levosimendan (versus placebo) and no difference 19 20 322 in survival |49]. In this trial the randomization was not stratified according to the presence or absence of left 21 22 323 ventricular dysfunction [49]. A small (n=77) single-centre trial reported decreased mortality with esmolol in 23 24 324 selected septic shock patients [41]. Interestingly, drugs with positive chronotropic effects may be associated 25 26 325 higher risk of death than those without or with negative chronotropic effects (figure 2). 27 28 326 Other forms of shock 29 30 327 In other forms of distributive shock provoked by anaphylaxis or pancreatitis, there is a paucity of high quality 31 32 328 evidence and randomised trials examining the effect of vasoactive agents on survival. Synthetic human 33 34 329 angiotensin II has recently been reported to improve MAP in a multicentre, double-blind trial of vasodilatory 35 36 330 shock due to a variety of causes and refractory to traditional vasoactive drugs [25]. However, caution is advised 37 38 331 in low cardiac output shock. A non-significant trend to improved survival (secondary outcome) was also noted. 39 40 332 Vasopressin (up to 0.06 U/min) and early methylene blue administration may also improve survival in 41 42 333 vasoplegic shock post-cardiac surgery [45,88]. 43 44 334 Despite the widespread utilization of vasoactive drugs in cardiogenic shock, there is a paucity of evidence to 45 46 335 guide selection. The SOAP II trial reported a statistically significant higher risk of mortality with dopamine 47 48 336 compared to norepinephrine in the pre-defined sub-group of patients with cardiogenic shock [85]. Despite being 49 50 337 the largest randomised trial to date supporting norepinephrine in cardiogenic shock, some have raised questions 51 52 338 regarding the widespread validity of its results [36]. Norepinephrine is associated with fewer arrhythmias and 53 54 339 based on current data is likely the vasoactive durg of choice for most patients with cardiogenic shock [36]. 55 56 340 Additional considerations such as the cause or presentation type of cardiogenic shock may also influence 57 58 vasoactive drug selection. Routine use of inotropes in patients with heart failure has been associated with 59 341 60 61 62 13 63 64 65 342 increased mortality [89]. However, in patients with cardiogenic shock, inotropes are utilised for haemodynamic 1 2 343 support and have an important role in optimising perfusion to vital organs [90]. Dobutamine and milrinone both 3 4 344 improve inotropy that increases cardiac output. Both agents are associated with arrhythmias and systemic 5 6 345 hypotension. Studies comparing these two agents suggest similar clinical outcomes although milrinone has a 7 8 346 longer half-life and is associated with more profound hypotension [91]. 9 10 347 Haemorrhagic shock is the most common type of shock seen with trauma [92]. The therapeutic goals are 11 12 348 restoration of blood volume and definitive control of bleeding [93]. Vasoactive drugs can be transiently utilised 13 14 349 in the presence of life-threatening hypotension [94]. The impact of vasoactive drugs on trauma outcome is poorly 15 16 350 understood. Animal studies and a small clinical trial suggest that vasopressin in conjunction with rapid 17 18 351 haemorrhage control may improve blood pressure without causing increased blood loss, leading to improved 19 20 352 outcomes [95-97]. However, observational studies have shown that vasoactive drug use in general is an 21 22 353 independently associated with increased mortality in trauma patients [98-100]. 23 24 25 354 Practical use 26 27 28 In routine, physicians should consider as much as possible to individualize the use of vasoactive drugs taking 29 355 30 into account patient’s comorbidities and physiological characteristics, the aetiology of shock, the local 31 356 32 33 357 environement and their own experiences with the various vasoactive drugs available on the market. 34 35 36 358 Choice of vasoactive drugs 37 38 359 After adequate fluid resuscitation and assessment, determining vasoactive drug choice depends upon the 39 40 360 aetiology and pathophysiology of the hypotensive episode (figure 3). In hypovolaemic, cardiogenic and 41 42 361 obstructive shock, hypotension results from decreased CO. In these types of shock, regional perfusion may 43 44 362 correlate with global perfusion [100]. However, distributive shock (sepsis, pancreatitis etc.) is more complicated 45 46 363 with vasoplegia, shunting, decreased oxygen extraction and low, normal or high CO. 47 48 364 In fluid-refractory hypotension, vasoactive agents are indicated and may be initiated during fluid resuscitation, 49 50 365 and subsequently weaned as tolerated [26]. Ultrasound, when possible, can help ascertain shock aetiology and/or 51 52 366 assist continued management. 53 54 367 In cardiogenic shock, decreased CO aetiology is generally due to poor myocardial function. Individualized MAP 55 56 368 goals are required as the hypoperfusion risk is balanced against the potential negative impact on CO, myocardial 57 58 369 oxygen consumption, ischaemia and dysrhythmias. In acute heart failure (excluding pre-revascularisation 59 60 370 myocardial infarction), guidelines recommend inotropes (dobutamine, dopamine, phosphodiesterase III 61 62 14 63 64 65 371 inhibitors) as the first line agent [35,101]. In persistently hypotensive cardiogenic shock with tachycardia, 1 2 372 norepinephrine is advised [35,101] and in patients with bradycardia, dopamine may be considered [36]. In 3 4 373 specific afterload dependent states (aortic stenosis, mitral stenosis), phenylephrine or vasopressin is advised [36]. 5 6 374 In distributive shock, norepinephrine is recommended as the initial vasoactive drug after appropriate fluid 7 8 375 resuscitation [2, 102]. If hypotension persists, vasopressin (up to 0.03UI/min) should be considered for reducing 9 10 376 norepinephrine [83] and possibly renal replacement therapy requirements [82]. 11 12 377 Myocardial depression is common in septic shock [103]. Persistent hypotension with evidence of myocardial 13 14 378 depression and decreased perfusion may benefit from inotropic therapy by adding dobutamine to norepinephrine 15 16 379 or using epinephrine as a single agent. Dopamine is only recommended in hypotensive patients with bradycardia 17 18 380 or low risk for tachycardia [2,35,104]. Phenylephrine should be reserved for salvage therapy. 19 20 381 Uncertainty surrounding the optimal use of levosimendan exists and should be clarified prior to including it in 21 22 382 standardized treatment guidelines]. Likewise, β-1 antagonists cannot be recommended while we await for their 23 24 383 evaluation in a multicentre trial (https://doi.org/10.1186/ISRCTN12600919). 25 26 27 384 Therapeutic targets 28 29 385 Haemodynamic support should optimise perfusion to vital organs ensuring adequate cellular delivery of oxygen. 30 31 386 Vasoactive drugs titrated to specific targets reflect optimal end-organ perfusion (e.g. urinary output, serum 32 33 387 lactate clearance). Mean arterial pressure reflects tissue perfusion. Specific organs have different tolerance to 34 35 388 hypotension based on their ability to autoregulate blood flow. However, there is a threshold MAP where tissue 36 37 389 perfusion may be linearly dependent on blood pressure. Current guidelines recommend that vasopressors be 38 39 390 titrated to maintain a MAP of 65 mm Hg in the early resuscitation of septic shock [2]. However, the optimal 40 41 391 MAP target for patient with shock is still a point of debate. Small studies targeting higher MAPs (85 mm Hg 42 43 392 versus 65 mm Hg) were associated with higher cardiac index but no significant change in other measurements of 44 45 393 global and regional perfusion [105,106]. A multicentre trial compared vasopressor titration to MAP of 65-70 mm 46 47 394 Hg versus 80-85 mm Hg on mortality in patients with septic shock [107]. Although no mortality difference was 48 49 395 reported (28 or 90 days), the higher target (80-85 mm Hg) was associated with more arrhythmias. In patients 50 51 396 with documented chronic hypertension, the higher target MAP (80-85 mm Hg) was associated with decreased 52 53 397 renal replacement therapy. Patients 75 years or older, may benefit from lower rather than higher target (MAP 60- 54 55 398 65 vs 75-80 mm Hg). These finding suggests that although 65 mm Hg may be a good starting target for most 56 57 399 patients, clinicians may need to individualize the target based on specific patient history and findings. 58 59 60 61 62 15 63 64 65 400 Inotropes should be titrated with concomitant measurements of CO and tissue perfusion. Targeting 1 2 401 supraphysiologic cardiac output does not improve outcomes and should be avoided [108]. Clinicians should 3 4 402 complement haemodynamic targets with other serial markers of systemic and organ perfusion, such as lactate, 5 6 403 mixed or central venous oxygen saturations, urine output, skin perfusion, renal and liver function tests, mental 7 8 404 status and other haemodynamic variables. Elevated lactate has been shown to correlate with increased mortality 9 10 405 in various types of shock. Although lactate does not increase solely because of poor tissue perfusion it can be 11 12 406 utilised as a marker of the adequacy of haemodynamic support. Lactate guided resuscitation has been 13 14 407 consistently shown to be effective [109,110]. 15 16 17 408 Monitoring and weaning 18 19 409 Administration of vasoactive agents should always be targeted to effect and not based on a fixed dose (but a 20 21 410 maximal dose may be considered for some agents, e.g. vasopressin or angiotensin). Vasoactive drugs should 22 23 411 target a precise blood pressure level using intra-arterial monitoring. As inotropes and vasopressors impact 24 25 412 cardiac function and tissue perfusion, CO monitoring is desired primarily using echocardiographic evaluations 26 27 413 and measurements of blood lactate and mixed-venous or central venous O2 saturation at regular intervals. 28 29 414 However, some patient populations may benefit from pulmonary artery catheter or pulse wave analysis with or 30 31 415 without calibration [111, 112]. 32 33 416 The importance of vasoactive agent de-escalation is comparable to the indication for initiation [26]. Physicians 34 35 417 and nurses may maintain a higher blood pressure than desired or continue a supra-therapeutic dose of inotropes, 36 37 418 as they overestimate the risk of re-aggravation. We suggest that weaning of vasoactive drugs should be 38 39 419 performed as soon as haemodynamic stabilisation is achieved. Computerised assisted weaning may reduce 40 41 420 unnecessary exposure to vasoactive drugs [113]. 42 43 421 The sequence of withdrawal of vasopressin is usually after weaning of norepinephrine, as performed in VASST 44 45 422 and VANISH, as withdrawing vasopressin first was associated with more haemodynamic instability [114,115]. 46 47 48 423 Serious adverse events 49 50 51 52 424 Arrhythmias are the most frequent complications of vasoactive drugs, ranging from 2 – 25%. 2-15% with 53 54 425 norepinephrine [33, 82-84], about 15% with epinephrine [33,34], up to 25% with dopamine [85], about 1 to 2% 55 56 426 with vasopressin [82,83], about 6% with synthetic human angiotensin II [25], up to 25% with dobutamine [108], 57 58 427 and about 6% with levosimendan [49] (table 2). The risk of arrhythmias may be lower with norepinephrine and 59 60 428 vasopressin than with dopamine, epinephrine, dobutamine, or levosimendan. In a multinational prospective 61 62 16 63 64 65 429 cohort study, treatment with catecholamines was the main trigger of life-threatening arrhythmias in ICU patients, 1 2 430 which were independently associated with hospital mortality and neurological sequelae [116]. The prevalence of 3 4 431 arrhythmias may be higher when catecholamines are titrated toward MAP values of 80-85 [107]. 5 6 7 432 Acute coronary events occurred in 1-4% of research participants, a prevalence that was consistent across trials 8 9 433 (and between groups) investigating catecholamines, vasopressin, angiotensin II or levosimendan (33,34,49,82- 10 11 434 84). The prevalence of stroke, limb ischemia, and intestinal ischemia was 0.3-1.5%, 2%, and 0.6-4% [33,82,83]. 12 13 435 Central nervous bleeding was reported in roughly 1% of catecholamine-treated septic shock [33]. 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J Cardiovasc Pharmacol 47 48 703 Ther;22(6):552-563. 49 50 704 51 52 53 705 54 55 56 57 58 59 60 61 62 26 63 64 65 706 Figure 1: Impact of norepinephrine and dobutamine on cardiac output and its determinants, regional and 1 2 707 microvascular perfusions 3 4 5 708 The effects of norepinephrine and dobutamine are denoted with colored arrows: blue arrows denote an increase 6 7 709 in the corresponding hemodynamic variable positive interaction, red arrows denote a negative 8 9 710 interactiondecrease in the corresponding hemodynamic variable, bicolor red/blue arrows denote variable effects 10 11 711 (can be either positive or negative, depending on time, patient condition or blood pressure level). Plain arrows 12 13 712 denote an effect observed in the majority of the patients, dotted arrow represent an effect observed in some but 14 15 713 not all patients (but without detrimental effect). The thickness of the arrow represents the magnitude of the 16 17 714 effect. An evanescent arrow represents an effect that decreases over time. 18 19 20 715 Figure 2: Potential interaction with drugs associated chronotropic effects and mortality in septic shock 21 22 716 trials 23 24 25 717 Forrest plots of sepsis trials stratified according to drugs associated with no or negative chronotropic effects 26 27 718 (panel A) or with positive chronotropic effects (panel B). Drugs that lowered or kept heart rate constant were 28 29 719 associated with an odds ratio of dying of less than 1 with the 95% confidence interval including no effect or 30 31 720 harm (panel A). Drugs that induced tachycardia were associated with an odds ratio of dying of more than 1 with 32 33 721 the 95% confidence interval including no effect or benefit (panel B). 34 35 36 722 Figure 3: Decision tree for the use of vasoactive drugs according to the aetiology of circulatory failure 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 27 63 64 65 723 Table 1. Summary of Non-Cardiovascular Effects of Vasoactive Drugs 1 2 TRH = thyrotrophic releasing hormone; hGW = human growth hormone; LH = luteinizing hormone; TSH = 3 724 4 5 725 thyroid stimulating hormone ; IL-6 = interleukin 6 6 7 8 Metabolic Effects 9 10 11 12 insulin release by Pancreas (Stimulation of -adrenergic receptors) 13 14 Inhibition of lipolysis in adipose tissue (Stimulation of -adrenergic receptors) 15 16 hepatic glucose production and glycogen breakdown (Stimulation of -adrenergic receptors) 17 18 skeletal muscle glycogenolysis and lactate production (Stimulation of -adrenergic receptors) 19 20 Endocrine Effects 21 22

23 24 serum concentrations of anterior pituitary hormones: prolactin, TRH, hGW, and LH (Dopamine) 25 26 27 TSH secretion (Dopamine) 28 29 Stabilization of the hypothalamic-pituitary axis (Vasopressin) 30 31 Immunological Effects 32 33 34 35 Transient T-cell hyperresponsiveness (Dopamine) 36 37 endotoxin mediated release of pro-inflammatory cytokines (Norepinephrine and Epinephrine) 38 39 Upregulation of anti-inflammatory cytokines (Norepinephrine and Epinephrine) 40 41 Potential stimulation of bacterial growth (Norepinephrine and Epinephrine) 42 43 levels of circulating proinflammatory cytokines (Levosimendan, Vasopressin)) 44 45 46 IL-6 levels and nitrite/nitrate levels (Selepressin) 47 48 726 49 50 727 51 52 53 54 55 56 57 58 59 60 61 62 28 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Table 2: main serious adverse reactions associated with vasoactive drugs 22 23 Molecules Arrhythmias Vascular Metabolic 24 25 26 Supra-ventricular Ventricular Myocardial Stroke limbs Other tissues/ 27 28 ischemia organs 29 30 Dopamine Atrial fibrillation; multifocal Ventricular + + + + Not described 31 32 atrial tachycardia; cardiac tachycardia/ 33 34 conduction abnormalities fibrillation 35 36 Dobutamine Atrial fibrillation; multifocal Ventricular + Not Not Not described hypokalemia 37 38 atrial tachycardia, tachycardia/ described described 39 40 fibrillation 41 42 Epinephrine* Atrial fibrillation; multifocal Ventricular +++ + + + Lactic acidosis; 43 44 atrial tachycardia, tachycardia/ hyperglycaemia; 45 46 fibrillation hypoglycaemia; 47 48 insulin resistance; 49 50 hypokalemia; 51 52 Norepinephrine Atrial fibrillation; multifocal Ventricular ++ + + + Not described 53 54 atrial atchycardia, tachycardia/ 55 56 bradycardia fibrillation 57 58 Vasopressin Atrial fibrilation; bradycardia Ventricular ++ + + + hyponatremia 59 60 61 62 29 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Molecules Arrhythmias Vascular Metabolic 22 23 Supra-ventricular Ventricular Myocardial Stroke limbs Other tissues/ 24 25 26 ischemia organs 27 28 tachycardia/ 29 30 fibrillation 31 32 Angiotensin II† ± Ventricular Not described Not + Not described Not described 33 34 tachycardia described 35 36 Levosimendan Atrial fibrillation; multifocal Ventricular Not described Not Not Not described Metabolic 37 38 atrial tachycardia; junctional tachycardia/ described described alkalosis ; 39 40 tachycardia fibrilation hypokalemia 41 42 Esmolol/ Bradycardia; conduction + Not + Not described Hyperkalemia; 43 44 Landiolol abnormalities; sinus arrest; described metabolic 45 46 asystole acidosis 47 48 *epinephrine my also be associated with brain haemorrhage 49 50 †synthetic human angiotensin II 51 52 53 54 55 56 57 58 59 60 61 62 30 63 64 65 Figure 1 Click here to download Figure Figure 1.docx

Figure 1: Impact of norepinephrine and dobutamine on cardiac output and its determinants, regional and microvascular perfusions

The effects of norepinephrine and dobutamine are denoted with colored arrows: blue arrows denote a positive interaction, red arrows denote a negative interaction, bicolor red/blue arrows denote variable effects (can be either positive or negative, depending on time, patient condition or blood pressure level). Plain arrows denote an effect observed in the majority of the patients, dotted arrow represent an effect observed in some but not all patients (but without detrimental effect). The thickness of the arrow represents the magnitude of the effect. An evanescent arrow represents an effect that decreases over time.

Figure Click here to download Figure Figure 2A.pptx

Risk of death with drugs with no or negative chronotropic effects Figure 2B Click here to download Figure Figure 2B.pptx

Risk of death with drugs with positive chronotropic effects Figure 3 Click here to download Figure Figure 3.pptx