Manuscript Click here to download Manuscript A global perspective on vasoactive agents in shock R2.docx Click here to view linked References 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 a1 a2 b1 b2 b3 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 a or b 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 b receptor stimulation. b-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].